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WO2024125322A1 - Dipyridamole pour prévenir et traiter des maladies allergiques et/ou inflammatoires et sa préparation - Google Patents

Dipyridamole pour prévenir et traiter des maladies allergiques et/ou inflammatoires et sa préparation Download PDF

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Publication number
WO2024125322A1
WO2024125322A1 PCT/CN2023/135865 CN2023135865W WO2024125322A1 WO 2024125322 A1 WO2024125322 A1 WO 2024125322A1 CN 2023135865 W CN2023135865 W CN 2023135865W WO 2024125322 A1 WO2024125322 A1 WO 2024125322A1
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Prior art keywords
dipyridamole
cream
gel
present application
allergic
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Ceased
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PCT/CN2023/135865
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English (en)
Chinese (zh)
Inventor
卢秉泰
刘明
彭博
韩杨
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Pediatric Immunity And Healthcare Guangzhou Biotechnology Co Ltd
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Pediatric Immunity And Healthcare Guangzhou Biotechnology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present application belongs to the field of drug development technology, and specifically relates to the use of dipyridamole and its preparations in preventing and treating allergic and/or inflammatory diseases.
  • Dipyridamole is also known as dipyridamole, with a chemical formula of 2,2',2",2-[4,8-dipiperidinylpyrimido[5,4-d]pyrimidine-2,6-diyl]bis-nitro]-tetraethanol.
  • Dipyridamole is a phosphodiesterase inhibitor that can inhibit platelet aggregation and has an anti-thrombotic effect. In the related art, it was once a commonly used drug for the treatment of coronary heart disease, and was rarely used to prevent myocardial ischemia or to prevent platelet aggregation in cardiac surgery.
  • Inflammatory diseases can generally be divided into acute inflammatory diseases and chronic inflammatory diseases. They are mainly caused by the overactivation of the human immune system, which triggers the infiltration of immune cells in tissues and the massive release of inflammatory cytokines, leading to inflammatory diseases. Common acute inflammatory diseases include inflammatory bowel disease, autoimmune diseases, gastritis, pneumonia, gout, etc. Acute inflammation is usually an immune response that occurs after the body is stimulated by external factors (such as pathogenic microorganisms), and is usually manifested as pain, redness, swelling, fever, etc. in the tissues. Compared with acute inflammatory diseases, inflammatory skin diseases are a type of chronic inflammatory disease, usually caused by allergens, sources of infection or endocrine.
  • Common chronic inflammatory skin diseases include acne and rosacea (rosacea).
  • Acne is a common inflammatory skin disease, and common causes include excessive sebum secretion, blockage of the sebaceous gland ducts of the hair follicles, bacterial infection, and inflammatory response.
  • Allergic disease is a series of diseases caused by the body's immune system's hypersensitivity to harmless substances in the environment, mainly including atopic dermatitis, allergic rhinitis, allergic asthma, food allergies, hay fever and other severe allergic reactions.
  • allergic diseases are one of the most common diseases in the human body, affecting about 25% of the world's population. The manifestations and severity of the disease vary greatly. Mild diseases will affect the quality of life, and in severe cases, they can be life-threatening. Chronic allergic patients require long-term maintenance treatment, which brings a heavy economic burden to society.
  • allergic diseases are caused by the local release of IgE-mediated mediators (such as histamine) when the affected parts such as the nasal cavity or airway come into contact with allergens, causing a variety of immune cell and cytokine-mediated inflammatory diseases such as asthma.
  • IgE-mediated mediators such as histamine
  • allergic conjunctivitis and atopic dermatitis are local inflammations of the skin caused by allergens.
  • inflammatory diseases and allergic diseases are inflammatory infiltration in tissues. Inflammatory infiltration can be caused by the aggregation of inflammatory cells or the release of inflammatory cytokines.
  • anti-inflammatory therapy is the most commonly used means.
  • glucocorticoids the most effective anti-inflammatory means in clinical practice is the use of glucocorticoids, but the side effects of glucocorticoids greatly limit their application in this regard.
  • the present application aims to solve at least one of the technical problems existing in the above-mentioned prior art.
  • the present application proposes the application of dipyridamole in the preparation of medicines for preventing, adjuvant therapy or treating allergic and/or inflammatory diseases.
  • dipyridamole by using dipyridamole, allergic and/or inflammatory diseases can be effectively prevented, adjuvant therapy or treated, with substantially no side effects, providing new treatment means and treatment ideas for clinically treating related diseases, reducing the impact of related diseases on the quality of life of patients, and having extremely high clinical significance and practical value.
  • the first aspect of the present application provides the use of dipyridamole derivatives in the preparation of medicines for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.
  • the allergic diseases include skin, respiratory, digestive and eye diseases caused by allergies.
  • the allergies include food allergies, dust allergies, mite allergies, drug allergies, etc.
  • the allergic diseases include: allergic rhinitis, allergic conjunctivitis, allergic asthma, allergic dermatitis, allergic urticaria, food allergy, dust allergy, mite allergy, hay fever, drug allergy, allergic bronchial asthma, allergic sinusitis, and allergic respiratory distress syndrome.
  • the allergic diseases include: allergic conjunctivitis, allergic rhinitis, allergic urticaria, and asthma caused by allergies.
  • Allergic urticaria also known as acute urticaria or chronic urticaria, commonly known as wheals, is a localized edema reaction caused by dilation of small blood vessels and increased permeability of the skin and mucous membranes. It usually subsides within 2 to 24 hours, but new rashes occur repeatedly, and the course of the disease can last from a few days to several years.
  • the cause of urticaria is very complicated, and about 3/4 of patients cannot find the cause, especially chronic urticaria.
  • the wheals last for several minutes to several hours, and in a few cases, they can last for several days before disappearing without leaving any traces. Those who recover from the disease in a short period of time are called acute urticaria. If the disease recurs at least twice a week and for more than 6 consecutive weeks, it is called chronic urticaria. Urticaria can be diagnosed based on the clinical appearance of wheal-like rashes.
  • Allergic conjunctivitis is conjunctivitis caused by allergies.
  • the conjunctiva is stimulated by allergens such as pollen, dust, dust mites, and animal dander, resulting in hypersensitivity reactions, and allergic symptoms such as itchy eyes, redness of the whites of the eyes, tearing, and increased secretions appear.
  • Allergic conjunctivitis is more common in children and young people, and has a high incidence rate worldwide.
  • allergic conjunctivitis can be divided into five different subtypes: seasonal allergic conjunctivitis, perennial allergic conjunctivitis, giant papillary conjunctivitis, vernal keratoconjunctivitis, and atopic keratoconjunctivitis.
  • inflammatory diseases can be divided into different types according to different classification methods, for example, according to infectious/non-infectious/post-infectious hyperplasia, or according to the site of inflammation, or according to self/non-self, but specific diseases should be included therein, and the same disease may have different classifications according to different classification methods, but it does not affect the manifestations/pathogenic factors/and treatment methods and effects of the disease.
  • the inflammatory diseases include, for example, dermatitis, asthma, conjunctivitis, rosacea, urticaria, sty, gastritis, rhinitis, pharyngitis, adnexitis, urethritis, vaginitis, mastitis, inflammatory bowel disease, frostbite, acne, etc.
  • Conjunctivitis is an inflammation of the conjunctiva caused by microbial infection (virus, bacteria, chlamydia, etc.), external stimulation (physical stimulation, chemical loss) or allergic reaction, commonly known as "pink eye”. According to different causes, conjunctivitis includes infectious conjunctivitis, immune conjunctivitis, secondary conjunctivitis, and other types of conjunctivitis.
  • Rhinitis is an inflammation of the nasal mucosa caused by viruses, bacteria, allergens (such as pollen), various physical and chemical factors (such as irritating gases) or certain systemic diseases, and is mainly manifested by symptoms such as nasal congestion, nasal itching, runny nose, sneezing, etc.
  • allergens such as pollen
  • various physical and chemical factors such as irritating gases
  • certain systemic diseases mainly manifested by symptoms such as nasal congestion, nasal itching, runny nose, sneezing, etc.
  • different classification methods for example, according to the cause classification, it can be divided into allergic rhinitis and non-allergic rhinitis; according to the speed of onset classification, it can be divided into acute rhinitis and chronic rhinitis.
  • the inflammatory disease includes infectious diseases, non-infectious diseases, and post-infectious hyperplasia.
  • the infectious diseases include infectious conjunctivitis, infectious rhinitis, infectious rosacea, infectious urticaria, infectious asthma, etc.
  • the infectious disease includes a microbial infectious disease, such as a viral infectious disease, a fungal infectious disease, a bacterial infectious disease, a parasitic infectious disease, and a mycoplasma infectious disease.
  • a microbial infectious disease such as a viral infectious disease, a fungal infectious disease, a bacterial infectious disease, a parasitic infectious disease, and a mycoplasma infectious disease.
  • the viral infectious diseases include herpes, viral conjunctivitis, viral rhinitis, new coronavirus pneumonia, influenza, viral hepatitis, viral rhinitis, viral pharyngitis, and viral enteritis.
  • the viral hepatitis includes hepatitis A, hepatitis B, and hepatitis C.
  • the herpes includes EV71 viral herpes.
  • Herpes is a viral skin disease characterized by changes in the skin and mucous membranes. It is mainly caused by infection with the human herpes virus (HHV). According to the cause of the disease, it can be classified into: herpes simplex (caused by herpes simplex virus), varicella (caused by varicella-zoster virus), and herpes zoster (caused by reactivation of herpes zoster virus lurking in the ganglia).
  • herpes simplex caused by herpes simplex virus
  • varicella caused by varicella-zoster virus
  • herpes zoster caused by reactivation of herpes zoster virus lurking in the ganglia.
  • viral enteritis manifests as nausea, abdominal pain, diarrhea, and vomiting.
  • Viral enteritis is usually an acute intestinal inflammatory lesion caused by a variety of viruses, including rotavirus, norovirus, canine parvovirus, and adenovirus.
  • the viral enteritis includes rotavirus enteritis, norovirus enteritis, and adenovirus enteritis.
  • the fungal infectious diseases include tinea pedis and ringworm of cats.
  • Ringworm is a skin disease of cats, which is often found on the face, trunk, limbs and tail. It is characterized by round or oval ringworm spots covered with gray scales, and the fur becomes rough. The fur of the ringworm spots falls off in clumps, breaks off or falls off. Ringworm is mainly caused by fungal infections, such as Microsporum canis and Trichophyton mentagrophytes.
  • the bacterial infectious diseases include bacterial conjunctivitis, bacterial rhinitis, purulent tonsillitis, acne, sty caused by bacterial infection, bacterial gastritis, bacterial pharyngitis, and bacterial mastitis.
  • the gastritis caused by bacteria includes gastritis caused by Helicobacter pylori.
  • the bacterial mastitis includes mastitis caused by Staphylococcus aureus.
  • the parasitic infectious disease includes ascariasis infection and malaria infection.
  • the mycoplasma infectious disease includes adnexitis caused by mycoplasma infection.
  • the non-infectious diseases include non-infectious dermatitis, abdominal pain caused by lactose intolerance, conjunctivitis caused by external stimuli, rosacea caused by neurological disorders, urticaria caused by physical stimulation, pharyngitis caused by external stimulation, inflammatory bowel disease, and mastitis caused by external pressure.
  • Inflammatory bowel disease refers to a group of nonspecific chronic gastrointestinal inflammatory diseases of unknown cause, including ulcerative colitis (UC), Crohn’s disease (CD) and indeterminate colitis (IC).
  • UC ulcerative colitis
  • CD Crohn’s disease
  • IC indeterminate colitis
  • Acne is a chronic inflammatory skin disease of the pilosebaceous gland unit, which mainly occurs in adolescents and has a great impact on their psychological and social life.
  • the clinical manifestations are characterized by polymorphic skin lesions such as acne, papules, pustules, nodules, etc. on the face.
  • the onset of acne is mainly related to increased androgen levels and sebum secretion, as well as bacterial infection, abnormal sebaceous gland keratinization, inflammation and other causes.
  • the non-infectious dermatitis includes traumatic dermatitis (traumatic dermatitis), dermatitis caused by surgical wounds, solar dermatitis, frostbite, and insect bite dermatitis.
  • the post-infectious hyperplasia includes thyroid nodules, hemorrhoids, scar hyperplasia, sty, thyroid nodules, breast nodules, and breast hyperplasia.
  • Hemorrhoids are the most common anal disease in clinical practice. They refer to the pathological hypertrophy of the anal cushions at the lower end of the rectum. The cause of the disease is not yet fully understood. Depending on the location of occurrence, hemorrhoids include internal hemorrhoids, external hemorrhoids, and mixed hemorrhoids. Internal hemorrhoids are pathological changes or displacements of the supporting structure, vascular plexus, and arteriovenous anastomosis of the anal cushions (anal canal vascular cushions). External hemorrhoids are pathological dilation or thrombosis of the subcutaneous vascular plexus distal to the dentate line. Mixed hemorrhoids are a mixture of internal and external hemorrhoids.
  • Scar hyperplasia also known as keloid, is caused by excessive proliferation of fibrous connective tissue. After the skin is traumatized, an inflammatory response occurs first, and then myofibroblasts appear in the wound, divide and proliferate to synthesize collagen fibers, causing collagen deposition to form scars, accompanied by itching, tenderness, or local decreased sensation.
  • inflammatory diseases are classified according to the site of infection, and inflammatory diseases in various sites can be included therein.
  • the inflammatory diseases include: inflammatory diseases of the brain, inflammatory diseases of the heart, inflammatory diseases of the skin, inflammatory diseases of the eyes and their surrounding areas, inflammatory diseases of the nose, inflammatory diseases of the mouth, inflammatory diseases of the ears, inflammatory diseases of the parotid gland, inflammatory diseases of the pharynx, inflammatory diseases of the thyroid gland, inflammatory diseases of the thymus gland, inflammatory diseases of the adnexa, inflammatory diseases of the respiratory system, inflammatory wrist diseases, tendonitis, arthritis, gastroenteritis, inflammatory diseases of vulvar itching, vaginitis, prostatitis, pancreatitis, inflammatory diseases of the bladder, urethritis, inflammatory diseases of the kidneys, inflammatory diseases of the pelvis, inflammatory diseases of the spine, anal inflammatory diseases, vascular inflammatory diseases and other inflammatory diseases.
  • the other inflammatory diseases include systemic lupus erythematosus, inflammatory edema, graft-versus-host disease, multiple sclerosis, cystic fibrosis, ischemia-reperfusion injury, vascular restenosis, osteoblastic inflammation, sepsis, and neurodegenerative diseases.
  • the skin inflammatory diseases include: herpes, solar dermatitis, psoriasis, eczematous dermatitis, contact dermatitis, seborrheic dermatitis, rosacea, lichen planus, vasculitis, pityriasis rubra pilaris, cellulitis, folliculitis, carbuncle, pemphigus, epidermal blisters, urticaria, angioedema, vasculitis, erythema and cutaneous eosinophilia, acne, ringworm, hand, foot and mouth virus, sty, etc.
  • the pemphigus includes bullous pemphigus.
  • Stye is clinically known as hordeolum, commonly known as "stye”. It is an acute suppurative inflammatory lesion of the eyelid gland, with typical symptoms of acute inflammatory bowel such as redness, swelling, heat, and pain. There are hard nodules at the lesion. It is a common eye disease that can occur in people of any age. People with excessive sebum secretion, blepharitis, seborrheic dermatitis, rosacea, hypertension, diabetes and other people with decreased immunity are more susceptible to the disease. Other inducing factors include touching the eyes with unclean hands, poor hygiene of the eyelid area, staphylococcal infection, and aseptic inflammation caused by blockage of the meibomian gland opening.
  • the brain inflammatory disease includes meningitis, encephalitis caused by viral infection, and autoimmune encephalomyelitis.
  • the meningitis includes purulent meningitis caused by bacterial infection, tuberculosis caused by Mycobacterium tuberculosis, Type meningitis.
  • the cardiac inflammatory disease includes myocarditis.
  • the ocular inflammatory disease includes conjunctivitis, retinitis-diabetic retinopathy.
  • the ear inflammatory disease includes otitis media, otitis interna, and otitis externa.
  • the otitis media includes acute otitis media, chronic otitis media, and secretory otitis media.
  • the adnexal inflammatory disease includes inflammatory reactions caused by metritis, oophoritis, and dysmenorrhea.
  • the respiratory inflammatory disease includes pneumonia and asthma.
  • the arthritis includes rheumatoid arthritis, osteoarthritis, and rheumatoid arthritis.
  • the gastroenteritis includes inflammatory bowel inflammation, acute or chronic colitis, acute or chronic proctitis.
  • the spondylitis includes ankylosing spondylitis.
  • the anal inflammatory disease includes hemorrhoids.
  • the vascular inflammatory disease includes immune vasculitis.
  • the inflammatory disease includes autoinflammatory disease and non-autoinflammatory disease.
  • the inflammatory diseases include: acute and chronic inflammatory gastrointestinal diseases, acne, rosacea, acute and chronic inflammation of the eyes and their glands, solar dermatitis, gynecological inflammation, and pharyngitis.
  • solar dermatitis also known as acute sunburn and sunburn
  • sunburn is an acute skin injury reaction caused by strong light exposure. It is more common in late spring and early summer, and is more common in children, women, skiers and water workers. The severity of symptoms is related to light intensity, exposure time, skin color, physical constitution, etc.
  • the acute and chronic inflammatory gastrointestinal diseases include: gastritis, ulcerative colitis and Crohn's disease.
  • the acute and chronic inflammation of the eye and its glands include sty, conjunctivitis, and blepharitis.
  • dipyridamole has a significant soothing effect on the symptoms of allergic and inflammatory skin disease modeling mice induced by calcipotriol, especially for the expression of IL-4 and TSLP in allergic and/or inflammatory diseases.
  • IL-4 and thymic stromal lymphopoietin (TSLP) are two important cytokines that induce allergic and/or inflammatory diseases.
  • TSLP thymic stromal lymphopoietin
  • IL-4 and thymic stromal lymphopoietin are two important cytokines that induce allergic and/or inflammatory diseases.
  • increased IL-4 levels can cause mouse models to produce symptoms similar to allergic and inflammatory related dermatitis.
  • Overexpression of IL-4 can lead to Th2 differentiation of T cells, IgE class switching in B cells, and increased mast cells.
  • TSLP is highly expressed in the skin epithelial cells of patients with inflammatory skin diseases, and overexpression of TSLP in keratinocytes (the most common cell type in the skin) can cause strong itching, induce scratching, the development of dermatitis phenotypes, and even worse, can cause asthma-like lung inflammation.
  • IgE dipyridamole reduces plasma and inflammatory site IgE in allergic and/or inflammatory diseases and inhibits mast cell infiltration.
  • IgE is considered to be a hallmark antibody for allergic and/or inflammatory diseases such as dermatitis.
  • IgE binds to its corresponding antigen, it prompts mast cells to release particles such as heparin and histamine, triggering an immune response.
  • allergic reaction refers to the reaction of tissue damage or functional disorder that occurs when an immune body is stimulated by the same antigen again.
  • allergen After the allergen enters the body, it induces allergen-specific B cells to produce antibody responses.
  • Such antibodies bind to the surface receptors of mast cells and basophils, making the body sensitized to the allergen.
  • allergen When the same allergen enters the body again, it specifically binds to the antibodies on the surface of sensitized mast cells and basophils, stimulating cell degranulation and releasing bioactive mediators, which act on effector tissues and organs, causing local or systemic allergic reactions.
  • the drug is an internal preparation or an external preparation, preferably an external preparation.
  • the drug is in the form of an external dosage form, including but not limited to ointments, creams, gels, lotions, tinctures, suspensions, liniments, spirits, powders, oils, pastes, plasters, coatings, aerosols, solutions, sprays, and patches.
  • an external dosage form including but not limited to ointments, creams, gels, lotions, tinctures, suspensions, liniments, spirits, powders, oils, pastes, plasters, coatings, aerosols, solutions, sprays, and patches.
  • the topical preparation further comprises one or more of the following substances: solvents, emulsifiers, softeners, antioxidants, preservatives, chelating agents, pH regulators, thickeners, penetration enhancers, and sunscreens.
  • the drug is applicable to animals, and the animals are selected from humans, cats, cows, sheep, pigs, dogs, chickens, ducks, geese, rabbits, and mice; preferably, the animals are humans, more preferably infants, children, teenagers, adults, or the elderly; most preferably, children, such as infants aged 0-2 years, children aged 2-12 years, teenagers aged 12-18 years, or adults aged 18 years or older.
  • the drug is applied to the skin, nails, or hair.
  • the effective content of dipyridamole and/or its derivatives in the pharmaceutical composition is 0.01% to 60%, preferably 0.05% to 20%, more preferably 0.1% to 12% or 0.1% to 10%, for example 0.1%, 0.2%, 0.3%, 0.5%, 0.8%, 1%, 2%, 3%, 5%, 6%, 8%, 10%, 12%.
  • the concentration of dipyridamole and/or its derivatives in the pharmaceutical composition is 0.1 mg/g to 120 mg/g, 0.1 to 100 mg/g, 1 mg/g to 120 mg/g, preferably 1 to 50 mg/g, more preferably 1-20 mg/g, for example 3 mg/g, 5 mg/g.
  • the frequency of use of the drug is: once every 1 to 24 hours.
  • the frequency of use of the drug is: 1-3 times a day, preferably 2-3 times a day.
  • the frequency of use of the drug is: once every 1 hour, every 2 hours, every 4 hours, every 6 hours, every 8 hours, every 12 hours or every 24 hours.
  • the dosage of the drug per time is: calculated as dipyridamole, 1-250 mg per time, preferably 5-100 mg per time, and more preferably 10-50 mg per time.
  • the drug is administered in a cosmetically effective amount.
  • cosmetically effective amount refers to a dose sufficient to achieve the desired cosmetic effect on the treated subject.
  • the drug is administered in a therapeutically effective amount.
  • therapeutically effective amount refers to a dose sufficient to achieve the desired therapeutic effect in a subject.
  • the drug is used in the form of a topical drug preparation for skin application.
  • the drug is administered by coating or spraying the drug on the skin surface corresponding to the affected area.
  • the dosage of the drug each time is: 0.1-25 mg/cm 2 in terms of dipyridamole.
  • 0.1-25 mg/cm 2 in terms of dipyridamole is applied or sprayed on the skin surface corresponding to the affected area.
  • the dosage of the drug each time is: 0.2-10 mg/cm 2 in terms of dipyridamole.
  • 0.2-10 mg/cm 2 in terms of dipyridamole is applied or sprayed on the skin surface corresponding to the affected area.
  • the dosage of the drug each time is: 0.5-5 mg/cm 2 in terms of dipyridamole.
  • 0.5-5 mg/cm 2 in terms of dipyridamole is applied or sprayed on the skin surface corresponding to the affected area.
  • the drug further contains other pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients include, but are not limited to, diluents, absorbents, wetting agents, adhesives, disintegrants, lubricants, colorants, coating materials, solvents, pH regulators, antibacterial agents, isotonic regulators, and chelating agents.
  • the topical preparation may further include one or more of the following: moisturizers, gels (also referred to as "gel bases"), water, and ointment bases.
  • the drug further includes a second active ingredient.
  • the second active ingredient includes at least one of an active ingredient for anti-inflammatory diseases, an active ingredient for anti-allergic diseases, an anti-inflammatory active ingredient, and an anti-allergic active ingredient.
  • the second ingredient in the drug is preferably at least one of an active ingredient for anti-allergic diseases and an anti-allergic active ingredient.
  • the second ingredient in the drug is preferably at least one of an active ingredient for anti-inflammatory diseases and an anti-inflammatory active ingredient.
  • the anti-inflammatory active ingredients include: steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs.
  • the non-steroidal anti-inflammatory drugs include aspirin, benolate, salicylic acid, acetaminophen, indomethacin, diclofenac, sulindac, nemetbutalone, ibuprofen, naproxen, piroxicam, meloxicam, celecoxib, etoricoxib, and nimesulide.
  • the steroidal anti-inflammatory drugs include adrenal cortical hormones, androgens, estrogens, such as hydrocortisone, prednisone, dexamethasone, and the like.
  • the anti-inflammatory active ingredients include: antifungal drugs or active ingredients, antiviral drugs or active ingredients, antifungal drugs or active ingredients, antiparasitic drugs or active ingredients, and antimycoplasma drugs or active ingredients.
  • the antifungal drugs or active ingredients include amphotericin B, nystatin, griseofulvin, Clotrimazole, econazole, miconazole, ketoconazole, bifonazole, terbinafine, ciclopirox olamine, amorolfine.
  • the antiviral drugs or active ingredients include acyclovir, acetaminophen, amantadine, chlorpheniramine maleate, ribavirin, amantadine and its salts (eg, hydrochloride), human interferon, and the like.
  • the antibacterial drug or active ingredient includes antibiotics, sulfonamides, imidazoles, nitroimidazoles, quinolones, such as penicillin, cephalosporin, cephamycin antibiotics, sulfamethoxazole (SMZ), sulfadiazine (SD), ketoconazole, miconazole, econazole, clotrimazole, metronidazole (MNZ), dimetridazole (DMZ), isopronidazole (IPZ), seconidazole (SCZ), ornidazole (ONZ), tinidazole (TNZ) and ronidazole (RNZ), norfloxacin, pefloxacin (Pefloxacin, mefloxacin), enoxacin (Enoxacin, fluazinic acid), ofloxacin (Ofloxacin, fluazinic acid) and ciprofloxacin (Ciprofloxacin), norfloxacin
  • the active ingredient for anti-inflammatory diseases includes the active ingredient of the inflammatory disease drugs mentioned above in the present application, such as acne treatment drugs or active ingredients, rosacea treatment drugs or active ingredients, rhinitis treatment drugs or active ingredients, conjunctivitis treatment drugs or active ingredients, etc.
  • the acne treatment drug or active ingredient includes sulfur, clindamycin, erythromycin, vitamin A ester, benzoyl peroxide, azelaic acid, tretinoin, isotretinoin, adapalene, hyaluronic acid or its salts (such as sodium, zinc, silver, calcium, potassium salt), ergothioneine.
  • the rhinitis treatment drug or active ingredient includes at least one of a glucocorticoid, an antibacterial drug, and an ⁇ receptor agonist.
  • the glucocorticoids include hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, dexamethasone acetate, triamcinolone acetonide acetate, mometasone furoate, halometasone, beclomethasone dipropionate, fluocinolone acetonide, halcinonide, and betamethasone propionate.
  • the alpha receptor agonist includes ephedrine, ephedrine hydrochloride, oxymetazoline, and xylometazoline.
  • the conjunctivitis treatment drugs or active ingredients include aminoglycosides or active ingredients (such as gentamicin, neomycin, tobramycin, etc.), fluoroquinolones or active ingredients (such as gatifloxacin, norfloxacin, ofloxacin, etc.), amides or active ingredients (such as chloramphenicol), tetracyclines or active ingredients, macrolides or active ingredients (such as erythromycin, rifampicin), acyclovir eye drops and ganciclovir eye gel, sodium sulfacetamide (such as 15%) or rifampicin eye drops, and corticosteroid eye drops.
  • aminoglycosides or active ingredients such as gentamicin, neomycin, tobramycin, etc.
  • fluoroquinolones or active ingredients such as gatifloxacin, norfloxacin, ofloxacin, etc.
  • amides or active ingredients such as chloramphenicol
  • the active ingredient for allergic diseases/antiallergic active ingredient refers to the tissue damage or physiological dysfunction caused by the body being stimulated by antigenic substances.
  • the drugs or ingredients that prevent and treat allergic diseases caused by various antigenic substances are antiallergic active ingredients or drugs.
  • the anti-allergic active ingredients include: antihistamines, allergic reaction mediator release inhibitors, histamine desensitization drugs, leukotriene receptor antagonists, drugs that inhibit antigen-antibody reactions, drugs that improve or control allergic reaction symptoms, and active ingredients of the above drugs.
  • the antihistamine drugs or active ingredients include diphenhydramine, promethazine, chlorpheniramine, etc.
  • Antihistamine drugs or active ingredients can compete with histamine for histamine H1 receptors on effector cells, so that histamine cannot bind to H1 receptors, thereby inhibiting its effect of causing allergic reactions.
  • the allergic reaction mediator release-inhibiting drug or active ingredient includes sodium cromoglycate, ketotifen, etc.
  • the allergic reaction mediator release-inhibiting drug or active ingredient can stabilize the mast cell membrane, prevent the release of histamine and other allergic reaction mediators, and produce an anti-allergic effect.
  • the histamine desensitization drugs or active ingredients include betahistine, histamine diluent, dust mite injection, etc. These drugs are repeatedly injected into patients to improve tolerance to histamine.
  • the leukotriene receptor antagonist drugs or active ingredients include montelukast, zafirlukast, etc., which are mainly used for respiratory allergies.
  • the drug or active ingredient that inhibits antigen-antibody reaction includes glucocorticoids, immunosuppressants, etc., wherein the glucocorticoids are as described in the present application.
  • the drugs for improving or controlling allergic symptoms include smooth muscle antispasmodics, such as salbutamol, etc.; and drugs for reducing edema caused by allergies, such as calcium gluconate, etc.
  • the active ingredient for anti-allergic diseases includes the inflammatory disease drugs mentioned above in the present application.
  • Active ingredients such as drugs or active ingredients for treating allergic rhinitis, drugs or active ingredients for treating allergic conjunctivitis, etc.
  • the drug is in the form of an external dosage form, including but not limited to ointments, lotions, tinctures, liniments, spirits, powders, oils, pastes, plasters, coatings, and aerosols.
  • dipyridamole For some common local inflammatory diseases, especially chronic inflammatory diseases, topical use of drugs can achieve the purpose of rapid suppression of inflammation, which is more direct and effective than oral drugs, and also effectively reduces systemic side effects. Therefore, local drugs or external preparations are also important means for treating inflammatory diseases.
  • the oil-water partition coefficient (logP) of dipyridamole is -1.22, and it has poor water solubility, is soluble in oily solvents such as ethanol or DMSO, and has good transdermal absorption.
  • Topical or external use of dipyridamole is suitable for controlling local inflammation of the skin, which can increase the drug concentration of the affected part and reduce systemic side effects. Moreover, it has been experimentally verified that dipyridamole has a good inhibitory effect on local allergies and inflammation when used externally.
  • the medicine is a cream, a gel, or an ointment.
  • a wipe cream or gel
  • dipyridamole as the main ingredient
  • it is found that it can effectively treat local inflammatory diseases and allergic diseases represented by allergic conjunctivitis, allergic rhinitis, inflammatory bowel disease, acne, rosacea, as well as other diseases such as scar hyperplasia and hemorrhoids.
  • the second aspect of the present application provides a pharmaceutical composition, which contains dipyridamole and/or its derivatives.
  • the derivative includes a pharmaceutically acceptable salt, ester, hydrate, solvate, polymorph, isomer or prodrug of dipyridamole.
  • the isomers include structural isomers (eg, tautomers), stereoisomers, optical isomers, regioisomers, and geometric isomers.
  • the pharmaceutical composition further contains a pharmaceutically acceptable adjuvant.
  • the excipients include but are not limited to solvents, emulsifiers, lubricants, humectants, preservatives, antioxidants, consistency regulators, pH regulators, diluents, absorbents, binders, disintegrants, colorants, coating materials, antibacterial agents, isotonic regulators, and chelating agents.
  • the effective content of dipyridamole and/or its derivatives in the pharmaceutical composition is 0.01% to 60%, preferably 0.05% to 20%, more preferably 0.1% to 12% or 0.1% to 10%, for example 0.1%, 0.2%, 0.3%, 0.5%, 1%, 2%, 3%, 5%, 8%, 10%.
  • the concentration of dipyridamole and/or its derivatives in the pharmaceutical composition is 0.1-100 mg/g, preferably 1-50 mg/g, more preferably 1-20 mg/g, for example 3 mg/g, 5 mg/g.
  • the third aspect of the present application provides a dipyridamole cream, which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, and 0.1% to 60% of diethylene glycol monoethyl ether.
  • the mass percentage of dipyridamole and/or its derivatives is 0.01% to 10%, 0.1% to 12% or 0.1% to 10%.
  • the mass percentage of diethylene glycol monoethyl ether is 0.3% to 50%, 1% to 45%, for example, 2%, 5%, 6%, 8%, 10%, 12%, 15%, 18%, 25%, 30%, 42%.
  • the other ingredient of the cream is water.
  • the cream contains, by mass percentage, 10% to 95% water, preferably 20% to 90% water, and more preferably 30% to 70% water, for example, about 30% water, about 35% water, about 40% water, about 45% water, about 50% water, about 55% water, about 60% water, about 62% water, about 65% water, about 68% water, and about 70% water.
  • the dipyridamole cream contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether and water.
  • the dipyridamole cream contains 0.01% to 10% of dipyridamole and/or its derivatives, and 0.3% to 50% of diethylene glycol monoethyl ether and water, by mass percentage. In some embodiments of the present application, the dipyridamole cream contains 0.1% to 15% of dipyridamole and/or its derivatives, 1% to 45% of diethylene glycol monoethyl ether and 10% to 95% of water, by mass percentage. In some embodiments of the present application, the dipyridamole cream contains 0.1% to 10% of dipyridamole and/or its derivatives, 1% to 45% of diethylene glycol monoethyl ether and 10% to 95% of water, by mass percentage.
  • the dipyridamole cream contains, calculated by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether and 10% to 95% of water.
  • dipyridamole dissolves in water in a pH-dependent manner, and has a strong solubility when the pH is less than 3.5.
  • too low acidity may lead to the risk of irritation, resulting in no effective and available dipyridamole external preparations in the prior art.
  • the cream further contains an emulsifier, preferably 0.3% to 40% of the emulsifier by mass, and more preferably 0.5% to 30% of the emulsifier by mass.
  • the emulsifier includes one or more of polyethylene glycol stearate, phospholipids, sodium lauryl sulfate, Span surfactants, Tween surfactants, higher fatty alcohols, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, 15-hydroxystearate polyethylene glycol ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, triethanolamine, stearic acid glyceryl, caprylic acid capric acid polyethylene glycol glyceride, propylene glycol monocaprylate, propylene glycol monolaurate, polyglycerol oleate, and polyethylene glycol cetearyl alcohol ether.
  • Span is the transliteration of Span, which is a polyol ester compound generated by the esterification reaction of sorbitan (anhydrous sorbitol) and fatty acids, namely, anhydrous sorbitan fatty acid ester, which is an important non-ionic, oil-in-water surfactant, including Span-20, Span-40, Span-60, Span-65, Span-80, Span-85, etc. Its melting point is 52-57°C, soluble in hot ethanol, ether, methanol and carbon tetrachloride, slightly soluble in ether, petroleum ether, and can be dispersed in hot water. It has strong emulsifying, dispersing and lubricating effects, and can be mixed with various surfactants, especially Tween-60, and the effect of compound use is better.
  • Tween is a non-ionic surfactant and is also widely used as an emulsifier and solubilizer for oily substances. It is a partial fatty acid ester of a series of polyoxyethylene sorbitan and is generally considered to be a non-toxic and non-irritating material. Its types include Tween 20 (TWEEN-20), Tween 21 (TWEEN-21), Tween 40 (TWEEN-40), Tween 60 (TWEEN-60), Tween 61 (TWEEN-61), Tween 80 (TWEEN-80), Tween 81 (TWEEN-81), Tween 85 (TWEEN-85), etc.
  • Higher alcohols also known as higher fatty alcohols, refer to mixtures of monohydric alcohols containing more than three carbon atoms. Alcohols in the range of C6 to C10 are usually called plasticizer alcohols, while alcohols above C12 are called detergent alcohols. These alcohols include n-propanol, sec-butanol, amyl alcohol, isopentanol, isobutanol, etc.
  • Polyoxyethylene fatty acid esters are dispersed in water and soluble in hot ethanol, hot oil, benzene, xylene and other solvents. They are widely used as o/w emulsifiers. They are non-ionic surfactants with good surface activities such as emulsification, solubilization, wetting, dispersion, softening and antistatic properties. They are non-toxic and non-irritating.
  • Types include polyoxyethylene-7 stearate; polyoxyethylene-10 stearate; polyoxyethylene-12 stearate; polyoxyethylene-20 stearate; polyoxyethylene-75 stearate; polyoxyethylene-150 stearate; PEG-2 stearate (CAS: 106-11-6); PEG-3 stearate (CAS: 10233-24-6); PEG-4 stearate (CAS: 106-07-0); PEG-5 stearate; PEG-6 stearate (CAS: 10108-28-8); PEG-8 stearate (CAS: 70802-40-3); PEG- 9 stearate (cas: 5349-52-0); PEG-14 stearate (cas: 10289-94-8); PEG-15 stearate; PEG-18 stearate; PEG-23 stearate; PEG-25 stearate; PEG-30 stearate; PEG-32 stearate; PEG-35 stearate; PEG-36 stearate; PEG-40 stearate
  • Fatty alcohol polyoxyethylene ether also known as polyoxyethylene fatty alcohol ether
  • AEO Fatty alcohol polyoxyethylene ether
  • This type of surfactant is an ether formed by the condensation of polyethylene glycol (PEG) and fatty alcohol, represented by the following general formula: RO(CH 2 CH 2 O)nH, where n is the degree of polymerization.
  • PEG polyethylene glycol
  • RO RO(CH 2 CH 2 O)nH
  • Polyethylene glycol stearate molecular formula: C 18 H 35 O 2 ⁇ (C 2 H 4 O) n ⁇ H, is used in cosmetics, pharmaceutical emulsifiers, soap thickeners, softeners, emulsion stabilizers, etc.
  • polyoxyethylene sorbitan monostearate Such as polyoxyethylene sorbitan monostearate, polyethylene glycol (400) monooctadecanoate, polyethylene glycol (400) monostearate, Travel Chemical T-60, polyoxyethylene stearate, polyoxyethylene sorbitan monostearate, PEG-5 stearate, PEG-7 stearate, PEG-25 stearate, PEG-23 stearate, PEG-30 stearate, PEG-18 stearate, PEG-20 stearate, PEG-10 stearate, etc.
  • the emulsifier is polyethylene glycol-7-stearate.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and 0.3% to 40% of polyethylene glycol stearate.
  • a dipyridamole cream contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and 0.3% to 40% of polyethylene glycol-7-stearate.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-7-stearate, and the balance is water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-7-stearate, and the balance is water.
  • the mass ratio of diethylene glycol monoethyl ether and polyethylene glycol-7-stearate is 1-50:1-20, preferably 1-10:1-3, for example, 1:2, 3:2, etc.
  • the cream further comprises one or more of a lubricant, a moisturizer and a preservative.
  • the cream further comprises one or more of a lubricant, a moisturizer, a preservative and a consistency regulator.
  • the cream further includes one or more of an antioxidant, a consistency regulator, a pH regulator, and a pigment.
  • the cream on the basis of the cream containing dipyridamole and/or its derivatives and diethylene glycol monoethyl ether, or on the basis of the cream also containing dipyridamole and/or its derivatives and diethylene glycol monoethyl ether, and an emulsifier (such as polyethylene glycol-7-stearate), the cream further contains one or both of a lubricant or a consistency regulator.
  • a lubricant such as polyethylene glycol-7-stearate
  • the cream further comprises one or both of a lubricant or a consistency regulator, and also comprises one or more of a moisturizer, a preservative, an antioxidant, a pH regulator, and a pigment.
  • the cream further comprises one or more of a lubricant, a moisturizer, a preservative, an antioxidant, a consistency regulator, a pH regulator, and a pigment.
  • Lubricants refer to substances that prevent skin moisture or irritation, make the skin soft, soften, smooth, supple, restore moisture, impermeable, lubricating, moisturizing, protecting and/or cleansing, including absorbent humectants or humidifying lubricants that can absorb moisture from the surrounding atmosphere and increase the moisture of the stratum corneum; including barrier protection lubricants that can form an occlusive layer when deposited on the skin surface to protect the skin from the influence of large molecules such as excreta, enzymes and other irritants.
  • Representative barrier protector lubricants for use in the present application include, but are not limited to, the following lubricants: petroleum-based lubricants; fatty acid esters; fatty alcohols; alkyl ethoxylates; fatty alcohol ethers; polyhydroxy polyesters; glycerides; free sterols; sterol esters and their derivatives; triglycerides and their derivatives; sphingolipids; vegetable or animal oils; hydrogenated vegetable oils; kaolin and its derivatives; vitamins such as B3 (niacinamide), VC (ascorbic acid), D3, VE (tocopherol), VE esters (nicotinate tocopheryl esters); or mixtures of these lubricants.
  • lubricants such as B3 (niacinamide), VC (ascorbic acid), D3, VE (tocopherol), VE esters (nicotinate tocopheryl esters); or mixtures of these lubricants.
  • Suitable petroleum-based lubricants include paraffins, i.e., hydrocarbons or hydrocarbon mixtures; for example, those hydrocarbons having a chain length of 16-32 carbon atoms.
  • Petroleum-based hydrocarbons with these chain lengths include mineral oil (also known as “liquid petrolatum”) and petrolatum (also known as “ozokerite,” “petroleum jelly,” and “mineral jelly”).
  • Mineral oil generally refers to a mixture of lower viscosity hydrocarbons with 16-20 carbon atoms.
  • Petrolatum generally refers to a mixture of more viscous hydrocarbons with 16-32 carbon atoms. Petrolatum and mineral oil are preferred lubricants.
  • Suitable fatty acid ester lubricants include those derived from C12-C28 fatty acids, preferably C16-C22 saturated fatty acids, and short chain (C1-C8, preferably C1-C3) monohydric alcohols.
  • Representative examples of the esters include methyl palmitate, methyl stearate, isopropyl laurate, isopropyl myristate, isopropyl palmitate, ethylhexyl palmitate, and mixtures thereof.
  • Suitable fatty acid ester lubricants can also be derived from esters of longer chain fatty alcohols (C12-C28, preferably C12-C16) and shorter chain fatty acids (e.g., lactic acid), such as lauryl lactate and cetyl lactate.
  • esters of longer chain fatty alcohols C12-C28, preferably C12-C16
  • shorter chain fatty acids e.g., lactic acid
  • Suitable alkyl ethoxylate type lubricants include C12-C22 fatty alcohol ethoxylates having an average degree of ethoxylation of about 2 to about 30, including lauryl, cetyl and stearyl ethoxylates having an average degree of ethoxylation of about 2 to about 23, laureth-3, laureth-23, ceteth-10, steareth-10, and the like.
  • Suitable fatty alcohol type lubricants include C12-C22 fatty alcohols, preferably C16-C18 fatty alcohols.
  • Representative examples include cetyl alcohol and stearyl alcohol, and mixtures thereof.
  • Suitable fatty alcohol ether type lubricants include ethers derived from C12-C18 fatty alcohols or C12-C18 fatty alcohols and lower alcohols.
  • Suitable fatty ester lubricants also include polyol polyesters, especially "liquid" polyol polyesters whose complete melting temperature is body temperature or below (i.e., about 37°C).
  • polyols include, but are not limited to, polyols such as pentaerythritol; sugars such as raffinose, maltose glucose, galactose, sucrose, glucose, xylose, fructose, maltose, lactose, mannose and erythritol; sugar alcohols such as erythritol, xylitol, maltitol, mannitol and sorbitol.
  • sucrose polyol polyesters such as sucrose polycotton oil fatty acid esters, sucrose polysoybean oil fatty acid esters, and sucrose polybehenate and mixtures of these polyhydroxy polyesters.
  • Lubricants suitable for the present application include various C1-C30 monoesters and polyesters of glycerol and their derivatives, including glyceryl esters, acetylated glyceryl esters, ethoxylated glyceryl esters of C12-C28 fatty acids, triethylene glycol, and their derivatives, including glyceryl tri(behenic acid) ester, glyceryl stearate, glyceryl palmitate, glyceryl distearate, glyceryl dipalmitate, etc.
  • Lubricants suitable for the present application also include sphingolipids, such as ceramide, sphingosine, phytosphingosine, and the like.
  • An effective lubricant with super barrier properties can be a mixture of components that simulate the lipid complexes that form the skin's natural water barrier, such as fetal sebum or its mimics, such as a mixture of sterols, sterol esters and triglycerides as fetal sebum mimics; or other substances naturally produced in the stratum corneum, such as sodium pyrrolidone carboxylate, sodium lactate/lactic acid, free fatty acids, L-proline, guanidine, pyrrolidone, ceramide and urea.
  • Other lubricants derived from natural sources are also suitable for this application, such as hydrolyzed proteins and other collagen-derived proteins; keratin and its derivatives; acetamide MEA, etc.
  • the lubricant is selected from one or more of isopropyl palmitate, isopropyl myristate, dimethicone, diisopropyl adipate, caprylic glyceride, caprylic anhydride oil, caprylic capric macrogol glyceride, isohexadecane, hydrogenated castor oil, mineral oil, caprylic/capric triglyceride, lauric acid, and linoleic acid.
  • the lubricant is one or both of isopropyl myristate and isopropyl palmitate.
  • the mass proportion of the lubricant in the dipyridamole cream is 0.5% to 40%.
  • the mass proportion of the lubricant in the dipyridamole cream is 1% to 30%.
  • the mass proportion of the lubricant in the dipyridamole cream is 5% to 20%, for example, 5%, 8%, 10%, etc.
  • Moisturizers are a class of hydrophilic substances that replenish moisture to the skin, relieve dryness, maintain the moisture of the cosmetics themselves, and stabilize the main products. Common ones include polyols, polyols, hydroxyethyl urea, etc. According to different sources, they can be divided into natural moisturizers existing in humans, animals, and plants and non-natural synthetic moisturizers.
  • Natural moisturizers include plant extracts, low molecular weight moisturizers, high molecular weight moisturizers, polyols, amino acids, polysaccharides, organic salts, sorbitol, hyaluronic acid, hydrolyzed hyaluronic acid, betaine, D-panthenol, trehalose, oligofructose and glycine.
  • Synthetic moisturizers include polyols, polyols, hydroxyethyl urea, glycerol, urea, glycerol polyether-26, 1,2-pentanediol, 1,2-hexanediol, 1,3-propylene glycol, diglycerol, 1,3-butylene glycol, etc.
  • the humectant is selected from one or more of glycerol, propylene glycol, 1,3-butylene glycol, and polyethylene glycol.
  • the humectant is one or both of glycerol and 1,3-butylene glycol.
  • the mass proportion of the moisturizer in the dipyridamole cream is 0.5% to 50%.
  • the mass proportion of the moisturizer in the dipyridamole cream is 1% to 30%.
  • the mass proportion of the moisturizer in the dipyridamole cream is 2% to 25%.
  • the mass proportion of the moisturizer in the dipyridamole cream is 5% to 20%, for example, 5%, 10%, or 20%.
  • the preservative is selected from at least one of a chemical preservative and a natural preservative.
  • the chemical preservative is selected from benzoic acid (sodium), sorbic acid (potassium), parabens (also known as parabens), propionates, sulfites and their salts, nitrates and nitrites.
  • the chemical preservatives of the present application include methyl paraben, sodium methyl paraben, ethyl paraben, sodium ethyl paraben, sorbic acid, potassium sorbate, dehydroacetic acid, sodium dehydroacetate, diacetic acid, sodium diacetate, propionic acid, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glycol, propylene glyco
  • Natural preservatives are food preservatives that use metabolites of plants, animals or microorganisms as raw materials and are produced through extraction, enzymatic conversion or fermentation. Natural preservatives include plant-based food preservatives, animal-based food preservatives and microbial-based food preservatives; plant-based food preservatives, such as spices, Chinese herbal medicine, pectin decomposition products, other plant extracts (gingko leaf extract, water chestnut peel extract, etc.); animal-based food preservatives, such as protamine, chitosan, propolis, etc.; microbial-based food preservatives, such as lysozyme, nisin, natamycin, ⁇ -polylysine, etc. Further, natural preservatives include at least one of nisin, natamycin and chitosan.
  • the preservative is selected from one or more of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium ethylparaben, benzyl alcohol, phenoxyethanol, sorbic acid, benzoic acid, and sodium benzoate.
  • the preservative is sodium ethylparaben.
  • the mass proportion of the preservative in the dipyridamole cream is 0% to 10%.
  • the mass proportion of the preservative in the dipyridamole cream is 0% to 5%.
  • the mass proportion of the preservative in the dipyridamole cream is 0% to 1%, for example, 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1%.
  • the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), disodium edetate, ascorbic acid, sodium metabisulfite, propyl gallate, sodium ascorbate, isoascorbic acid, sodium pyrosulfite, sodium thiosulfate, propyl gallate, ⁇ , tocopherol, proanthocyanidins, glutathione, lipoic acid, astaxanthin, vitamin E, ⁇ -carotene, coenzyme Q, isoflavones, ⁇ -isohydroxy acids, flavonoids, phenylpropanoid phenolic compounds, fumaric acid, cysteine, methionine, thiodipropionic acid, sulfites (such as sodium sulfite), bisulfites (such as sodium bisulfite), dithioaminobenzoic acid compounds, citric acid, malic
  • BHT butylated
  • the antioxidant is selected from one or more of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), disodium ethylenediaminetetraacetic acid, ⁇ , tocopherol (VE), ascorbic acid (AA), sodium metabisulfite, anhydrous sodium sulfite, propyl gallate, sodium ascorbate, isoascorbic acid, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, and thioglycerol.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • VE disodium ethylenediaminetetraacetic acid
  • ⁇ tocopherol
  • AA ascorbic acid
  • sodium metabisulfite sodium metabisulfit
  • the antioxidant is one or both of butylated hydroxyanisole (BHA) and anhydrous sodium sulfite.
  • the antioxidant accounts for 0% to 5% by mass in the dipyridamole cream.
  • the mass proportion of the antioxidant in the dipyridamole cream is 0% to 1%, for example, 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1%.
  • the consistency regulator is selected from one or more of a natural thickener, a synthetic thickener or an inorganic thickener.
  • natural thickeners include: plant-derived polymers such as gum arabic, carrageenan, galactan, agar, quince seed, guar gum, tragacanth gum, mannan, locust bean gum, wheat starch, rice starch, tara gum, corn starch and potato starch; microbial-derived polymers such as curdlan, xanthan gum, succinoglucan, dextran and pullulan, etc.; and protein polymers such as albumin, casein, collagen, gelatin and fibroin.
  • plant-derived polymers such as gum arabic, carrageenan, galactan, agar, quince seed, guar gum, tragacanth gum, mannan, locust bean gum, wheat starch, rice starch, tara gum, corn starch and potato starch
  • microbial-derived polymers such as curdlan, xanthan gum, succinoglucan, dextran and pullulan, etc.
  • protein polymers such as albumin, casein, collagen, gelatin
  • Examples of synthetic thickeners include: cellulose polymers such as ethyl cellulose, carboxymethyl cellulose and its salts, carboxymethyl ethyl cellulose and its salts, carboxymethyl starch and its salts, cross-linked carboxymethyl cellulose and its salts, crystalline cellulose, cellulose acetate, cellulose acetate phthalate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, methyl cellulose and methyl hydroxypropyl cellulose; starch polymers such as pregelatinized starch, partially pregelatinized starch, hydroxymethyl starch, dextrin and methyl starch; alginate polymers such as sodium alginate, potassium alginate, ammonium sulfate and propylene glycol alginate; and other polysaccharide polymers, such as sodium chondroitin sulfate and sodium hyaluronate, cetearyl alcohol
  • inorganic thickener examples include hydrated silica, colloidal alumina, bentonite, laponite, and the like.
  • the consistency regulator is selected from one or more of an alcohol consistency regulator, an ester consistency regulator, kind.
  • the consistency regulator is selected from one or more of cetearyl alcohol, cetyl alcohol, stearyl alcohol, glyceryl monostearate, glyceryl mono- and distearate, carbomer, liquid paraffin, vaseline, and glyceryl behenate.
  • the consistency regulator is cetearyl alcohol, for example, 2% by mass of cetearyl alcohol or 3% by mass of cetearyl alcohol.
  • the consistency regulator is hexadecanol, for example, 5% (wt%) hexadecanol, 8% (wt%) hexadecanol.
  • the consistency regulator is liquid paraffin, for example, 8% (wt%) liquid paraffin.
  • the consistency regulator is glyceryl monostearate, such as 5% (wt%) glyceryl monostearate, 10% glyceryl monostearate.
  • the consistency regulator is glyceryl monostearate and cetearyl alcohol, for example, 5% (wt%) glyceryl monostearate and 8% cetearyl alcohol.
  • the consistency regulator is cetyl alcohol and liquid paraffin, for example, 3% (wt%) cetyl alcohol and 8% (wt%) liquid paraffin.
  • the mass proportion of the consistency regulator in the dipyridamole cream is 0% to 50%.
  • the mass proportion of the consistency regulator in the dipyridamole cream is 0.1% to 30%.
  • the mass proportion of the consistency regulator in the dipyridamole cream is 2% to 20%, for example, 2%, 3%, 5%, 8%, 12%, 13%, 15%, 18%, 20%, 30% of the consistency regulator.
  • the pH adjuster includes an acidic pH adjuster or an alkaline pH adjuster
  • the alkaline pH adjuster includes monosodium fumarate, sodium citrate, potassium citrate, monosodium citrate, sodium dihydrogen phosphate, phosphate, calcium sulfate, calcium lactate, sodium acetate, calcium hydroxide, potassium hydroxide, sodium hydroxide, triethanolamine, arginine, sodium hydroxide, potassium hydroxide, etc.
  • the acidic pH adjuster includes fumaric acid, metatartaric acid, citric acid, lactic acid, malic acid, L(+)-tartaric acid and tartaric acid, glacial acetic acid and acetic acid, adipic acid, phosphoric acid, hydrochloric acid, citric acid, lactic acid, etc.
  • the pH adjuster includes an acidic pH adjuster or an alkaline pH adjuster, selected from one or more of sodium hydroxide, sodium bicarbonate, sodium citrate, triethanolamine, citric acid, hydrochloric acid, and sodium dihydrogen phosphate.
  • the mass proportion of the pH regulator in the dipyridamole cream is 0% to 10%.
  • the mass proportion of the pH regulator in the dipyridamole cream is 0% to 5%, for example, 0%, 1%, 2%, 3%, 4%, or 5%.
  • the pH regulator is added in an amount such that the pH of the dipyridamole cream is between 5-8, preferably between 5-7, more preferably between 6-7, for example, 6-6.5.
  • a dipyridamole cream which contains 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, water, and one or more of an emulsifier, a lubricant, a moisturizer, and a preservative.
  • a dipyridamole cream which contains 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, an emulsifier, water, and one or more of a lubricant, a moisturizer, and a preservative.
  • a dipyridamole cream which contains 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, an emulsifier, a lubricant, water, and one or two of a moisturizer and a preservative.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, an emulsifier, a lubricant, a moisturizer, a preservative, and water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, water, and one or more of an emulsifier, a lubricant, a moisturizer, and a preservative.
  • a dipyridamole cream is provided, wherein, by mass percentage, the dipyridamole cream It contains 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, an emulsifier, water, and one or more of a lubricant, a moisturizer, and a preservative.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, an emulsifier, a lubricant, water, and one or two of a moisturizer and a preservative.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, an emulsifier, a lubricant, a moisturizer, a preservative, and water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and 0.3% to 40% of emulsifier, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, 0.1% to 50% of consistency regulator, and one or more of water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of emulsifier, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, 0.1% to 50% of consistency regulator, and the balance of water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-stearate, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, and the balance of water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-stearate, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, 0.1% to 50% of consistency regulator, and the balance of water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of an emulsifier, 1% to 30% of a lubricant, 1% to 30% of a moisturizer, 0% to 1% of a preservative, 1% to 30% of a consistency regulator, and one or more of water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, 1% to 30% of consistency regulator, and the balance water.
  • a dipyridamole cream contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-stearate, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, and the balance of water.
  • a dipyridamole cream contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-stearate, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, 1% to 30% of consistency regulator, and the balance of water.
  • the lubricant is isopropyl myristate and/or isopropyl palmitate.
  • the moisturizer is glycerol and/or 1,3-butylene glycol.
  • the preservative is sodium ethylparaben.
  • the consistency regulator is cetearyl alcohol, and/or cetyl alcohol, and/or liquid paraffin, and more preferably cetearyl alcohol.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and 0.3% to 40% of polyethylene glycol-7-stearate, 0.5% to 40% of isopropyl myristate and/or isopropyl palmitate, 0.5% to 50% of glycerol and/or 1,3-butylene glycol, water, and 0% to 10% of one or more of sodium ethylparaben.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-7-stearate, 0.5% to 40% of isopropyl myristate and/or isopropyl palmitate, 0.5% to 50% of glycerol and/or 1,3-butylene glycol, 0% to 10% of sodium ethylparaben, and the remainder is water.
  • a dipyridamole cream is provided, wherein, by mass percentage, the dipyridamole cream It contains 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-7-stearate, 1% to 30% of isopropyl myristate, 1% to 30% of isopropyl palmitate, 1% to 30% of glycerol, 1% to 30% of 1,3-butylene glycol, 0% to 10% of sodium ethylparaben, and the balance is water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-7-stearate, 0.5% to 40% of isopropyl myristate and/or isopropyl palmitate, 0.5% to 50% of glycerol and/or 1,3-butylene glycol, 0.1% to 50% of cetearyl alcohol, 0% to 10% of sodium ethylparaben, and the balance is water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, 0.3% to 40% of polyethylene glycol-7-stearate, 1% to 30% of isopropyl myristate, 1% to 30% of isopropyl palmitate, 1% to 30% of glycerol, 1% to 30% of 1,3-butylene glycol, 0.1% to 50% of cetearyl alcohol, 0% to 10% of sodium ethylparaben, and the balance is water.
  • a dipyridamole cream contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-7-stearate, 1% to 30% of isopropyl myristate and/or isopropyl palmitate, 1% to 30% of glycerol and/or 1,3-butylene glycol, 0% to 1% of sodium ethylparaben, and the balance is water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-7-stearate, 5% to 20% of isopropyl myristate, 5% to 20% of isopropyl palmitate, 5% to 20% of glycerol, 5% to 20% of 1,3-butylene glycol, 0% to 1% of sodium ethylparaben, and the balance is water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-7-stearate, 1% to 30% of isopropyl myristate and/or isopropyl palmitate, 1% to 30% of glycerol and/or 1,3-butylene glycol, 1% to 30% of cetearyl alcohol, 1,3-butylene glycol, 0% to 10% of sodium ethylparaben, and the balance is water.
  • a dipyridamole cream which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of polyethylene glycol-7-stearate, 5% to 20% of isopropyl myristate, 5% to 20% of isopropyl palmitate, 5% to 20% of glycerol, 5% to 20% of 1,3-butylene glycol, 1% to 30% of cetearyl alcohol, 0% to 1% of sodium ethylparaben, and the balance is water.
  • the pigment is selected from pigments of different colors depending on the required color, including synthetic pigments, natural pigments, including red pigments, purple pigments, such as carmine, erythrosine, allura red, red iron oxide, titanium dioxide, zinc oxide, talc, kaolin, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, amaranth, new red, lemon yellow, sunset yellow, indigo, brilliant blue, carotene, chlorophyll, turmeric, impatiens glycoside, rose glycoside, capsanthin, etc.
  • synthetic pigments including synthetic pigments, natural pigments, including red pigments, purple pigments, such as carmine, erythrosine, allura red, red iron oxide, titanium dioxide, zinc oxide, talc, kaolin, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, amaranth, new red, lemon yellow, sunset yellow, indigo, brilliant blue, carotene, chlorophyll, turmeric, impatiens glycoside, rose glycoside, capsanthin, etc.
  • the pigments are carmine and titanium dioxide, preferably 0% to 5% carmine and 0% to 5% titanium dioxide in mass percentage, for example 0.01% carmine and 3% titanium dioxide.
  • the dipyridamole cream using the pigment has a significant color difference compared to the dipyridamole cream that does not contain a pigment component.
  • the color is obviously closer to human skin color, and the visual sensory effect is better than the dipyridamole cream that does not contain a pigment component. It is particularly suitable for use on parts of the human body that need to be exposed, such as the face, neck, arms, and calves, and is more easily accepted by patients.
  • the pigment when the desired cream is purple, is manganese violet, cobalt violet, ultramarine violet, sweet potato root extract, methyl violet, benzyl violet, or the like.
  • the pigment when the desired cream is white, the pigment is titanium white, zinc oxide, lithopone (lidocone), antimony white, and the like.
  • the pigment when the desired cream is green, is zinc green, iron green, chromium oxide, chromium hydroxide, cobalt titanate, chlorophyll, phthalocyanine green, and the like.
  • the pigment when the desired cream is yellow, the pigment is lead chrome yellow, zinc chrome yellow, cadmium yellow, antimony yellow, iron yellow, fast yellow, benzidine yellow, hansa yellow, ⁇ -carotene, etc.
  • the pigment when the desired cream is black, the pigment is carbon black, pine smoke, graphite, aniline black, etc.
  • the pigment when the desired cream is blue, the pigment is ultramarine, iron blue, phthalocyanine blue, peacock blue, Indanthrene blue, etc.
  • the pigment when the desired cream is red, is iron titanate, iron red, cadmium red, molybdenum red, toluidine red, lithotripsy red, para red, scarlet, or the like.
  • the pigment is aluminum powder, copper powder, or the like.
  • the above colors can also be prepared by those skilled in the art using more than one pigment according to the color mixing principle, for example, blue and yellow can be prepared into green.
  • the pigment accounts for 0% to 10% by mass in the dipyridamole cream.
  • the pigment accounts for 0% to 5% by mass in the dipyridamole cream.
  • the fourth aspect of the present application provides a dipyridamole gel, which comprises, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, and 0.1% to 60% diethylene glycol monoethyl ether.
  • the dipyridamole gel comprises 0.01% to 10% or 0.01% to 12% by mass of dipyridamole or its derivatives, for example, 0.1% to 12%, 0.1% to 10%, 0.5% to 12%, 0.2%, 0.3%, 0.5%, 1%, 3%, 5%, 8%, 10%.
  • the dipyridamole gel comprises a gelling agent in an amount of 0.2%-10% by mass.
  • the dipyridamole gel comprises a gelling agent with a mass percentage of 0.5%-5%, for example, 1%, 1.5%, 1.6%, 2%, 2.5%, 3%, 3.5%, etc.
  • the dipyridamole gel comprises 0.3%-50% by mass of ethylene glycol monoethyl ether.
  • the dipyridamole gel comprises ethylene glycol monoethyl ether in a mass percentage of 2%-30%, for example, 2%, 5%, 10%, 15%, 30%.
  • a dipyridamole gel the remaining component of which is water, preferably 10% to 98% by mass of water.
  • a dipyridamole gel comprises 20%-95% water by mass.
  • a dipyridamole gel comprises 30%-90% water by mass, for example, about 30%, 35%, 40%, 45%, 50%, 60%, 70%, 75%, 80%, 85%, or 90% water.
  • the gelling agent comprises one or more of carbomer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, and sodium carboxymethyl cellulose.
  • the gel is carbomer.
  • the dipyridamole gel comprises 0.1% to 20% by mass of carbomer, preferably 0.2% to 10% by mass of carbomer, and more preferably 0.5% to 5% by mass of carbomer.
  • the carbomer includes carbomer 980NF, carbomer 974NF, carbomer 940 and the like.
  • the dipyridamole gel further comprises one or more of a surfactant, a pH adjuster, a moisturizer, an antioxidant, and a preservative.
  • the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of a moisturizer, a surfactant, and a preservative.
  • the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of 0.1% to 50% moisturizer, 0.1% to 50% surfactant, and 0% to 5% preservative.
  • the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of an antioxidant and a surfactant.
  • the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of a moisturizer, a pH regulator, and a preservative.
  • the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of 0.1% to 50% moisturizer, 0% to 10% pH adjuster, and 0% to 5% preservative.
  • the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of an antioxidant and a surfactant.
  • the gel comprises, by mass percentage, one or more of 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gel, 0.1% to 60% diethylene glycol monoethyl ether, and 0% to 5% antioxidant and 0.1% to 50% surfactant.
  • the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of a surfactant, a pH regulator, a moisturizer, an antioxidant, and a preservative.
  • the gel includes, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of 0.1% to 50% surfactant, 0% to 10% pH regulator, 0.1% to 50% moisturizer, 0% to 5% antioxidant, and 0% to 5% preservative.
  • the moisturizer is selected from one or more of vaseline, glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol.
  • the humectant is 1,3-butanediol.
  • the mass proportion of the moisturizer in the dipyridamole gel is 0.1% to 50%.
  • the mass proportion of the moisturizer in the dipyridamole gel is 1% to 30%, for example, 2%, 5%, 10%, 15%, 20%, etc.
  • the preservative is selected from one or more of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium ethylparaben, benzyl alcohol, phenoxyethanol, sorbic acid, benzoic acid, and sodium benzoate.
  • the preservative is sodium ethylparaben.
  • the mass proportion of the preservative in the dipyridamole ointment is 0% to 5%.
  • the mass proportion of the preservative in the dipyridamole ointment is 0% to 2%.
  • the mass proportion of the preservative in the dipyridamole gel is 0% to 1%, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1%.
  • the surfactant is selected from one or more of sodium lauryl sulfate, Spans, Tweens, poloxamers, triethanolamine, caprylic/capric acid macrogol glycerides, 15-hydroxystearate macrogol esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyethylene glycol cetearyl alcohol ether.
  • the surfactant is triethanolamine.
  • the mass proportion of the surfactant in the dipyridamole gel is 0.1% to 50%.
  • the mass proportion of the surfactant in the dipyridamole gel is 0.5% to 30%, for example, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30%.
  • the pH adjuster may be one or more of sodium hydroxide, sodium bicarbonate, sodium citrate, triethanolamine, citric acid, hydrochloric acid, and sodium dihydrogen phosphate.
  • the pH adjuster is triethanolamine.
  • the mass proportion of the pH regulator in the dipyridamole gel is 0% to 10%.
  • the mass proportion of the pH regulator in the dipyridamole gel is 0% to 5%, for example, 0.5%, 1%, 2%, 3%, 4%, or 5%.
  • the pH adjuster is added according to the pH value required by the gel.
  • the pH regulator is added in an amount such that the pH of the dipyridamole gel is between 5-8, preferably between 5-7, more preferably between 6-7, for example, 6-6.5.
  • the antioxidant is selected from one or more of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), disodium ethylenediaminetetraacetate, ⁇ -tocopherol (VE), ascorbic acid (AA), sodium metabisulfite, propyl gallate, sodium ascorbate, and isoascorbic acid.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • VE disodium ethylenediaminetetraacetate
  • ⁇ -tocopherol ⁇ -tocopherol
  • AA ascorbic acid
  • sodium metabisulfite sodium metabisulfite
  • propyl gallate sodium ascorbate
  • isoascorbic acid isoascorbic acid.
  • the antioxidant is butylated hydroxyanisole (BHA) or ascorbic acid (AA).
  • the antioxidant accounts for 0% to 5% by mass in the dipyridamole ointment.
  • the mass proportion of the antioxidant in the dipyridamole ointment is 0% to 1%, for example, 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%.
  • a dipyridamole gel comprises, by mass percentage, 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and one or more of a moisturizer, a preservative, a pH adjuster, a surfactant, and water.
  • a dipyridamole gel comprises, by mass percentage, 0.01% to 10% dipyridamole or its derivatives, 0.5% to 5% gelling agent, 0.3% to 50% diethylene glycol monoethyl ether, and one or more of a moisturizer, a preservative, a pH adjuster, a surfactant, and water.
  • a dipyridamole gel comprises, by mass percentage, one or more of 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, 0.1% to 50% moisturizing agent, 0% to 5% preservative, 0% to 10% pH adjusting agent, 0.1% to 50% surfactant, 0% to 5% antioxidant, and 10% to 98% water.
  • a dipyridamole gel comprises, by mass percentage, one or more of 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, 0.1% to 50% moisturizing agent, 0% to 5% preservative, 0% to 10% pH regulator, 0.1% to 50% surfactant, and 10% to 98% water.
  • a dipyridamole gel comprises, by mass percentage, one or more of 0.01% to 10% dipyridamole or its derivatives, 0.5% to 5% gelling agent, 0.3% to 50% diethylene glycol monoethyl ether, 1% to 30% moisturizing agent, 0% to 1% preservative, 0% to 5% pH adjusting agent, 0.5% to 30% surfactant, and 30% to 90% water.
  • the gel is carbomer, such as carbomer 980NF, carbomer 974NF, carbomer 940, etc.
  • the humectant is 1,3-butylene glycol.
  • the preservative is sodium ethylparaben.
  • the pH regulator or surfactant is triethanolamine.
  • a dipyridamole gel comprises, by mass percentage, 0.01% to 20% of dipyridamole or its derivatives, 0.1% to 20% of carbomer, 0.1% to 60% of diethylene glycol monoethyl ether, and one or more of 1,3-butylene glycol, sodium ethylparaben, triethanolamine, and water.
  • a dipyridamole gel comprises, by mass percentage, 0.01% to 20% of dipyridamole or its derivatives, 0.1% to 20% of carbomer, 0.1% to 60% of diethylene glycol monoethyl ether, 1,3-butylene glycol, sodium ethyl hydroxybenzoate, triethanolamine and water.
  • a dipyridamole gel comprises, by mass percentage, 0.01% to 10% of dipyridamole or its derivatives, 0.5% to 5% of carbomer, 0.3% to 50% of diethylene glycol monoethyl ether, and one or more of 1,3-butylene glycol, sodium ethylparaben, triethanolamine, and water.
  • a dipyridamole gel comprises, by mass percentage, 0.01% to 10% of dipyridamole or its derivatives, 0.5% to 5% of carbomer, 0.3% to 50% of diethylene glycol monoethyl ether, 1,3-butylene glycol, sodium ethyl hydroxybenzoate, triethanolamine and water.
  • a dipyridamole gel comprises, by mass percentage, one or more of 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% carbomer, 0.1% to 60% diethylene glycol monoethyl ether, 0.1% to 50% 1,3-butylene glycol, 0% to 5% sodium ethylparaben, 0% to 50% triethanolamine, and 10% to 98% water.
  • a dipyridamole gel comprises, by mass percentage, 0.01% to 20% of dipyridamole or its derivatives, 0.1% to 20% of carbomer, 0.1% to 60% of diethylene glycol monoethyl ether, 0.1% to 50% of 1,3-butylene glycol, 0% to 5% of sodium ethyl hydroxybenzoate, and 0% to 50% of triethanolamine.
  • a dipyridamole gel comprises, by mass percentage, 0.01% to 20% of dipyridamole or its derivatives, 0.1% to 20% of carbomer, 0.1% to 60% of diethylene glycol monoethyl ether, 0.1% to 50% of 1,3-butylene glycol, 0% to 5% of sodium ethylparaben, 0% to 50% of triethanolamine, and 10% to 98% of water.
  • a dipyridamole gel comprises, by mass percentage, one or more of 0.01% to 10% dipyridamole or its derivatives, 0.5% to 5% carbomer, 0.3% to 50% diethylene glycol monoethyl ether, 1% to 30% 1,3-butylene glycol, 0% to 1% sodium ethylparaben, 0.5% to 30% triethanolamine, and 30% to 90%.
  • a dipyridamole gel comprises, by mass percentage, 0.01% to 10% of dipyridamole or its derivatives, 0.5% to 5% of carbomer, 0.3% to 50% of diethylene glycol monoethyl ether, 1% to 30% of 1,3-butylene glycol, 0% to 1% of sodium ethylparaben, and 0.5% to 30% of triethanolamine.
  • a dipyridamole gel comprises, by mass percentage, 0.01% to 10% of dipyridamole or its derivatives, 0.5% to 5% of carbomer, 0.3% to 50% of diethylene glycol monoethyl ether, 1% to 30% of 1,3-butylene glycol, 0% to 1% of sodium ethylparaben, 0.5% to 30% of triethanolamine, and 30% to 90% of water.
  • the fifth aspect of the present application provides a dipyridamole ointment.
  • the ointment described in the present application is based on the cream provided in the second aspect, and the final product does not contain water.
  • the ointment described in the present application is based on the cream provided in the second aspect, and the final product does not contain Contains water, and the mass percentage of the consistency regulator is 0.1%-98%.
  • the ointment described in the present application is based on the cream provided in the second aspect, the final product does not contain water, and the mass percentage of the consistency regulator is 0.5%-95%.
  • the ointment described in the present application is based on the cream provided in the second aspect, the final product does not contain water, and the mass percentage of the consistency regulator is 1%-90%, for example 50%, 60%, 70%, 80%, 90%.
  • a dipyridamole ointment which contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and 0.3% to 40% of emulsifier, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, 0.1% to 50% of consistency regulator, 0% to 10% of pH regulator, 0% to 5% of antioxidant, and 0% to 10% of pigment.
  • emulsifier 0.5% to 40% of lubricant
  • 0.5% to 50% of moisturizer 0% to 10% of preservative
  • 0.1% to 50% of consistency regulator 0% to 10% of pH regulator, 0% to 5% of antioxidant, and 0% to 10% of pigment.
  • a dipyridamole ointment which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, 1% to 90% of consistency regulator, 0% to 5% of pH regulator, 0% to 1% of antioxidant, and 0% to 5% of pigment.
  • a dipyridamole ointment contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, 1% to 90% of consistency regulator, 0% to 5% of pH regulator, 0% to 1% of antioxidant, and
  • a dipyridamole ointment which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of an emulsifier.
  • a dipyridamole ointment which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of an emulsifier, 1% to 30% of a lubricant, 1% to 30% of a moisturizer, and 1% to 90% of one or more of a consistency regulator.
  • a dipyridamole ointment which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of emulsifier, and 1% to 90% of consistency regulator.
  • a dipyridamole ointment which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 1% to 90% of a consistency regulator.
  • a dipyridamole ointment which contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, and 1% to 90% of consistency regulator.
  • the ointment described in the present application contains 0.01% to 60%, preferably 0.1% to 10%, 0.2% to 5% or 0.2% to 2.5% of dipyridamole and/or its derivatives by mass.
  • the ointment described in the present application also includes one or more selected from the following: solvent, ointment base, thickener, humectant, preservative.
  • the ointment described in the present application includes dipyridamole and/or its derivatives, solvent, ointment base, humectant, preservative.
  • the ointment described in the present application includes dipyridamole and/or its derivatives, solvent, ointment base, humectant, preservative.
  • the ointment described in the present application includes dipyridamole and/or its derivatives, solvent, ointment base, thickener, preservative. In some embodiments of the present application, the ointment described in the present application includes dipyridamole and/or its derivatives, solvent, ointment base, thickener, preservative.
  • the ointment described in the present application comprises 0.5% to 60, preferably 1% to 50%, 5% to 50%, 2% to 40% or 8% to 40% (such as 8%, 10%, 20%, 30%, 35%, 40%) of a solvent by mass percentage.
  • the solvent is selected from diols, such as one or two of hexylene glycol and 1,3-butanediol, such as hexylene glycol and 1,3-butanediol.
  • the solvent is selected from diethylene glycol monoethyl ether, glycols, such as one or more of diethylene glycol monoethyl ether, hexanediol and 1,3-butanediol.
  • the mass ratio of hexanediol to 1,3-butanediol is 1:5-5:1, preferably 1:2-2:1, more preferably 3:5-5:3, for example 1:2; 3:5; 1:1; 5:3; 2:1, etc.
  • the ointment described in the present application comprises 40% to 99%, preferably 50% to 95%, 50% to 99%, 55% to 92% or 60% to 98% (e.g., 57%, 60%, 65%, 70%, 75%, 80%, 90%) of an ointment base by mass percentage.
  • the ointment base is selected from liquid paraffin, vaseline, polyethylene glycol (e.g., selected from any one or more of PEG50 to PEG8000, PEG100 to PEG6000, PEG200 to PEG5000, PEG300 to PEG4000, PEG400, PEG500, PEG1000, PEG2000, and PEG3000).
  • the ointment base is A mixture of PEG400 and PEG4000. In some preferred embodiments, the ointment base is a mixture of liquid paraffin and vaseline. In some preferred embodiments, the ointment base is a mixture of liquid paraffin, PEG400 and PEG4000. In some preferred embodiments, the ointment base is a mixture of vaseline, PEG400 and PEG4000. In some preferred embodiments, the ointment base is a mixture of liquid paraffin, vaseline, PEG400 and PEG4000. In some preferred embodiments, the ointment base is a mixture of liquid paraffin, vaseline, PEG400 and PEG4000. In some preferred embodiments, the ointment base is a mixture of liquid paraffin, vaseline, PEG400 and PEG4000.
  • the mass ratio of PEG400 and PEG4000 is 3.5:1 to 1:1, preferably 3:1 to 1.25:1, more preferably 2.5:1 to 1.5:1, for example 2:1; 2.1:1; 2.2:1; 2.3:1; 2.4:1; 2.5:1, etc.
  • the ointment described in the present application contains 0.01% to 1%, preferably 0.02% to 0.5%, 0.05% to 0.5% or 0.05% to 0.3% (for example, 0.08%, 0.09%, 0.1%, 0.12%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%) of a preservative by mass.
  • the preservative is selected from one or more of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium ethylparaben, benzyl alcohol, phenoxyethanol, sorbic acid, benzoic acid, and sodium benzoate.
  • the ointment described in the present application contains 0% to 30%, preferably 0% to 10%, 0% to 5% of a thickener by mass percentage.
  • the thickener is polyethylene glycol stearate, such as polyethylene glycol-7-stearate, polyethylene glycol-5-stearate, PEG-25 stearate, PEG-23 stearate, PEG-30 stearate, PEG-18 stearate, PEG-20 stearate, PEG-10 stearate, etc.
  • the ointment described in the present application contains 0% to 50%, preferably 0% to 40% (e.g., 5%, 10%, 20%, 25%, 32%, 35) of moisturizer by mass.
  • the polyol is, for example, one or more of glycerol, propylene glycol, and 1,3-butylene glycol.
  • the ointment described in the present application includes 0.01% to 60% dipyridamole and/or its derivatives, 0.5% to 60% solvent, 40% to 99% ointment base, 0.01% to 1% preservative, 0% to 30% thickener, and 0% to 50% moisturizer.
  • the ointment described in the present application includes 0.01% to 60% dipyridamole and/or its derivatives, 0.5% to 60% glycols, 40% to 99% liquid paraffin, vaseline, one or more of polyethylene glycol, 0.01% to 1% sodium ethylparaben, 0% to 30% polyethylene glycol stearate, and 0% to 50% polyol.
  • the ointment described in the present application includes 0.01% to 60% dipyridamole and/or its derivatives, 0.5% to 60% of diethylene glycol monoethyl ether, one or more of hexylene glycol and 1,3-butylene glycol, 40% to 99% of liquid paraffin, vaseline, one or more of polyethylene glycol, 0.01% to 1% sodium ethylparaben, 0% to 30% polyethylene glycol stearate, and 0% to 50% polyol.
  • the ointment described in the present application includes 0.01% to 60% dipyridamole and/or its derivatives, 0.5% to 60% of diethylene glycol monoethyl ether, one or more of hexylene glycol and 1,3-butylene glycol, 40% to 99% of liquid paraffin, vaseline, one or more of polyethylene glycol, and 0.01% to 1% sodium ethylparaben.
  • the ointment described in the present application includes 0.01% to 60% dipyridamole and/or its derivatives, 0.5% to 60% of one or two of hexylene glycol and 1,3-butylene glycol, 40% to 99% of liquid paraffin, vaseline, one or more of polyethylene glycol, and 0.01% to 1% sodium ethylparaben.
  • the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of diethylene glycol monoethyl ether, one or more of hexylene glycol and 1,3-butylene glycol, 50% to 95% of liquid paraffin, vaseline, one or more of polyethylene glycol, 0.02% to 0.5% sodium ethylparaben, 0% to 10% polyethylene glycol stearate, and 0% to 40% polyol.
  • the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of one or two of hexylene glycol and 1,3-butylene glycol, 50% to 95% of one or two of PEG400 and PEG4000, 0.02% to 0.5% sodium ethylparaben, 0% to 10% polyethylene glycol stearate, and 0% to 40% propylene glycol.
  • the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of a mixture of hexylene glycol and 1,3-butylene glycol, 50% to 95% of a mixture of PEG400 and PEG4000, 0.02% to 0.5% sodium ethylparaben, 0% to 10% polyethylene glycol-7-stearate, and 0% to 40% propylene glycol.
  • the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of a mixture of hexylene glycol and 1,3-butylene glycol, wherein 50% to 95% of a mixture of PEG400 and PEG4000, 0.02% to 0.5% sodium ethylparaben, 0% to 10% polyethylene glycol-7-stearate, 0% to 40% propylene glycol; wherein the mass ratio of hexylene glycol to 1,3-butanediol is 1:5-5:1, and the mass ratio of PEG400 to PEG4000 is 3.5:1 to 1:1.
  • the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of a mixture of hexylene glycol and 1,3-butylene glycol, wherein, 50% to 95% of a mixture of PEG400 and PEG4000, 0.02% to 0.5% sodium ethylparaben, 0% to 10% polyethylene glycol-7-stearate, and 0% to 40% propylene glycol; wherein, the mass ratio of hexylene glycol and 1,3-butylene glycol is 3:5-5:3, and the mass ratio of PEG400 and PEG4000 is 2.5:1 to 1.5:1.
  • the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of one or more of diethylene glycol monoethyl ether, hexylene glycol and 1,3-butylene glycol, 50% to 95% of liquid paraffin, vaseline, one or more of polyethylene glycol, and 0.02% to 0.5% sodium ethylparaben.
  • the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of one or two of hexylene glycol and 1,3-butylene glycol, 50% to 95% of one or two of PEG400 and PEG4000, and 0.02% to 0.5% sodium ethylparaben.
  • the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of a mixture of hexylene glycol and 1,3-butanediol, 50% to 95% of a mixture of PEG400 and PEG4000, and 0.02% to 0.5% sodium ethylparaben.
  • the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of a mixture of hexylene glycol and 1,3-butanediol, 50% to 95% of a mixture of PEG400 and PEG4000, and 0.02% to 0.5% sodium ethylparaben; wherein the mass ratio of hexylene glycol and 1,3-butanediol is 1:5-5:1, and the mass ratio of PEG400 and PEG4000 is 3.5:1 to 1:1.
  • the ointment described in the present application includes 0.1% to 10% dipyridamole and/or its derivatives, 1% to 50% of a mixture of hexylene glycol and 1,3-butanediol, 50% to 95% of a mixture of PEG400 and PEG4000, and 0.02% to 0.5% sodium ethyl hydroxybenzoate; wherein the mass ratio of hexylene glycol and 1,3-butanediol is 3:5-5:3, and the mass ratio of PEG400 and PEG4000 is 2.5:1 to 1.5:1.
  • the dipyridamole derivative includes a pharmaceutically acceptable salt, ester, hydrate, solvate, polymorph, isomer or prodrug of dipyridamole.
  • the pharmaceutically acceptable salt of dipyridamole includes a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, and the like.
  • metal salts include: alkali metal salts, such as sodium salts, potassium salts, and the like; alkaline earth metal salts, such as calcium salts, magnesium salts, barium salts, and the like; and aluminum salts.
  • salts formed with organic bases include salts formed with the following organic bases: trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like.
  • Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • Preferred examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
  • Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and the like.
  • Preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.
  • salts are preferred.
  • examples thereof include inorganic salts, for example, alkali metal salts (for example, sodium salts, potassium salts, etc.), alkaline earth metal salts (for example, calcium salts, magnesium salts, etc.), ammonium salts, etc.
  • examples thereof include salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and salts formed with organic acids, for example, acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • organic acids for example, acetic acid, phthalic
  • the dipyridamole salt is dipyridamole sodium chloride or dipyridamole hydrochloride.
  • the isomers include structural isomers, stereoisomers, optical isomers, regioisomers, and geometric isomers.
  • the sixth aspect of the present application provides a method for preparing the dipyridamole cream described in the third aspect of the present application, comprising the following steps: mixing the oil phase components in the cream matrix and heating them to 70-80°C to melt, adding dipyridamole and/or its derivatives to obtain an oil phase mixture; mixing the water phase components in the cream matrix and heating them to 70-80°C to obtain an water phase mixture; under stirring conditions, adding the water phase mixture to the oil phase mixture, homogenizing and continuously stirring, and obtaining the dipyridamole ointment after cooling.
  • the dipyridamole ointment is a cream.
  • the oil phase component in the cream base includes cetearyl alcohol, isopropyl myristate, isopropyl palmitate, diethylene glycol monoethyl ether and polyethylene glycol-7-stearate.
  • the aqueous phase component in the cream base includes glycerin, 1,3-butylene glycol, sodium ethylparaben and water.
  • the oil phase components in the cream base are mixed and heated to 80° C. to melt.
  • the aqueous phase components in the cream base are mixed and heated to 80°C.
  • the homogenizing rotation speed is 1000-10000 rpm.
  • the homogenization time is 1-20 min.
  • the homogenization is performed at 5000 rpm for 3 min.
  • the seventh aspect of the present application provides another preparation method of the dipyridamole cream described in the third aspect of the present application, comprising the following steps: dissolving or dispersing dipyridamole and/or its derivatives in diethylene glycol monoethyl ether, heating to 50°C to obtain a premixed solution; mixing the other oil phase components in the cream matrix except diethylene glycol monoethyl ether and heating to 70-80°C to melt to obtain an oil phase mixed solution; mixing the water phase components in the cream matrix and heating to 70-80°C to obtain an water phase mixed solution; under stirring, adding the water phase mixed solution to the oil phase mixed solution, cooling to 50°C, adding the premixed solution, homogenizing and continuously stirring, and obtaining the dipyridamole cream after cooling.
  • the oil phase component in the cream base includes cetearyl alcohol, isopropyl myristate, isopropyl palmitate, diethylene glycol monoethyl ether and polyethylene glycol-7-stearate.
  • the aqueous phase component in the cream base includes glycerin, 1,3-butylene glycol, sodium ethylparaben and water.
  • the oil phase components in the cream base except diethylene glycol monoethyl ether are mixed and heated to 80° C. to melt.
  • the aqueous phase components in the cream base are mixed and heated to 80°C.
  • the homogenizing rotation speed is 1000-10000 rpm.
  • the homogenization time is 1-20 min.
  • the homogenization is performed at 5000 rpm for 3 min.
  • the eighth aspect of the present application provides a method for preparing the dipyridamole gel described in the fourth aspect of the present application, comprising the following steps: dissolving dipyridamole and/or its derivatives in diethylene glycol monoethyl ether, adding a moisturizer to obtain a premixed solution; mixing the other components in the gel matrix except the pH adjuster, adding the gelling agent, stirring until swelling, and obtaining a gel solution; adding the premixed solution to the gel solution, adjusting the pH, and stirring evenly to obtain the dipyridamole gel.
  • the ninth aspect of the present application provides a use of the dipyridamole cream described in the third aspect of the present application, the gel described in the fourth aspect, or the dipyridamole ointment described in the fifth aspect in the preparation of medicines for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.
  • a method for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases comprising administering dipyridamole to a patient.
  • the effective content of dipyridamole and/or its derivatives in the drug is 0.01% to 60%, preferably 0.05% to 20%, and more preferably 0.1% to 10%, for example 0.1%, 0.2%, 0.3%, 0.5%, 1%, 2%, 3%, 5%, 8%, 10%.
  • the concentration of dipyridamole and/or its derivatives in the drug is 1-100 mg/g, preferably 1-50 mg/g, more preferably 1-20 mg/g, for example 3 gm/g, 5 mg/g.
  • the dipyridamole drug includes a dipyridamole external preparation or an internal preparation.
  • the drug is in the form of an external dosage form, including but not limited to ointments, creams, gels, lotions, tinctures, suspensions, liniments, spirits, powders, oils, pastes, plasters, coatings, aerosols, solutions, sprays, and patches.
  • an external dosage form including but not limited to ointments, creams, gels, lotions, tinctures, suspensions, liniments, spirits, powders, oils, pastes, plasters, coatings, aerosols, solutions, sprays, and patches.
  • dipyridamole topical preparation includes dipyridamole cream, gel and ointment.
  • the drug is used once every 1 to 24 hours.
  • the frequency of use of the drug is: 1-3 times a day, preferably 2-3 times a day.
  • the frequency of use of the drug is: once every 1 hour, every 2 hours, every 4 hours, every 6 hours, every 8 hours, every 12 hours or every 24 hours.
  • the dosage of the drug per time is: calculated as dipyridamole, 1-250 mg per time, preferably 5-100 mg per time, and more preferably 10-50 mg per time.
  • the drug is administered in a cosmetically effective amount.
  • the drug is administered in a therapeutically effective amount.
  • the drug is used in the form of a topical drug preparation for skin application.
  • the drug is administered by coating or spraying the drug on the skin surface corresponding to the affected area.
  • the dosage of the drug each time is: 0.1-25 mg/cm 2 in terms of dipyridamole.
  • 0.1-25 mg/cm 2 in terms of dipyridamole is applied or sprayed on the skin surface corresponding to the affected area.
  • the dosage of the drug each time is: 0.2-10 mg/cm 2 in terms of dipyridamole.
  • 0.2-10 mg/cm 2 in terms of dipyridamole is applied or sprayed on the skin surface corresponding to the affected area.
  • the dosage of the drug each time is: 0.5-5 mg/cm 2 in terms of dipyridamole.
  • 0.5-5 mg/cm 2 in terms of dipyridamole is applied or sprayed on the skin surface corresponding to the affected area.
  • the drug further comprises a second active ingredient.
  • the second active ingredient is as described in the first aspect of the present application.
  • dipyridamole topical preparation includes the cream described in the third aspect of the present application, the gel described in the fourth aspect, or the ointment described in the fifth aspect.
  • the eleventh aspect of the present application provides the use of diethylene glycol monoethyl ether or a composition thereof with polyethylene glycol stearate in the preparation of a dipyridamole topical preparation.
  • a dipyridamole topical preparation is prepared based on the diethylene glycol monoethyl ether as a raw material.
  • a dipyridamole topical preparation is prepared based on the composition of diethylene glycol monoethyl ether and polyethylene glycol stearate as a raw material.
  • diethylene glycol monoethyl ether is used as a solvent in the dipyridamole topical preparation.
  • the topical preparation includes ointments, creams, gels, lotions, tinctures, suspensions, liniments, spirits, powders, oils, pastes, plasters, coatings, aerosols, solutions, sprays, patches, such as ointments, creams, and gels.
  • the mass percentage of diethylene glycol monoethyl ether in the external preparation is 0.1% to 60%, preferably 0.3% to 50%.
  • the mass percentage of the polyethylene glycol stearate in the external preparation is 0.3% to 40%, preferably 0.5% to 30%.
  • the polyethylene glycol stearate includes polyethylene glycol-7-stearate, polyethylene glycol-5-stearate, PEG-25 stearate, PEG-23 stearate, PEG-30 stearate, PEG-18 stearate, PEG-20 stearate, PEG-10 stearate, etc., for example, polyethylene glycol-7-stearate.
  • the use of diethylene glycol monoethyl ether or a combination of diethylene glycol monoethyl ether and polyethylene glycol stearate in a dipyridamole topical preparation can increase skin permeability by 10%, 20%, 30%, 40%, 50%, 60% or more; the efficacy of diethylene glycol monoethyl ether or its combination with polyethylene glycol stearate can be improved.
  • the use of diethylene glycol monoethyl ether or a composition thereof with polyethylene glycol stearate in a dipyridamole topical preparation is used to prepare a topical preparation for treating allergic and/or inflammatory diseases.
  • the allergic and/or inflammatory diseases described in the ninth aspect, the tenth aspect or the eleventh aspect of the present application are as described in the allergic and/or inflammatory diseases described in the first aspect of the present application.
  • an external preparation comprising dipyridamole and/or its derivatives as an active ingredient for preventing, adjuvant therapy or treating allergic and/or inflammatory diseases.
  • the topical preparation comprises 0.01% to 60%, 0.05% to 20%, 0.1% to 15%, 0.1% to 12%, or 0.1% to 10% of dipyridamole and/or its derivatives.
  • the topical preparation is a cream, a gel or an ointment.
  • the external preparation is a cream
  • the composition of the cream is as described above.
  • the external preparation is a gel
  • the composition of the gel is as described above.
  • the external preparation is an ointment
  • the composition of the ointment is as described above.
  • the topical preparation can be used in combination with a second active ingredient to prevent, assist in the treatment of, or treat allergies.
  • the second active ingredient is as described above.
  • the allergic and/or inflammatory disease is as described above.
  • dipyridamole and/or its derivatives in the thirteenth aspect of the present application, provided is the use of dipyridamole and/or its derivatives, pharmaceutical compositions or topical preparations containing the same in the preparation of medicaments for reducing the levels of inflammatory cytokines, IgE levels and/or mast cell degranulation in the skin and/or plasma of patients with allergic and/or inflammatory diseases.
  • the inflammatory cytokine can be selected from IL-4, TSLP, IL-1b, IL-6, TNF- ⁇ and the like.
  • the pharmaceutical composition or topical preparation contains 0.01% to 60%, 0.05% to 20%, 0.1% to 15%, 0.1% to 12%, or 0.1% to 10% of dipyridamole and/or its derivatives.
  • dipyridamole and/or its derivatives, pharmaceutical compositions or topical preparations containing the same are provided for reducing the levels of inflammatory cytokines, IgE levels and/or mast cell degranulation in the skin and/or plasma of patients with allergic and/or inflammatory diseases.
  • the topical preparation is a cream, a gel or an ointment.
  • the external preparation is a cream
  • the composition of the cream is as described above.
  • the external preparation is a gel
  • the composition of the gel is as described above.
  • the external preparation is an ointment
  • the composition of the ointment is as described above.
  • the topical preparation can be used in combination with a second active ingredient for the prevention, adjuvant treatment or treatment of allergic and/or inflammatory diseases.
  • the second active ingredient is as described above.
  • the dipyridamole topical preparation in this application is highly safe for human body, has no side effects in human and animal experiments, and can be widely used on any skin of human body, especially on highly sensitive skin such as face.
  • Figure 1 is a physical photo of the dipyridamole natural skin color cream and the dipyridamole cream without pigment components in the examples of the present application, wherein the right picture is the dipyridamole natural skin color cream, and the left picture is the dipyridamole cream without pigment components.
  • FIG2 is a comparison of the cumulative retention results of creams with different solvents.
  • FIG3 is a comparison of the cumulative retention results of gels in different solvents.
  • Figures 4 and 5 are representative images of the back skin of mice with allergic and inflammatory skin diseases modeled by calcipotriol in the validation example of this application on the 5th day after application of different formulations of dipyridamole topical preparations.
  • Figure 6 shows the back skin scoring results of mice with allergic and inflammatory skin diseases modeled by calcipotriol in the verification example of the present application after applying different formulations of dipyridamole topical preparations on the 5th day; wherein, Ns: no statistical difference; *: P ⁇ 0.05; **: P ⁇ 0.01; ***: P ⁇ 0.001; ****: P ⁇ 0.001.
  • Figure 7 shows the levels of inflammatory factors IL-4 and TSLP in the back of mice with allergic and inflammatory skin diseases modeled by calcipotriol 14 days after modeling in the validation example of the present application; wherein, Ns: no statistical difference; *: P ⁇ 0.05; **: P ⁇ 0.01; ***: P ⁇ 0.001; ****: P ⁇ 0.001.
  • FIG8 is a comparison of the TSLP protein concentrations in the plasma of each group of model mice in the verification example of the present application; wherein, Ns: no statistical difference; *: P ⁇ 0.05; **: P ⁇ 0.01; ***: P ⁇ 0.001; ****, P ⁇ 0.001.
  • FIG9 is a comparison of TSLP protein concentrations in the skin tissues of the model mice in each group in the verification example of the present application; wherein, Ns: no statistical difference; *: P ⁇ 0.05; **: P ⁇ 0.01; ***: P ⁇ 0.001; ****: P ⁇ 0.001.
  • FIG10 is a comparison of the IgE protein concentrations in the plasma of each group of model mice in the verification example of the present application; wherein, Ns: no statistical difference; *: P ⁇ 0.05; **: P ⁇ 0.01; ***: P ⁇ 0.001; ****: P ⁇ 0.001.
  • FIG11 is a comparison of the IgE protein concentrations in the back skin tissues of the model mice in each group in the verification example of the present application; wherein, Ns: no statistical difference; *: P ⁇ 0.05; **: P ⁇ 0.01; ***: P ⁇ 0.001; ****: P ⁇ 0.001.
  • FIG. 12 is a representative case diagram of the actual therapeutic effect of dipyridamole cream and gel on human acne in the verification example of this application.
  • FIG. 13 is a representative case diagram of the actual therapeutic effect of using the dipyridamole cream and gel in the verification example of this application to treat human urticaria half an hour before and after.
  • FIG. 14 is a representative case diagram of the actual treatment effect of using the dipyridamole cream and gel in the verification example of this application to treat human urticaria before and after 2 months.
  • FIG. 15 is a representative case diagram of the actual therapeutic effect of using the dipyridamole cream and gel in the verification example of this application to treat ringworm in cats.
  • FIG. 16 shows the results of the antihistamine allergy to the dipyridamole cream and ointment of the present application as determined by skin prick test.
  • FIG. 17 shows a comparison of the results before and after application of the dipyridamole cream of the present application to allergy patients.
  • the terms “comprise, comprises and comprising” or their equivalents are open-ended expressions, meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.
  • dipyridamole or its derivatives in the preparation of drugs for preventing, adjuvant therapy or treating allergic and/or inflammatory diseases.
  • the application according to item 1 is characterized in that the allergic diseases include skin diseases caused by allergies, respiratory diseases caused by allergies, digestive tract diseases caused by allergies, and eye diseases caused by allergies.
  • the application according to 1 is characterized in that the allergic diseases include: allergic rhinitis, allergic conjunctivitis, allergic asthma, allergic dermatitis, allergic urticaria, food allergy, dust allergy, mite allergy, hay fever, drug allergy, allergic bronchial asthma, allergic sinusitis, allergic respiratory distress, preferably allergic conjunctivitis, allergic rhinitis, allergic urticaria.
  • the use according to item 1 is characterized in that the inflammatory diseases include infectious diseases, non-infectious diseases, and post-infectious hyperplasia.
  • infectious diseases include infectious conjunctivitis, infectious rhinitis, infectious rosacea, infectious urticaria, infectious asthma, and infectious diarrhea.
  • infectious diseases include viral infectious diseases, fungal infectious diseases, bacterial infectious diseases, parasitic infectious diseases, and mycoplasma infectious diseases.
  • the use according to 6 is characterized in that the viral infectious diseases include herpes, viral conjunctivitis, viral rhinitis, new coronavirus pneumonia, influenza, viral hepatitis, viral rhinitis, viral pharyngitis, viral enteritis, viral diarrhea, chickenpox, and mumps.
  • the viral infectious diseases include herpes, viral conjunctivitis, viral rhinitis, new coronavirus pneumonia, influenza, viral hepatitis, viral rhinitis, viral pharyngitis, viral enteritis, viral diarrhea, chickenpox, and mumps.
  • the viral hepatitis includes hepatitis A, hepatitis B, and hepatitis C.
  • herpes includes EV71 viral herpes.
  • bacterial infectious diseases include bacterial conjunctivitis, bacterial rhinitis, purulent tonsillitis, acne, sty caused by bacterial infection, bacterial gastritis, bacterial pharyngitis, and bacterial mastitis.
  • gastritis caused by bacteria includes gastritis caused by Helicobacter pylori.
  • bacterial mastitis includes mastitis caused by Staphylococcus aureus.
  • non-infectious diseases include non-infectious dermatitis, abdominal pain caused by lactose intolerance, conjunctivitis caused by external stimulation, glaucoma, cataracts, dry eyes, non-specific keratitis, rosacea caused by neurological disorders, urticaria caused by physical stimulation, pharyngitis caused by external stimulation, inflammatory bowel disease, and mastitis caused by external pressure.
  • non-infectious dermatitis includes traumatic dermatitis, dermatitis caused by surgical wounds, solar dermatitis, frostbite, and insect bite dermatitis.
  • inflammatory bowel disease includes ulcerative colitis, Crohn's disease, and indeterminate colitis.
  • the post-infectious hyperplasia includes thyroid nodules, hemorrhoids, scar hyperplasia, sty, thyroid nodules, breast nodules, and breast hyperplasia.
  • the inflammatory diseases include dermatitis, asthma, conjunctivitis, rosacea, urticaria, sty, gastritis, rhinitis, pharyngitis, adnexitis, urethritis, vaginitis, mastitis, inflammatory bowel disease, frostbite, acne, blackheads, enlarged pores, red blood streaks, seborrheic dermatitis, seborrheic alopecia, scleroderma, vitiligo, purpura, nevus, melanoma, preferably conjunctivitis, rosacea, rhinitis, acne.
  • the external preparation comprises ointments, creams, gels, lotions, tinctures, suspensions, liniments, spirits, powders, oils, pastes, plasters, coatings, aerosols, solutions, sprays, and patches.
  • the external preparation further comprises one or more of the following substances: solvents, emulsifiers, softeners, antioxidants, preservatives, chelating agents, pH regulators, thickeners, penetration enhancers, and sunscreens.
  • the dosage of the drug each time is: 1-250 mg each time, preferably 5-100 mg each time, more preferably 10-50 mg each time, calculated as dipyridamole; or; the drug is administered in a cosmetically effective amount; or the drug is administered in a therapeutically effective amount.
  • the use according to 28 is characterized in that the drug is administered by coating or spraying the drug on the skin surface corresponding to the affected area.
  • the dosage of the drug each time is: 0.1-25 mg per cm 2 , preferably 0.2-10 mg/cm 2 , and more preferably 0.5-5 mg/cm 2 , calculated as dipyridamole.
  • the pharmaceutically acceptable salt of dipyridamole includes dipyridamole sodium chloride or dipyridamole hydrochloride.
  • the use according to any one of 31-32 is characterized in that the mass percentage of dipyridamole and/or its derivatives in the drug is 0.01% to 60%, preferably 0.1% to 10%; or the concentration of dipyridamole or its salt is 0.1 to 100 mg/g, preferably 1 to 50 mg/g, and more preferably 1 to 20 mg/g.
  • the second active ingredient includes at least one of an active ingredient for anti-inflammatory diseases, an active ingredient for anti-allergic diseases, an anti-inflammatory active ingredient, and an anti-allergic active ingredient.
  • anti-inflammatory active ingredients include: steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs.
  • non-steroidal anti-inflammatory drugs include aspirin, benolate, salicylic acid, acetaminophen, indomethacin, diclofenac, sulindac, nemetbutalone, ibuprofen, naproxen, piroxicam, meloxicam, celecoxib, etoricoxib, nimesulide; or, the steroidal anti-inflammatory drugs include adrenal cortical hormones, androgens, estrogens, such as hydrocortisone, prednisone, dexamethasone.
  • anti-inflammatory active ingredients include: antifungal drugs and/or their active ingredients, antiviral drugs and/or their active ingredients, antibacterial drugs and/or their active ingredients, antiparasitic drugs and/or their active ingredients, antimycoplasma drugs and/or their active ingredients.
  • antifungal drugs or active ingredients include amphotericin B, nystatin, griseofulvin, clotrimazole, econazole, miconazole, ketoconazole, bifonazole, terbinafine, ciclopirox olamine, and amorolfine;
  • the antiviral drugs or active ingredients include acyclovir, acetaminophen, amantadine, chlorpheniramine maleate, ribavirin, amantadine and its salts, and human interferon;
  • the antibacterial drugs or active ingredients include antibiotics, sulfonamides, imidazoles, nitroimidazoles, quinolones, preferably penicillin, cephalosporin, cephamycin antibiotics, sulfamethoxazole, sulfadiazine, ketoconazole, miconazole, econazole, clotrimazole, Nidazole, dimetridazole, isopronidazole, seconidazole, ornidazole, tinidazole and ronidazole, norfloxacin, pefloxacin, enoxacin, ofloxacin and ciprofloxacin.
  • the active ingredient for anti-inflammatory diseases includes the active ingredient of a drug for treating any inflammatory disease described in 4-20, preferably an acne treatment drug or active ingredient, a rosacea treatment drug or active ingredient, a rhinitis treatment drug or active ingredient, or a conjunctivitis treatment drug or active ingredient.
  • the acne treatment drugs or active ingredients include sulfur, clindamycin, erythromycin, vitamin A ester, benzoyl peroxide, azelaic acid, retinoic acid, isotretinoin, adapalene, hyaluronic acid or its salt, ergothioneine;
  • the rhinitis treatment drugs or active ingredients include glucocorticoids, antibacterial drugs, and alpha receptor agonists;
  • the conjunctivitis treatment drugs or active ingredients include aminoglycoside drugs or active ingredients, fluoroquinolone drugs or active ingredients, amide drugs or active ingredients, tetracycline drugs or active ingredients, macrolide drugs or active ingredients, acyclovir eye drops and ganciclovir eye gel, sulfacetamide sodium or rifampicin eye drops, and corticosteroid eye drops.
  • glucocorticoids include hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, dexamethasone acetate, triamcinolone acetonide acetate, mometasone furoate, halometasone, beclomethasone dipropionate, fluocinolone acetonide, halcinonide, and betamethasone propionate;
  • the alpha receptor agonists include ephedrine, ephedrine hydrochloride, oxymetazoline, and xylometazoline.
  • aminoglycoside drugs or active ingredients include gentamicin, neomycin, and tobramycin;
  • the fluoroquinolone drugs or active ingredients include gatifloxacin, norfloxacin, and ofloxacin;
  • the amide alcohol drugs or active ingredients include chloramphenicol
  • the macrolide drugs or active ingredients include erythromycin and rifampicin.
  • anti-allergic active ingredients include: antihistamines, allergic reaction mediator release inhibitors, histamine desensitization drugs, leukotriene receptor antagonists, antigen-antibody reaction inhibitors, drugs for improving or controlling allergic reaction symptoms, and active ingredients of the above drugs.
  • antihistamine drugs or active ingredients include diphenhydramine, promethazine, and chlorpheniramine;
  • the allergic reaction mediator release-inhibiting drugs or active ingredients include sodium cromoglycate and ketotifen;
  • histamine desensitization drugs or active ingredients include betahistine, histamine diluent, and dust mite injection;
  • the leukotriene receptor antagonist drugs or active ingredients include montelukast and zafirlukast;
  • the drugs or active ingredients that inhibit antigen-antibody reactions include glucocorticoids and immunosuppressants;
  • the drugs for improving or controlling allergic symptoms include smooth muscle spasmolytics and drugs for alleviating edema caused by allergies.
  • glucocorticoids include hydrocortisone acetate, hydrocortisone butyrate, dexamethasone, dexamethasone acetate, triamcinolone acetonide acetate, mometasone furoate, halometasone, beclomethasone dipropionate, fluocinolone acetonide, halcinonide, and betamethasone propionate;
  • the smooth muscle antispasmodics include salbutamol
  • the drug for reducing edema caused by allergies includes calcium gluconate.
  • the drug is applicable to animals, and the animals are selected from humans, cats, cows, sheep, pigs, dogs, chickens, ducks, geese, rabbits, and mice; preferably, the animals are humans, more preferably infants, children, teenagers, adults or the elderly; most preferably, children.
  • dipyridamole cream characterized in that, in terms of mass percentage, the dipyridamole cream contains 0.01%-20% of dipyridamole and/or its derivatives, and 0.1%-60% of diethylene glycol monoethyl ether.
  • the dipyridamole cream according to 50 characterized in that the mass percentage of the dipyridamole and/or its derivatives is 0.01%-10%.
  • dipyridamole cream according to 50 or 51 characterized in that the mass percentage content of diethylene glycol monoethyl ether is 0.3% to 50%.
  • dipyridamole cream according to 50 or 51 characterized in that the mass percentage of diethylene glycol monoethyl ether is 2%-30%.
  • the dipyridamole cream according to any one of 50-53, characterized in that the cream base further comprises an emulsifier, preferably 0.3% to 40% of the emulsifier, more preferably 0.5% to 30% of the emulsifier.
  • dipyridamole cream according to any one of 50-53, characterized in that the cream further comprises one or more of an emulsifier, a lubricant, a moisturizer, a preservative, an antioxidant, a consistency regulator, a pH regulator, a pigment, and water.
  • the dipyridamole cream according to 55 is characterized in that the emulsifier includes one or more of polyethylene glycol stearate, phospholipids, sodium lauryl sulfate, Span surfactants, Tween surfactants, higher fatty alcohols, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, 15-hydroxystearate polyethylene glycol ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, triethanolamine, stearic acid glyceryl, caprylic acid capric acid polyethylene glycol glyceride, propylene glycol monocaprylate, propylene glycol monolaurate, polyglycerol oleate, and polyethylene glycol cetearyl alcohol ether.
  • the emulsifier includes one or more of polyethylene glycol stearate, phospholipids, sodium lauryl sulfate, Span surfactants, Tween surfactants, higher fatty alcohols,
  • the dipyridamole cream according to 56 characterized in that the polyethylene glycol stearate includes polyoxyethylene sorbitan monostearate, polyethylene glycol monooctadecanoate, polyethylene glycol monostearate, T-60, polyoxyethylene stearate, polyoxyethylene sorbitan monostearate, PEG-5 stearate, PEG-7 stearate, PEG-25 stearate, PEG-23 stearate, PEG-30 stearate, PEG-18 stearate, PEG-20 stearate, PEG-10 stearate, preferably PEG-7 stearate.
  • the polyethylene glycol stearate includes polyoxyethylene sorbitan monostearate, polyethylene glycol monooctadecanoate, polyethylene glycol monostearate, T-60, polyoxyethylene stearate, polyoxyethylene sorbitan monostearate, PEG-5 stearate, PEG-7 stearate, PEG-25 stearate, PEG
  • the dipyridamole cream according to 55 characterized in that the cream further comprises a lubricant and/or a consistency regulator.
  • the dipyridamole cream according to 58 characterized in that the cream further comprises one or more of a moisturizer, a preservative, an antioxidant, a pH adjuster, a pigment, and water.
  • the dipyridamole cream according to 58 characterized in that the lubricant is selected from one or more of isopropyl palmitate, isopropyl myristate, dimethicone, diisopropyl adipate, caprylic glyceride, caprylic anhydride oil, caprylic capric macrogol glyceride, isohexadecane, hydrogenated castor oil, mineral oil, caprylic/capric triglyceride, lauric acid, and linoleic acid, and is preferably one or both of isopropyl myristate and isopropyl palmitate.
  • the lubricant is selected from one or more of isopropyl palmitate, isopropyl myristate, dimethicone, diisopropyl adipate, caprylic glyceride, caprylic anhydride oil, caprylic capric macrogol glyceride, isohexadecane, hydrogenated
  • the dipyridamole cream according to 58 characterized in that the mass proportion of the lubricant in the dipyridamole cream is 0.5% to 40%, preferably 1% to 30%, and more preferably 5% to 20%.
  • the dipyridamole cream according to 58 characterized in that the consistency regulator is selected from one or more of cetearyl alcohol, cetyl alcohol, stearyl alcohol, glyceryl monostearate, glyceryl mono- and distearate, carbomer, liquid paraffin, vaseline, and glyceryl behenate, preferably one or more of cetearyl alcohol, cetyl alcohol, liquid paraffin, and glyceryl monostearate.
  • the dipyridamole cream according to 58 characterized in that the mass proportion of the consistency regulator in the dipyridamole cream is 0% to 50%, preferably 0.1% to 30%, and more preferably 0.1% to 30%.
  • the dipyridamole cream according to 59 characterized in that the moisturizer is selected from one or more of glycerol, propylene glycol, 1,3-butylene glycol, and polyethylene glycol, preferably one or two of glycerol and 1,3-butylene glycol.
  • the dipyridamole cream according to 59 is characterized in that the mass proportion of the moisturizer in the dipyridamole cream is 0.5% to 50%, preferably 1% to 30%, more preferably 2% to 25%, and more preferably 5%-20%.
  • the dipyridamole cream according to 59 characterized in that the preservative is selected from at least one of a chemical preservative and a natural preservative; preferably, the preservative is selected from one or more of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium ethylparaben, benzyl alcohol, phenoxyethanol, sorbic acid, benzoic acid, and sodium benzoate.
  • a chemical preservative and a natural preservative preferably, the preservative is selected from one or more of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium ethylparaben, benzyl alcohol, phenoxyethanol, sorbic acid, benzoic acid, and sodium benzoate.
  • the dipyridamole cream according to 59 characterized in that the mass proportion of the preservative in the dipyridamole cream is 0% to 10%, preferably 0% to 5%, and more preferably 0% to 1%.
  • the dipyridamole cream according to 59 characterized in that the antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, disodium edetate, ⁇ -tocopherol, ascorbic acid, sodium metabisulfite, anhydrous sodium sulfite, propyl gallate, sodium ascorbate, isoascorbic acid, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, and thioglycerol.
  • the antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, disodium edetate, ⁇ -tocopherol, ascorbic acid, sodium metabisulfite, anhydrous sodium sulfite, propyl gallate
  • the dipyridamole cream according to 59 characterized in that the mass proportion of the antioxidant in the dipyridamole cream is 0% to 5%, preferably 0% to 1%.
  • the pH adjuster comprises an acidic pH adjuster or an alkaline pH adjuster, preferably, the pH adjuster is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium citrate, triethanolamine, citric acid, hydrochloric acid, and sodium dihydrogen phosphate.
  • the dipyridamole cream according to 59 characterized in that the mass proportion of the pH regulator in the dipyridamole cream is 0% to 10%, preferably 0% to 5%.
  • the pigment comprises a synthetic pigment or a natural pigment; preferably, the pigment comprises one or more of carmine, erythrosine, allura red, red iron oxide, titanium dioxide, zinc oxide, talc, kaolin, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, amaranth, new red, lemon yellow, sunset yellow, indigo, brilliant blue, carotene, chlorophyll, turmeric, impatiens glycoside, rose glycoside, and capsanthin.
  • the pigment comprises a synthetic pigment or a natural pigment; preferably, the pigment comprises one or more of carmine, erythrosine, allura red, red iron oxide, titanium dioxide, zinc oxide, talc, kaolin, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, amaranth, new red, lemon yellow, sunset yellow, indigo, brilliant blue, carotene, chlorophyll, turmeric, impatiens glycoside, rose glycoside, and capsanthin.
  • the dipyridamole cream according to 59 characterized in that the mass proportion of the pigment in the dipyridamole cream is 0% to 10%, preferably 0% to 5%.
  • the dipyridamole cream according to 59 is characterized in that the cream contains 10% to 95% water by mass, preferably 20% to 90% water, and more preferably 30% to 70% water.
  • the dipyridamole cream according to 59 is characterized in that, in terms of mass percentage, the dipyridamole cream contains 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and 0.3% to 40% of emulsifier, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, 0.1% to 50% of consistency regulator, and one or more of water.
  • the dipyridamole cream according to 59 is characterized in that, in terms of mass percentage, the dipyridamole cream contains 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, 1% to 30% of consistency regulator, and one or more of water.
  • dipyridamole cream according to any one of 75-76, characterized in that the emulsifier is polyethylene glycol-stearate; and/or the lubricant is isopropyl myristate and/or isopropyl palmitate; and/or the moisturizer is glycerol and/or 1,3-butylene glycol; and/or the preservative is sodium ethylparaben; and/or the consistency regulator is cetearyl alcohol.
  • the preparation method of the dipyridamole cream described in any one of 50 to 77 comprises the following steps: mixing the oil phase components in the cream matrix and heating them to 70 to 80°C to melt, adding dipyridamole and/or its derivatives to obtain an oil phase mixture; mixing the water phase components in the cream matrix and heating them to 70 to 80°C to obtain an water phase mixture; adding the water phase mixture to the oil phase mixture under stirring, homogenizing and continuously stirring, and obtaining the dipyridamole cream after cooling.
  • the preparation method of the dipyridamole cream described in any one of 50 to 77 comprises the following steps: dissolving or dispersing dipyridamole and/or its derivatives in diethylene glycol monoethyl ether, heating to 50 to 60°C to obtain a premixed solution; mixing the other oil phase components in the cream matrix except diethylene glycol monoethyl ether and heating to 70 to 80°C to melt to obtain an oil phase mixed solution; mixing the water phase components in the cream matrix and heating to 70 to 80°C to obtain an water phase mixed solution; adding the water phase mixed solution to the oil phase mixed solution under stirring, cooling to 50 to 60°C, adding the premixed solution, homogenizing and continuously stirring, and obtaining the dipyridamole cream after cooling.
  • a dipyridamole gel characterized in that, in terms of mass percentage, it comprises 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, and 0.1% to 60% diethylene glycol monoethyl ether.
  • the dipyridamole gel according to 80 characterized in that the mass percentage of the dipyridamole and/or its derivatives is 0.01%-10%.
  • the dipyridamole gel according to 81 is characterized in that the mass percentage of diethylene glycol monoethyl ether is 0.3% to 50%, preferably 2% to 30%.
  • the dipyridamole gel according to 80 is characterized in that the mass percentage of the gel is 0.2% to 10%, preferably 0.5% to 5%.
  • the dipyridamole gel according to 80 is characterized in that the gelling agent comprises one or more of carbomer, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, and sodium carboxymethyl cellulose, preferably carbomer.
  • the dipyridamole gel according to 84 characterized in that the carbomer includes carbomer 980NF, carbomer 974NF, and carbomer 940.
  • dipyridamole gel according to any one of 80-86, characterized in that the dipyridamole gel further comprises one or more of a surfactant, a pH adjuster, a moisturizer, an antioxidant, a preservative, and water.
  • the dipyridamole gel according to 86 is characterized in that the mass percentage of water is 10% to 98%, preferably 20% to 95%, and more preferably 30% to 90%.
  • the dipyridamole gel according to 86 is characterized in that the moisturizer is selected from one or more of vaseline, glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol.
  • the dipyridamole gel according to 86 is characterized in that the mass proportion of the moisturizer in the dipyridamole gel is 0.1% to 50%, preferably 1% to 30%.
  • the dipyridamole gel according to 86 is characterized in that the preservative is selected from one or more of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium ethylparaben, benzyl alcohol, phenoxyethanol, sorbic acid, benzoic acid, and sodium benzoate.
  • the dipyridamole gel according to 86 is characterized in that the mass proportion of the preservative in the dipyridamole ointment is 0% to 5%, preferably 0% to 2%, and more preferably 0% to 1%.
  • the dipyridamole gel according to 86 is characterized in that the surfactant is selected from one or more of sodium lauryl sulfate, Spans, Tweens, poloxamers, triethanolamine, caprylic/capric acid macrogol glycerides, 15-hydroxystearate macrogol esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyethylene glycol cetearyl alcohol ether, and is preferably triethanolamine.
  • the surfactant is selected from one or more of sodium lauryl sulfate, Spans, Tweens, poloxamers, triethanolamine, caprylic/capric acid macrogol glycerides, 15-hydroxystearate macrogol esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyethylene glycol cetearyl alcohol ether, and is preferably triethanolamine.
  • the dipyridamole gel according to 86 is characterized in that the mass proportion of the surfactant in the dipyridamole gel is 0.1% to 50%, preferably 0.5% to 30%.
  • the dipyridamole gel according to 86 is characterized in that the pH regulator is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium citrate, triethanolamine, citric acid, hydrochloric acid, and sodium dihydrogen phosphate.
  • the pH regulator is selected from one or more of sodium hydroxide, sodium bicarbonate, sodium citrate, triethanolamine, citric acid, hydrochloric acid, and sodium dihydrogen phosphate.
  • the dipyridamole gel according to 86 is characterized in that the mass proportion of the pH regulator in the dipyridamole gel is 0% to 10%, preferably 0% to 5%.
  • the dipyridamole gel according to 86 is characterized in that the antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, disodium ethylenediaminetetraacetic acid, ⁇ -tocopherol, ascorbic acid, sodium metabisulfite, propyl gallate, sodium ascorbate, and isoascorbic acid.
  • the antioxidant is selected from one or more of butylated hydroxytoluene, butylated hydroxyanisole, disodium ethylenediaminetetraacetic acid, ⁇ -tocopherol, ascorbic acid, sodium metabisulfite, propyl gallate, sodium ascorbate, and isoascorbic acid.
  • the dipyridamole gel according to 86 is characterized in that the mass proportion of the antioxidant in the dipyridamole ointment is 0% to 5%, preferably 0% to 1%.
  • the dipyridamole gel according to 86 is characterized in that, in terms of mass percentage, it comprises one or more of 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% gelling agent, 0.1% to 60% diethylene glycol monoethyl ether, and 0.1% to 50% moisturizer, 0% to 5% preservative, 0% to 10% pH adjuster, 0.1% to 50% surfactant, 0% to 5% antioxidant, and 10% to 98% water.
  • the dipyridamole gel according to 86 is characterized in that, in terms of mass percentage, it comprises one or more of 0.01% to 20% dipyridamole or its derivatives, 0.1% to 20% carbomer, 0.1% to 60% diethylene glycol monoethyl ether, 0.1% to 50% 1,3-butanediol, 0% to 5% sodium ethyl hydroxybenzoate, 0% to 50% triethanolamine, and 10% to 98% water.
  • the method for preparing the dipyridamole gel described in any one of 100.80 to 99 comprises the following steps: dissolving dipyridamole and/or its derivatives in diethylene glycol monoethyl ether, adding a moisturizer to obtain a premixed solution; mixing the other components in the gel matrix except the pH adjuster, adding the gelling agent, stirring until swelling, and obtaining a gel solution; adding the premixed solution to the gel solution, adjusting the pH, and stirring evenly to obtain the dipyridamole gel.
  • a dipyridamole ointment characterized in that it comprises the cream component described in any one of 50-77 and does not contain water.
  • a dipyridamole ointment characterized in that it comprises the cream component described in any one of 50-77 and does not contain water, and the mass percentage of the consistency regulator in the dipyridamole ointment is 0.1%-98%, preferably 0.5%-95%, and more preferably 1%-90%.
  • a dipyridamole ointment characterized in that it contains, by mass percentage, 0.01% to 20% of dipyridamole and/or its derivatives, 0.1% to 60% of diethylene glycol monoethyl ether, and one or more of 0.3% to 40% of emulsifier, 0.5% to 40% of lubricant, 0.5% to 50% of moisturizer, 0% to 10% of preservative, 0.1% to 50% of consistency regulator, 0% to 10% of pH regulator, 0% to 5% of antioxidant, and 0% to 10% of pigment.
  • the dipyridamole ointment according to 103 is characterized in that, in terms of mass percentage, the ointment contains 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, 1% to 90% of consistency regulator, 0% to 5% of pH regulator, 0% to 1% of antioxidant, and 0% to 5% of pigment.
  • the ointment contains 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, 0% to 1% of preservative, 1% to 90% of consistency regulator, 0% to 5% of pH regulator, 0% to 1% of antioxidant
  • the dipyridamole ointment according to 104 is characterized in that it contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier, 1% to 30% of lubricant, 1% to 30% of moisturizer, and 1% to 90% of one or more of consistency regulator.
  • the dipyridamole ointment according to 104 is characterized in that it contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 0.5% to 30% of emulsifier.
  • the dipyridamole ointment according to 104 is characterized in that it contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, and 1% to 90% of a consistency regulator.
  • the dipyridamole ointment according to 104 is characterized in that it contains, by mass percentage, 0.01% to 10% of dipyridamole and/or its derivatives, 0.3% to 50% of diethylene glycol monoethyl ether, 0.5% to 30% of emulsifier, and 1% to 90% of consistency regulator.
  • dipyridamole cream described in any one of 50 to 77 in the preparation of a medicament for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.
  • dipyridamole gel described in any one of 80 to 99 in the preparation of a medicament for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases.
  • a method for preventing, assisting in the treatment or treating allergic and/or inflammatory diseases comprising the following steps: administering dipyridamole or a derivative thereof to a patient in need thereof.
  • the method according to 113 is characterized in that it includes the following steps: administering dipyridamole or its derivatives to the patient in need thereof in an external manner.
  • the method according to 114 is characterized in that it includes the following steps: topically administering the dipyridamole cream described in any one of items 50 to 77 and/or the dipyridamole gel described in any one of items 80 to 99 and/or the dipyridamole ointment described in any one of items 101 to 108 to the patient in need thereof.
  • the method according to any one of 114-115 is characterized in that the method of topical administration is: applying the dipyridamole cream described in any one of 50 to 77 and/or the dipyridamole gel described in any one of 80 to 99 and/or the dipyridamole ointment described in any one of 101 to 108 to the skin surface corresponding to the affected area.
  • the method according to any one of 112-116 is characterized in that the frequency of administration is: 1-3 times every 1 to 24 hours, or 1-3 times a day, preferably 2-3 times a day.
  • the method according to any one of 112-117 is characterized in that the dosage of the drug is: 1-250 mg each time, preferably 5-100 mg each time, and more preferably 10-50 mg, calculated as dipyridamole; or; the drug is administered in a cosmetically effective amount; or the drug is administered in a therapeutically effective amount.
  • the dosage of the administration is: 0.1-25 mg/cm 2 ; more preferably 0.2-10 mg/cm 2 , calculated as dipyridamole.
  • the method according to 113 is characterized in that the allergic disease is the disease described in 2 or 3; or the inflammatory disease is any one of the diseases described in 4-20.
  • experimental materials and reagents used were conventional consumables and reagents available from commercial channels.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • the preparation method of dipyridamole cream in this embodiment is as follows: weigh the A phase components according to the ratio shown in the above table, mix the other components except the main drug (API, i.e., dipyridamole) and heat to 80°C to melt, add API and stir to dissolve, and obtain the A phase solution. Weigh the B phase components according to the ratio shown in the above table, stir to uniformity after mixing, and heat to 80°C to obtain the B phase solution. Under stirring conditions, add the B phase solution to the A phase solution, homogenize at 5000rpm for 3min, continue stirring and cool to room temperature to obtain the dipyridamole cream.
  • API i.e., dipyridamole
  • the effective content of the main drug dipyridamole in the dipyridamole cream is 5 mg/g.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • the preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1.
  • the effective content of the main drug dipyridamole in the dipyridamole cream is 5 mg/g.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • the preparation method of dipyridamole cream in the present embodiment is as follows: weigh the A phase components according to the ratio shown in the above table, disperse or dissolve the main drug (API, i.e., dipyridamole) in diethylene glycol monoethyl ether, and keep warm at 50°C to obtain a phase A solution. Weigh the B phase components according to the ratio shown in the above table, mix and heat to 80°C to melt, and obtain a phase B solution. Weigh the C phase components according to the ratio shown in the above table, stir until dissolved after mixing, and heat to 80°C to obtain a phase C solution.
  • API i.e., dipyridamole
  • the effective content of the main drug dipyridamole in the dipyridamole cream is 5 mg/g.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • the preparation method of the dipyridamole cream in this embodiment is the same as that in embodiment 2.
  • the effective content of the main drug dipyridamole in the dipyridamole cream is 5 mg/g.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • the preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1.
  • the effective content of the main drug dipyridamole in the dipyridamole cream is 1 mg/g.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • the preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1.
  • the effective content of the main drug dipyridamole in the dipyridamole cream is 2 mg/g.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • phase A weigh phase A according to the prescription amount, disperse or dissolve the API in diethylene glycol monoethyl ether, keep warm at 50°C and set aside;
  • phase A At 55°C, add phase A to the mixture, homogenize for 3 min (5000 rpm) and continue stirring. Cool the sample to room temperature to obtain dipyridamole cream.
  • the effective content of the main drug dipyridamole in the dipyridamole cream is 10 mg/g.
  • a 2% dipyridamole cream 1 is provided, and its composition is shown in the following table:
  • the preparation method of the dipyridamole cream in this embodiment is the same as that in embodiment 7.
  • the effective content of the main drug dipyridamole in the dipyridamole cream is 20 mg/g.
  • the preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1.
  • the effective content of the main drug dipyridamole in the dipyridamole cream is 2 mg/g.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • the preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1.
  • the content of the main drug dipyridamole in the cream is 50 mg/g.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • the preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1.
  • the content of the main drug dipyridamole in the cream is 120 mg/g.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • the preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1.
  • the content of the main drug dipyridamole in the cream is 8 mg/g.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • Table 13 Composition and content of dipyridamole cream formula
  • the preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1.
  • the content of the main drug dipyridamole in the cream is 60 mg/g.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • the preparation method of the dipyridamole cream in this embodiment is the same as that in Example 1.
  • the content of the main drug dipyridamole in the cream is 50 mg/g.
  • a topical pharmaceutical preparation (dipyridamole natural skin color cream) based on the dipyridamole cream in the above embodiment is provided.
  • the topical pharmaceutical preparation is the dipyridamole cream in the above embodiment with the addition of auxiliary materials such as pigments, so that the color of the dipyridamole topical pharmaceutical preparation is closer to human skin color, as shown in FIG1 , thereby improving the visual perception of the patient, reducing the patient's psychological resistance, giving the patient a more pleasant and comfortable use experience, and improving the patient's willingness to use.
  • the ingredients of the dipyridamole natural skin color cream are shown in the following table:
  • the preparation method of the dipyridamole natural skin color cream in this embodiment is the same as that in Example 1, except that: in this embodiment, after adding the phase B solution to the phase A solution, the pigment is added, and then homogenized at 5000 rpm for 3 minutes, continuously stirred and cooled to room temperature to obtain the dipyridamole natural skin color cream.
  • the effective content of the main drug dipyridamole in the dipyridamole natural skin color cream is 5 mg/g.
  • a dipyridamole cream without pigment components was prepared as a control.
  • the actual photos of the dipyridamole natural skin color cream and the dipyridamole cream without pigment components are shown in Figure 1, where the right picture is the dipyridamole natural skin color cream and the left picture is the dipyridamole cream without pigment components. It can be found that the color difference between the two is significant.
  • the color of the dipyridamole natural skin color cream is obviously closer to the human skin color, and the visual sensory effect is better than the dipyridamole cream without pigment components, and it is easier to be accepted by patients.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • the effective content of the main drug dipyridamole in the dipyridamole cream is 5 mg/g.
  • Example 1 Compared with Example 1, in Comparative Example 1, Tween 80 is used as an emulsifier instead of polyethylene glycol-7-stearate, and diethylene glycol monoethyl ether is removed.
  • Cream comparative example 2 a dipyridamole cream
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • Cream Comparative Example 2 On the basis of Cream Comparative Example 2, Cream Comparative Examples 3 to 5 were prepared, and the mass percentages of dipyridamole were adjusted to 0.4%, 0.3%, 0.2%, and 0.1%, respectively, and the water content was adaptively adjusted, while other components and contents remained unchanged.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • the effective content of the main drug dipyridamole in the dipyridamole cream is 5 mg/g.
  • Tween 80 is used as an emulsifier instead of polyethylene glycol-7-stearate, and diethylene glycol monoethyl ether is removed.
  • a dipyridamole cream is provided, and its composition is shown in the following table:
  • Preparation method Mix stearic acid, glyceryl monostearate, white vaseline and liquid paraffin as the oil phase; separately mix glycerol, sodium lauryl sulfate, triethanolamine, ethylparaben and water as the water phase. Place them in appropriate containers, heat until they are melted or dissolved, put dipyridamole into the oil phase, slowly add the water phase into the oil phase after heating, and stir in the same direction while adding, until solidified and then packaged.
  • Cream Comparative Example 8 a dipyridamole cream
  • This example prepares a cream product.
  • the preparation method of the product comprises: uniformly mixing 1-100g of dipyridamole with a vanishing cream base to prepare 1000g of the product, and preparing an ointment with a dipyridamole concentration of 0.1-10% (in which the dipyridamole is difficult to dissolve and presents a granular texture visible to the naked eye).
  • the cream of the present application and the cream of the comparative example have effective therapeutic and preventive effects on dermatitis model mice, but the cream of the present application, especially Example 1 and Example 2, has significantly improved therapeutic and preventive effects compared with the cream comparative example.
  • the cream comparative example 1 of the present application has better cream properties, such as cream skin feel, viscosity, etc.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • the preparation method of dipyridamole gel in the present embodiment is: weigh each component according to the ratio shown in the above table, stir and dissolve the main drug (API, i.e., dipyridamole) in a solvent (diethylene glycol monoethyl ether), add a moisturizing agent (1,3-butylene glycol) and stir until uniform to obtain a main drug mixture.
  • the preservative sodium ethyl hydroxybenzoate
  • a gelling agent (carbomer 980NF) is slowly added under continuous stirring, and stirred until completely swollen to obtain a gel matrix.
  • the main drug mixture is added to the gel matrix, and a pH adjusting agent (trolamine) is added to adjust the pH to 6.0-6.5, and dipyridamole gel is obtained after stirring evenly.
  • the effective content of the main drug dipyridamole in the dipyridamole gel is 5 mg/g.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • the preparation method of dipyridamole gel in the present embodiment is similar to that of gel embodiment 1: each component is weighed according to the ratio shown in the above table, the main drug (API, i.e., dipyridamole) is stirred and dissolved in the solvent (diethylene glycol monoethyl ether), and a moisturizer (1,3-butylene glycol) is added and stirred until uniform to obtain a main drug mixture.
  • the preservative sodium ethyl hydroxybenzoate
  • a gelling agent (carbomer 980NF) is slowly added under continuous stirring conditions, and stirred until completely swollen to obtain a gel matrix.
  • the main drug mixture is added to the gel matrix, and a pH adjusting agent (triethanolamine) is added to adjust the pH to 6.0-6.5, and dipyridamole gel is obtained after stirring evenly.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • dipyridamole gel in this embodiment is the same as or similar to that of gel embodiment 1.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • dipyridamole gel in this embodiment is the same as or similar to that of gel embodiment 1.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • dipyridamole gel in this embodiment is the same as or similar to that of gel embodiment 1.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • dipyridamole gel in this embodiment is the same as or similar to that of gel embodiment 1.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • dipyridamole gel in this embodiment is the same as or similar to that of gel embodiment 1.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • dipyridamole gel in this embodiment is the same as or similar to that of gel embodiment 1.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • dipyridamole gel in this embodiment is the same as or similar to that of gel embodiment 1.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • dipyridamole gel in this embodiment is the same as or similar to that of gel embodiment 1.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • dipyridamole gel in this embodiment is the same as or similar to that of gel embodiment 1.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • the effective content of the main drug dipyridamole in the dipyridamole gel is 5 mg/g.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • the effective content of the main drug dipyridamole in the dipyridamole gel is 50 mg/g.
  • a dipyridamole gel is provided, and its composition is shown in the following table:
  • the effective content of the main drug dipyridamole in the dipyridamole gel is 50 mg/g.
  • a dipyridamole ointment is provided, and its composition is shown in the following table:
  • the preparation method of the dipyridamole ointment in this embodiment is as follows: weigh the components according to the ratio shown in the above table, mix the components except dipyridamole, heat to 70-80°C to melt, then add dipyridamole to dissolve, and cool to room temperature to obtain the ointment.
  • a dipyridamole ointment is provided, and its composition is shown in the following table:
  • dipyridamole ointment in this embodiment is the same as or similar to that of dipyridamole ointment embodiment 1.
  • a dipyridamole ointment is provided, and its composition is shown in the following table:
  • dipyridamole ointment in this embodiment is the same as or similar to that of dipyridamole ointment embodiment 1.
  • a dipyridamole ointment is provided, and its composition is shown in the following table:
  • dipyridamole ointment in this embodiment is the same as or similar to that of dipyridamole ointment embodiment 1.
  • dipyridamole ointment of this example was prepared according to the method of ointment example 5.
  • dipyridamole ointment of this example was prepared according to the method of ointment example 5.
  • dipyridamole ointment of this example was prepared according to the method of ointment example 5.
  • dipyridamole ointment of this example was prepared according to the method of ointment example 5.
  • dipyridamole ointment of this example was prepared according to the method of ointment example 5.
  • dipyridamole ointment of this example was prepared according to the method of ointment example 5.
  • diethylene glycol monoethyl ether of the present application has a very significant improvement effect compared with other commonly used oily solvents (for example, including but not limited to olive oil, liquid paraffin, vaseline, cetearyl alcohol, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, polyglycerol oleate), thereby achieving an unexpectedly significantly improved therapeutic effect in the treatment effect of the mouse dermatitis model.
  • oily solvents for example, including but not limited to olive oil, liquid paraffin, vaseline, cetearyl alcohol, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, polyglycerol oleate
  • the Franz diffusion cell method was used to take the back skin of Bama miniature pigs, wash it with physiological saline, check the skin integrity, and install it in a diffusion device.
  • the effective diffusion area of the diffusion cell was 1.77 cm 2
  • the volume of the receiving cell was 12 ml
  • the receiving solution was pH 7.4 phosphate buffer solution-anhydrous ethanol (70:30)
  • the stirring speed was 600 ⁇ 60rpm
  • the skin surface temperature was 32.0 ⁇ 1.0°C.
  • 0.3g of the preparation was evenly applied to the stratum corneum of the skin.
  • diethylene glycol monoethyl ether As can be seen from Figure 2, compared with glyceryl monostearate, diethylene glycol monoethyl ether has a very significant improvement in transdermal effect, about On this basis, the combination of diethylene glycol monoethyl ether and polyethylene glycol-7-stearate can further improve its transdermal effect.
  • topical preparations that need to be used on the skin surface, their skin feel (or tactile properties) is directly related to the patient's acceptance of them. Therefore, it is very important for a topical drug preparation to have a good skin feel to reduce the rebellious or resistant psychology generated by patients when using it.
  • the inventors selected different emulsifiers and thickeners for comparison to analyze the actual skin feel experience of different emulsifiers-thickeners on the human body.
  • the emulsifiers and thickeners provided in this application have the characteristics of delicate skin feel.
  • the selection of moisturizers can increase the viscosity of the cream, increase the convenience of use and compliance.
  • the inventors also unexpectedly discovered that the use of diethylene glycol monoethyl ether of the present application as a solvent has a very significant improvement effect compared with other commonly used solvents (for example, including but not limited to ethanol, isopropanol, propylene glycol, 1,3-butanediol, glycerol, etc.), thereby achieving an unexpectedly significantly improved therapeutic effect in the treatment of mouse dermatitis models.
  • solvents for example, including but not limited to ethanol, isopropanol, propylene glycol, 1,3-butanediol, glycerol, etc.
  • the inventors adopted the cumulative retention test method of the above-mentioned component screening experimental example 1, exemplarily adopted the components of gel example 1, replaced diethylene glycol monoethyl ether with ethanol, and compared the difference in cumulative retention, as shown in FIG3 .
  • diethylene glycol monoethyl ether As can be seen from Figure 3, compared with ethanol, diethylene glycol monoethyl ether has a very significant improvement in transdermal effect, which is about 40%, and thus has achieved unexpectedly significant improvement in the treatment effect of mouse dermatitis models. At the same time, compared with solvents such as ethanol, diethylene glycol monoethyl ether is non-irritating and highly safe in gel preparations.
  • Table 45 Solvent screening table in ointment
  • Verification Example 1 The soothing effect of dipyridamole on the symptoms of allergic and inflammatory skin disease model mice
  • calcipotriol solution will be applied to the right ear and back skin of mice to induce allergic and inflammatory dermatitis in mice, thereby testing the therapeutic effect of DIP on allergic and inflammatory skin diseases.
  • mice/group mice/group mice
  • a blank group no treatment
  • a modeling group no treatment
  • a cream comparative group using cream comparative example 1 for treatment after modeling, referred to as cream group 1
  • a cream treatment group using dipyridamole cream of cream example 2 for treatment after modeling, referred to as cream group 2)
  • a gel comparative group using gel comparative example 1 for treatment after modeling, named gel group 1
  • a gel treatment group 1 using gel example 1 for treatment after modeling, referred to as gel group 2
  • a crisaborole group using non-hormone positive drug crisaborole for treatment after modeling
  • a gel treatment group 2 using gel example 2 for treatment after modeling, referred to as gel group 3
  • a dexamethasone group using hormone positive drug dexamethasone for treatment after modeling
  • a blank cream group using a blank cream without adding dipyridamol
  • mice After the end of the administration on the 14th day, blood was drawn from the eyeballs of all mice to collect serum. After the mice were killed, the right ears and the central skin of the back of the mice were cut off. Among them, the ears were cut in half, one half was immersed in RNaselater for RNA extraction and fluorescence quantitative PCR detection; the other half was immersed in 4% paraformaldehyde solution for HE staining.
  • each symptom is scored from 0 to 3 points, among which, the standard for none (0 point) is: cannot be confirmed after careful observation; the standard for mild (1 point) is: can be confirmed after careful observation; the standard for moderate (2 points) is: obvious signs and can be confirmed immediately; the standard for severe (3 points) is: the signs are particularly obvious and can be confirmed immediately.
  • mice treated with the positive drug crisaborole were significantly lower than those of the modeling untreated group (modeling untreated group vs crisaborole group, exfoliation/erosion score p ⁇ 0.0001, dryness score p ⁇ 0.0001, total score p ⁇ 0.0001), however, there was no difference in the erythema/hemorrhage score between the two groups (p>0.05), which proves that the use of crisaborole can significantly improve the exfoliation/erosion, dryness and other symptoms of allergic and inflammatory dermatitis, but the effect on improving erythema caused by allergic and inflammatory dermatitis is not obvious.
  • mice in the cream treatment group were significantly lower than those in the crisaborole group (erythema/hemorrhage score p ⁇ 0.0001, exfoliation/erosion score p>0.05, dryness score p>0.05, total score p ⁇ 0.0001), and the erythema/hemorrhage, edema, exfoliation/erosion, dryness and total score of mice in the gel treatment group were significantly lower than those in the crisaborole group (erythema/hemorrhage score p ⁇ 0.0001, exfoliation/erosion score p ⁇ 0.0001, dryness score p ⁇ 0.0001, total score p ⁇ 0.0001), which proved that the use effect of the cream treatment group and the gel treatment group containing dipyridamole is better than that of the non-hormonal therapeutic drug crisaborole currently on the market.
  • the inventors found that the erythema/hemorrhage and total score of the mice in the cream treatment group were basically equivalent to those in the dexamethasone group, with no significant difference (erythema/hemorrhage score p>0.05, exfoliation/erosion score p>0.05, dryness score p>0.05, total score p>0.05), and the erythema/hemorrhage, edema, exfoliation/erosion, dryness symptoms and total score of the mice in the gel treatment group were equivalent to those of the dexamethasone group, with no significant difference (erythema/hemorrhage score p>0.05, exfoliation/erosion score p>0.05, dryness score p>0.05, total score p>0.05), which proves that the use effects of the cream treatment group and the gel treatment group containing dipyridamole are equivalent to those of the hormone therapy drug dexamethasone currently on the market.
  • mice in the cream treatment group The erythema/hemorrhage score and total score were significantly lower than those in the cream control group (p ⁇ 0.0001). All skin symptom scores of the gel-treated group were significantly lower than those of the gel control group (erythema/hemorrhage p ⁇ 0.05, exfoliation/erosion p ⁇ 0.0001, dryness p ⁇ 0.0001, total score p ⁇ 0.0001).
  • the formulation process of the present application is significantly superior to other formulations, including the comparative example, in improving the overall skin symptoms of allergic and inflammatory dermatitis in mice.
  • Verification Example 2 Dipyridamole reduces the expression of IL-4 and TSLP in allergic and/or inflammatory diseases
  • IL-4 and thymic stromal lymphopoietin are two important cytokines that induce allergic and/or inflammatory diseases. Specifically in skin-related allergic or inflammatory diseases, elevated IL-4 levels can cause atopic dermatitis symptoms similar to those associated with allergies and inflammation in mouse models. TSLP is highly expressed in the skin epithelial cells of patients with inflammatory skin diseases, and overexpression of TSLP in keratinocytes (the most common cell type in the skin) can cause intense itching, scratching, the development of dermatitis phenotypes, and even worse, asthma-like lung inflammation. In order to verify whether DIP has an inhibitory effect on the production of IL-4 and TSLP mRNA, in this example, the mRNA of the mouse skin obtained in Verification Example 1 was extracted for fluorescence quantitative PCR detection.
  • the specific steps are as follows: Add 1 mL TRIZOL to the mouse skin tissue in Verification Example 1 and grind thoroughly, incubate at room temperature for 5 minutes to allow the cells to be fully lysed. Add 200 ⁇ L chloroform, shake vigorously for 15 seconds, and incubate at room temperature for 2 to 15 minutes. Centrifuge at 12000 ⁇ g for 15 minutes, take the aqueous phase and mix it evenly with 500 ⁇ L isopropanol, and incubate at room temperature for 5 to 10 minutes. Centrifuge at 12000 ⁇ g for 10 minutes and discard the supernatant. Use 1 mL of ethanol to immerse the precipitated RNA and shake and wash. Centrifuge at 7500 ⁇ g for 5 minutes and discard the excess ethanol. After natural air drying, add 20 ⁇ L DEPC water to dissolve the RNA. Use the reverse transcription kit (purchased from Novazon) and the qPCR kit (purchased from Novazon) to detect the obtained RNA according to the instructions.
  • mice using each group of preparations including cream control group, cream treatment group, gel control group, gel treatment group, and crisaborole
  • mice using each group of preparations were observed to have a significant decrease in IL-4 mRNA level (P ⁇ 0.001), indicating that various DIP preparations and crisaborole can reduce the expression level of IL-4.
  • the mRNA level of TSLP in the skin of mice in the cream treatment group was significantly lower than that of mice in the modeling untreated group and crisaborole group (P ⁇ 0.05).
  • mouse IL-4 and TSLP ELISA kits mouse IL-4 ELISA kit and mouse TSLP ELISA kit were purchased from Sizhengbai
  • 10 ⁇ L of RIPA protein lysis buffer was added to the skin tissue per mg sample, and the tissue was fully ground on ice until it was completely dissolved. Then, it was shaken on ice for 30 minutes, and then centrifuged at 12000 ⁇ g to remove the precipitate. The supernatant was taken and the protein concentration was detected using an ELISA kit. The detection method was carried out according to the instructions.
  • mice using each group of preparations including cream control group, cream treatment group, gel control group, gel treatment group, and crisaborole
  • mice using each group of preparations were observed to have a significant decrease in the protein level of TSLP (P ⁇ 0.05), indicating that various DIP preparations and crisaborole can reduce the expression level of TSLP.
  • each group of DIP preparations and crisaborole can reduce the expression of TSLP in mouse plasma
  • the DIP cream treatment group has the most significant reduction in the expression of TSLP in mouse skin and plasma, both at the protein level and at the mRNA level, which is significantly better than the cream control group and is equivalent to the hormone-positive drug dexamethasone group.
  • Verification Example 3 Dipyridamole reduces plasma and inflammatory site IgE in allergic and/or inflammatory diseases and inhibits mast cell infiltration
  • IgE is considered to be a hallmark antibody for allergic and/or inflammatory diseases such as dermatitis. According to statistics, up to 80% of dermatitis patients have elevated IgE levels. IgE can bind to the Fc ⁇ RI molecule (IgE receptor) on the surface of mast cells. When IgE binds to its corresponding antigen, it prompts mast cells to release particles such as heparin and histamine, triggering an immune response.
  • Fc ⁇ RI molecule IgE receptor
  • a mouse IgE ELISA detection kit (commercially available) was used to further detect the protein level of IgE in the skin tissue and plasma of the mouse model of allergic and inflammatory dermatitis obtained in Verification Example 1.
  • 10 ⁇ L of RIPA protein lysis buffer was added to the skin tissue per mg sample, and the tissue was fully ground on ice until it was completely dissolved, and then continued to shake and lyse on ice for 30 minutes, and then centrifuged at 12000 ⁇ g to remove the precipitate, and the supernatant was taken to detect the protein concentration using an ELISA kit, and the detection method was carried out according to the instructions.
  • the IgE protein concentration in the plasma and skin of the mice in the modeling untreated group was significantly increased compared with that in the blank group (blank
  • the IgE protein concentration in the skin and plasma of the mice in the cream treatment group was significantly lower than that in the modeling untreated group, the crisaborole group, and the cream control group (P ⁇ 0.001).
  • the IgE mRNA levels in the skin and plasma of the mice in the gel treatment group showed a decreasing trend compared with those in the crisaborole group and the gel control group.
  • dipyridamole has an inhibitory effect on allergic reactions
  • a mouse model of rapid hypersensitivity reaction induced by trichosanthin was used as a disease model, and its therapeutic effect was determined by observing whether intraperitoneal injection of dipyridamole could inhibit the hypersensitivity reaction induced by trichosanthin.
  • mice Thirty female 8-week-old C57BL/6 mice were randomly divided into three groups, 10 mice in each group, namely, the blank group (no treatment), the modeling group (no treatment, injection of control solution) and the dipyridamole group (injection of dipyridamole).
  • mice in other groups were intraperitoneally injected with dipyridamole (50 mg/kg mouse body weight) once a day for 7 consecutive days.
  • all experimental animals in other groups, except the blank group were sensitized by intraperitoneal injection of 0.2 mL/mouse of trichosanthin injection (injection concentration 1.2 mg/mL).
  • all experimental animals in other groups, except the blank group were injected with 0.2 mL/mouse of trichosanthin injection (injection concentration 1.2 mg/mL) through the tail vein for antigen attack.
  • the reaction of mice in each group after antigen attack was observed, and the number of mice that died within 2 hours was recorded. All mice were killed after 2 hours, and peritoneal lavage fluid was taken.
  • Flow cytometry was used to quantitatively observe the number and proportion of mast cells in the peritoneal lavage fluid of mice.
  • the peritoneal lavage fluid was taken for cell smear, and the mast cell degranulation ratio was observed and calculated using toluidine blue staining. After staining, the mast cells without degranulation were intact, with clear outlines, and intact granular substances could be seen inside the cells; while the mast cells with degranulation were ruptured, with unclear outlines, and granules were excreted outward.
  • dipyridamole can inhibit the number and degranulation ratio of peritoneal mast cells in mice, thereby effectively inhibiting the hypersensitivity reaction of mice induced by trichosanthin.
  • Allergic conjunctivitis is an inflammation of the conjunctiva caused by an allergic reaction.
  • the main symptoms include redness, itching, swelling, tearing, and thread-like secretions.
  • the important feature of allergic conjunctivitis is the infiltration and degranulation of a large number of mast cells in the ocular tissue.
  • the inventors constructed an allergic conjunctivitis mouse model to observe whether dipyridamole eye drops can effectively treat allergic conjunctivitis.
  • mice Forty female 8-week-old C57BL/6 mice were randomly divided into four groups, 10 mice in each group, including a blank group (without any treatment), a modeling group (without any treatment), a dipyridamole eye drop group, and a 0.1% emedastine eye drop group.
  • sensitizer 100 mg OVA + 1 mg aluminum hydroxide adjuvant dissolved in 200 mL saline
  • 20 mL of stimulator 500 ⁇ g/mL OVA dissolved in saline
  • 20 mL of saline modeling group
  • 5 mg/mL dipyridamole solution dipyridamole eye drops group
  • 0.1% emedastine 0.1% emedastine (0.1% emedastine eye drops group
  • the eye swelling of each mouse was evaluated, and the evaluation content included four parameters: eyelid swelling, conjunctival edema, conjunctival redness and tearing.
  • the score range for each item ranged from 0 (no obvious symptoms) to 3 (the most severe symptoms), and the sum of the scores of the four parameters was combined to obtain the total eye swelling score for each animal.
  • the mice were killed, serum was collected, and the IgE concentration in the serum was detected (the IgE detection method is the same as that of Verification Example 3).
  • dipyridamole eye drops can significantly relieve the symptoms of eyelid swelling, conjunctival edema, conjunctival redness and tearing caused by allergic conjunctivitis, and the effect is significantly better than the reference drug 0.1% emedastine eye drops.
  • IgE is the main mediator molecule in allergic reactions, which can induce mast cells to release heparin, histamine and other particles, triggering immune responses.
  • the concentration of serum IgE can be used as an indicator to judge the course of the patient's disease.
  • the serum IgE concentrations of the dipyridamole eye drops group and the 0.1% emedastine eye drops group were significantly decreased to varying degrees.
  • dipyridamole eye drops can reduce the serum IgE concentration of allergic conjunctivitis model mice and alleviate the eye swelling and inflammation in allergic conjunctivitis.
  • Allergic rhinitis also known as allergic rhinitis
  • Allergic rhinitis is an allergic disease that can cause a variety of complications. Allergic rhinitis is the most common type of rhinitis. It is usually caused by the release of histamine mediated by IgE after the body comes into contact with allergens, triggering the infiltration of multiple immune cells and inflammatory factors downstream.
  • the main symptoms of allergic rhinitis include nasal itching, sneezing, hypersecretion of the nose, and swelling of the nasal mucosa.
  • the main treatment methods are antihistamines and nasal inhaled hormones. It is generally believed that allergic rhinitis cannot be cured, but can only be controlled.
  • the inventors constructed an allergic rhinitis mouse model to observe whether nasal drops of dipyridamole can effectively treat allergic rhinitis.
  • mice in each group were randomly divided into four groups, 10 mice in each group, including a blank group (without any treatment), a modeling group (without any treatment), a dipyridamole intranasal drop group, and a levocabastine (0.5 mg/mL) intranasal drop group.
  • sensitizer 50 mg OVA + 2 mg aluminum hydroxide adjuvant dissolved in 200 mL normal saline
  • the IgE detection method was the same as that of Verification Example 3).
  • rhinitis-related behaviors in mice is as follows: after intranasal OVA stimulation for 1 hour, the number of nose rubbing and sneezing behaviors of the mice within 5 minutes is recorded.
  • the number of sneezing and scratching in the modeling group mice was significantly higher than that in the blank group mice, while the average scores of various parameters in the levocabastine nasal drops group were significantly lower than those in the modeling group. This proves that the experimental model was successfully constructed and the positive reference drug worked well.
  • the number of sneezing and scratching in the dipyridamole nasal drops group mice was lower than that in the modeling group, and the therapeutic effect of dipyridamole nasal drops was significantly different from that in the modeling group mice (P ⁇ 0.05). This proves that dipyridamole eye drops can significantly relieve symptoms such as sneezing and scratching caused by allergic rhinitis, and the effect is significantly better than that of the reference drug.
  • Allergic rhinitis is a non-infectious inflammatory disease of the nasal mucosa in which an individual produces IgE and mediates the release of mediators (mainly histamine) after contact with allergens, and involves a variety of immune-active cells and cytokines. Therefore, allergic rhinitis is often accompanied by elevated serum IgE.
  • the serum IgE content of mice in the modeling group was significantly higher than that in the non-modeling group.
  • the serum IgE concentrations of the dipyridamole eye drops group and the levocabastine nasal drops group were significantly decreased to varying degrees.
  • dipyridamole nasal drops can reduce the serum IgE concentration of allergic rhinitis model mice and alleviate the symptoms of allergic rhinitis.
  • the inventors constructed an inflammatory bowel disease mouse model to observe whether dipyridamole can treat inflammatory bowel disease.
  • mice in each group were randomly divided into four groups, 10 mice in each group, including a blank group (without any treatment), a modeling group (without any treatment), a dipyridamole group (5 mg/mL), and a mesalazine group (5 mg/mL).
  • DAI water deionized water
  • DSS dextran sulfate sodium
  • Normal stool characteristics refer to formed stool; loose stool refers to pasty, semi-formed stool that does not adhere to the anus; loose stool refers to watery stool that can adhere to the anus.
  • mice On the 8th day, the experimental mice were killed, and the colon, small intestine and other tissues were collected. The colon length of each group of mice was measured, and the rectal side of the colon was cut off. After being rinsed with PBS, it was fixed in 4% polyformaldehyde solution, and HE staining was used to analyze the pathological damage of the colon in each group.
  • the steps of HE staining are as follows: fix the tissue sample in 4% paraformaldehyde for 24 hours. After paraffin embedding, cut the lung tissue into 4-5 mm slices with a freezing slicer, wash with distilled water for 1-2 seconds, stain with hematoxylin (60°C) for 30-60 seconds, wash away the hematoxylin with running water, 1% hydrochloric acid ethanol for 1-3 seconds, wash with water, turn blue with blueing solution for 5-10 seconds, rinse with running water for 15-30 seconds, stain with 0.5% eosin solution for 30-60 seconds, wash with distilled water for 1-2 seconds, and then dehydrate with 80%, 95% and 100% ethanol gradient alcohol in turn, dehydrate for 1-2 seconds each step, soak in xylene 3 times, 2-3 seconds each time, and finally seal with neutral resin. Observe under a microscope.
  • the detection method of intestinal inflammatory cytokines is as follows: the residual fat layer of the mouse colon mesentery is peeled off, weighed and dispersed into 1 mL PBS to obtain a single cell suspension. After centrifugation at 4°C and 1000g for 10 minutes, the supernatant is taken and the level of inflammatory cytokines in the supernatant is measured by ELISA kits (IL-1b, IL-6, TNF-a ELISA kits are all purchased from the market). The ELISA measurement process refers to the instruction manual of each detection kit.
  • mice The experimental results showed that the use of dipyridamole can significantly reduce the weight loss of mice (P ⁇ 0.05), and the stool characteristics and occult blood of mice were significantly reduced compared with the DSS model group, while there was no significant difference in the DSS model group (i.e., modeling group); histopathological results showed that feeding DSS significantly shortened the colon length (P ⁇ 0.05), and HE staining results showed structural changes such as crypt atrophy and twisting, infiltration of inflammatory cells such as lymphocytes and plasma cells in the intestinal wall, and chronic inflammatory changes such as thinning of the intestinal wall; in the group using dipyridamole cream and gel, the colon of mice was significantly longer than that of the DSS model group, and the pathological damage was significantly reduced, while there was no significant difference in the DSS model group.
  • Acne is a chronic inflammatory disease that usually affects the hair follicles and sebaceous glands. It mainly manifests as comedones, papules, pustules, nodules, cysts, and scars. Acne can occur in people of all ages, with the highest incidence in adolescents. Acne that occurs in adolescents is generally acne vulgaris, also commonly known as acne. Acne can also manifest as papules, pustules, nodules, cysts, scars, etc.
  • the inventors constructed a mouse acne model to observe whether dipyridamole can effectively treat acne.
  • mice Fifty female C57BL/6 mice aged 6 to 8 weeks were selected as experimental animals and randomly divided into 5 groups, 10 mice in each group, including a blank group (without any treatment), a modeling group (without any treatment), a dipyridamole cream Example 4 group (5 mg/mL), a dipyridamole gel Example 2 group (5 mg/mL), and a metronidazole (5 mg/mL) group.
  • dipyridamole cream Example 4 dipyridamole gel Example 2 and metronidazole are applied to the skin on both sides of the back of the mouse, and the condition of the mice is observed 2 weeks before and after the injection of the acne modeling bacterial suspension, and the degree of acne is evaluated by taking pictures.
  • Evaluation method of inflammatory cell infiltration and inflammatory cell cytokines Take the cut part of the mouse acne skin, use commercial digestion solution (purchased from Xingeyuan Company) to digest the lesions and control skin (blank group), centrifuge to remove the precipitate, and keep the supernatant. Use ELISA kit to determine the concentration of IL-1b inflammatory cytokines in the skin. The lower cell precipitate is analyzed by flow cytometry for the levels of CD45+ (immune cells), CD3+ (T cells), CD19+ (B cells), Gr-1+ (granulocytes), and F4/80+ (macrophages) cells and compared.
  • dipyridamole cream and gel can significantly change the histopathological changes of the acne model, significantly improve the cure rate (P ⁇ 0.05), and significantly reduce the concentration of inflammatory cytokines.
  • the metronidazole group can also improve the histopathological characteristics and The concentration of inflammatory cytokines was reduced (P ⁇ 0.05), but there was still a certain gap compared with dipyridamole cream and gel. This shows that dipyridamole cream and gel have significant acne treatment effects.
  • Rosacea also known as rosacea, is a skin disease that occurs in the central part of the face. It is also a chronic inflammatory disease caused by dysfunction of facial nerve vasoconstriction and capillary dilation. The main manifestations of rosacea are redness of the nose, papules, pustules, etc. It is common in people with more facial oil secretion. Emotional tension and excessive fatigue will aggravate the condition.
  • the inventors constructed a rosacea mouse model to observe whether dipyridamole can treat rosacea.
  • mice in each group 50 female C57BL/6 mice aged 6 to 8 weeks were selected and randomly divided into 4 groups, 10 mice in each group, namely, a blank group (without any treatment), a modeling group (without any treatment), a dipyridamole cream Example 6 group (2 mg/mL), and a dipyridamole gel Example 4 group (5 mg/mL).
  • LL-37 peptide amino acid sequence: LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES (SEQ ID NO: 1)
  • the hair on the back skin of the experimental mice was shaved with an electric razor.
  • LL-37 320 ⁇ M, InvivoGen
  • mice in the blank group were subcutaneously injected with 40 ⁇ L of injection water. Repeat twice a day for 48 hours.
  • dipyridamole cream and dipyridamole gel were wiped on the mouse skin every 6 hours. After the end, the dorsal skin condition was photographed, and the skin score was performed according to Table 49 to evaluate the back skin condition.
  • mice were anesthetized and killed.
  • the dorsal skin tissue specimens were taken and the tissues were fixed and sliced for evaluation.
  • dipyridamole cream and gel could significantly improve rosacea-like dermatitis, including improving inflammatory infiltration and angiogenesis in rosacea mice.
  • the dosage forms used include:
  • Dipyridamole tincture 1 Stir 5 g of dipyridamole with 1000 mL of 75% ethanol until dissolved to obtain a 5 mg/mL dipyridamole tincture product.
  • Dipyridamole comparative cream 1 that is, the dipyridamole cream in the above-mentioned cream comparative example 1.
  • the dipyridamole cream of the present application is the dipyridamole cream in the above-mentioned cream embodiment 2.
  • Dipyridamole comparative cream 2 that is, the dipyridamole cream in cream comparative example 8.
  • Dipyridamole comparative gel 1 the dipyridamole gel in the above-mentioned gel comparative example 1.
  • the dipyridamole gel of the present application is the dipyridamole gel in the above-mentioned gel embodiment 1.
  • Dipyridamole comparative gel 2 the dipyridamole gel in the above-mentioned gel comparative example 2.
  • the inventor uses facial skin that is more sensitive to external stimuli to verify the safety (irritation) of the above-mentioned effects and products (creams and gels) with better safety.
  • the test method is: 20 healthy volunteers were selected and divided into 2 groups, with 10 volunteers in each group. After thorough face cleansing, the cream of cream embodiment 2 or the gel of gel embodiment 1 was gently massaged and applied to the same side of the face and the depression behind the ear, respectively, with an application area of about 2 ⁇ 2 cm 2. After 2 hours, the skin condition was investigated (the erythema and edema after applying cream 2 or gel 2 were scored). Among them, the skin condition grading standard is shown in Table 49.
  • the skin conditions of the subjects are shown in Tables 50 and 51.
  • the cream and gel of the present application did not cause erythema or edema in the trial participants, have low skin irritation, high safety, and are suitable for a wide range of groups.
  • Histamine allergy generally refers to the skin stimulating the production of histamine, an inflammatory mediator, after the patient contacts the allergen and has an allergic reaction, which causes the surrounding capillaries to dilate and form edema/itching/erythema symptoms, thus causing skin allergic reactions. It is used to show the efficacy of the drug to be tested on allergic and inflammatory diseases.
  • the histamine concentration (10mg/ml) that can cause an allergic skin bulge of about 1cm in diameter within 15min was selected as the drug efficacy screening model concentration after preliminary experiments.
  • the specific experimental steps are as follows: the inside of the volunteer's arm was wiped and disinfected with 75% alcohol and evaporated to dry; PBS and histamine allergen (10 mg/ml, dissolved in PBS) were respectively transferred to the skin surface with a pipette of 20 ⁇ l and then pricked with a pricking needle with the same force (PBS and histamine allergen were grouped into two, and a total of 4 groups were used for drug administration testing).
  • the rash was wiped off and the area of the rash was measured, and then the drug was administered (2% vanishing cream of dipyridamole, 0.5% dipyridamole cream, 2% dipyridamole ointment, positive control drug Pi Yan Ping), and then the rash area was recorded once at 5min, 15min, 30min and 60min, and the largest and smallest bulge areas were selected for data statistical analysis.
  • the effective rate is the reduction rate of the blister diameter compared with the blank PBS group; the most effective rate is the horizontal comparison of the administration of 4 drugs to the same person after histamine allergen stimulation; the range of blister reduction is the longitudinal comparison after collecting data from 12 people; please see Figure 16):
  • the effective rate is 83.3% (10/12), the most effective rate is 8.3% (1/12), and the bulge reduction range is 0-50%
  • the effective rate was 66.7% (8/12), the most effective rate was 16.7% (2/12), and the range of bulge reduction was 0-44.4%.
  • the effective rate was 100% (12/12), the most effective rate was 66.7% (8/12), and the range of bulge reduction was 14.3-83.3%
  • the effective rate was 100% (12/12), the most effective rate was 33.3% (4/12), and the range of bulge reduction was 14.3-100%.
  • the efficacy standards for the above-mentioned allergic conjunctivitis and allergic rhinitis are: cured, markedly effective, effective, and ineffective.
  • the standard for cure is: the clinical symptoms basically disappear (for conjunctivitis, the symptoms such as apparent redness, swelling, itching, and pain basically return to normal; for rhinitis, the symptoms such as runny nose, nasal congestion, nasal itching, sneezing, and headache basically disappear), and the efficacy is ⁇ 90%.
  • the standard for marked efficacy is: the clinical symptoms are significantly improved (for conjunctivitis, the corneal and conjunctival lesions disappear and the itching of the eyes is eliminated; for rhinitis, the frequency of runny nose, nasal congestion, nasal itching, sneezing, etc. is significantly reduced), 50% ⁇ efficacy ⁇ 89%.
  • the standard for effective is: clinical symptoms are improved (for conjunctivitis, the corneal and conjunctival lesions are relieved and the itching of the eyes is relieved; for rhinitis, the symptoms such as runny nose, nasal congestion, nasal itching, sneezing, etc. are relieved), 20% ⁇ efficacy ⁇ 50%.
  • the criteria for ineffectiveness are: there is basically no improvement in clinical symptoms (for conjunctivitis, there is no improvement in corneal and conjunctival lesions and eye itching; for rhinitis, there is no improvement in the frequency or severity of runny nose, nasal congestion, nasal itching, and sneezing), and the efficacy index is less than 20%.
  • VAS scoring scales for conjunctivitis and rhinitis (which represent the perceptual indicators of allergic diseases in terms of psychophysics and physiology to the human body and the pain of the disease) (confirming the corresponding symptom degree by filling out forms and interviews).
  • conjunctivitis no symptoms are 0 points, and the most uncomfortable is 10 points (symptoms include the overall feeling of red eyes, swelling, itching, pain, congestion, tearing, photophobia, and foreign body sensation);
  • rhinitis no symptoms are 0 points, and the most uncomfortable is 10 points (symptoms include the overall feeling of nasal discharge, sneezing, nasal itching, and nasal congestion).
  • the efficacy criteria for the above-mentioned acne are: the main efficacy parameters are the reduction in the total number of inflammatory lesions (the sum of papules and pustules, the degree of reduction of redness, swelling and red marks) and the area of lesions (measured in centimeters "cm").
  • the standard for cure is: lesion reduction ⁇ 90%; the standard for marked effect is: lesion reduction 50% ⁇ 89%; the standard for onset of effectiveness is: lesion reduction 20% ⁇ 49%; the standard for ineffectiveness is: no change in the condition, or the lesion reduction result is less than 20%.
  • the cream and gel in the above embodiments can achieve a basic effective effect after 7 days of use, and have good acne removal and anti-inflammatory effects after 28 days, and have obvious skin lesion repair effects. It has the advantages of hidden blemish concealment, gentle and easy application, promoting wound healing, and preventing scar hyperplasia. Among them, a representative case can be seen in Figure 12.
  • the efficacy criteria for the above hemorrhoids are as follows: Cured: no bleeding, oozing, and basically no pain. Significantly effective: no bleeding, oozing, pain is significantly relieved, and wound healing time is significantly shortened. Effective: no bleeding, oozing, pain is relieved, and wound healing time is shortened. Ineffective: still There is no bleeding or oozing, no relief of pain, and no significant shortening of wound healing time.
  • the dipyridamole topical ointment (cream and gel) in the above embodiments has a significant therapeutic effect on hemorrhoids, and has the effect of quickly reducing swelling, relieving itching and relieving pain.
  • about 80% of the patients who tried the cream and gel responded that they had achieved relatively obvious symptom improvement on the 7th day of the first follow-up visit, and after a 3-month follow-up visit, it was found that the recurrence rate of hemorrhoids in patients using the cream and gel was low (no recurrence in the cream group, only 1 recurrence in the gel group), while the number of recurrences in the control group reached 4. It can be seen that the dipyridamole topical ointment is superior to the currently available positive control drug in terms of effectiveness, recurrence prevention rate, etc.
  • the efficacy criteria for the above-mentioned styes are as follows: Cured: The subjective symptoms disappear within 3 days, and the local redness, swelling and nodules subside and return to normal. Effective: The symptoms disappear within 3 days or only mild discomfort remains, and the local redness and swelling are significantly reduced, or there is only a subcutaneous nodule and the appearance is normal. Ineffective: The above criteria are not met after more than 3 days of treatment or the ulcer heals spontaneously.
  • the cream group was effective for all patients, the gel group also achieved an effective rate of 83.33%, and more than 90% of the patients' eyelid edema and induration subsided significantly, and the symptoms were basically eliminated within 1 day at the fastest. No recurrence was found in the cured patients after a follow-up visit after 14 days.
  • dipyridamole topical preparations have significant efficacy in treating sty diseases. In order to facilitate popularization and application, they can also be prepared into other local eye preparations (such as eye drops) for application in the later stage.
  • dipyridamole topical preparation has good animal experimental effects and high safety, and its anti-allergic, anti-inflammatory, antipruritic, analgesic and other efficacy and mechanism have been preliminarily analyzed
  • the above dipyridamole cream and gel can be further distributed and expanded to various groups of people who need anti-allergic and anti-inflammatory treatments for application based on its therapeutic mechanism. The following are the actual verification results of some cases.
  • Case 1 Patient Lin, male, 15 years old, had urticaria on his body for unknown reasons about 5 years ago. Among them, some acute urticaria would itch, and 5-8mm wheals would appear after scratching, which would be relieved after taking a bath or applying antipruritic ointment, but the urticaria at the elbows would not disperse for a long time after applying the ointment, forming a rash with pieces of aggregates. In severe cases, urticaria would appear all over the body, with wheals all over the body. He had been to the hospital for treatment and was prescribed the antiallergic drug cetirizine for three days, but the patient would still have an attack after stopping the drug.
  • Case 2 Patient Deng, female, 45 years old, developed urticaria on her abdomen and waist. The rash was in the form of red wheals. After applying the dipyridamole gel of this application, itching was quickly relieved within 5 minutes, and the wheals disappeared after 1 hour.
  • Case 3 Patient Liu, male, 36 years old, had recurrent urticaria on the back of his hands about 2 years ago, with redness, swelling and multiple The patient had a wheal and applied the dipyridamole cream of the present application. The patient reported that the immediate antipruritic effect was very good. After using it twice a day for two weeks, the redness, swelling and wheal were significantly reduced, the itching basically disappeared, and no side effects were observed.
  • Case 1 Patient Li, female, 44 years old, and her 10-year-old daughter, both suffered sunburn due to improper protection when traveling on the beach. They had symptoms such as flushing of the skin on their limbs, burning and stinging, and partial skin desquamation.
  • the mother and daughter tried the dipyridamole cream (cream example 3) and gel (gel example 2) of the present application, respectively, twice a day, thickly applied. After the trial, they reported that the burning and stinging sensation was significantly reduced on the same day, the skin no longer desquamated on the second day, and was basically cured on the third day.
  • Gastroenteritis including inflammatory bowel disease:
  • Case 1 Patient Ms. Wu, 30 years old, suffers from chronic gastritis and suffers from irregular gastric colic attacks all year round. She needs to take omeprazole, domperidone tablets and the like to relieve the symptoms. When gastric pain attacks occur on different days, she tries the dipyridamole cream (cream example 3) and gel (gel example 2) of the present application respectively, and finds that both can quickly stop gastric colic and thus relieve the symptoms of gastritis.
  • Inflammatory bowel disease mainly includes ulcerative colitis and Crohn's disease. It is a chronic recurrent disease with intestinal inflammation and epithelial damage as pathological characteristics and is difficult to cure. Moreover, according to epidemiological data, the duration and severity of chronic colitis are important risk factors for colitis-related colorectal cancer. In this regard, two patients with Crohn's disease and ulcerative colitis were found and the above-mentioned dipyridamole topical preparation was tried respectively. The results are as follows:
  • Case 1 Ms. Zhang, 65 years old, was previously diagnosed with Crohn's disease, a type of inflammatory bowel disease, by the hospital and applied the dipyridamole cream of this application externally.
  • dipyridamole topical preparation of the present application can be absorbed transdermally, can be anti-inflammatory and analgesic, and can be used to prevent and treat inflammatory bowel disease and prevent its progression to colorectal cancer.
  • Gynecological inflammation vulvar pruritus, dysmenorrhea, mastitis:
  • Case 1 Ms. Zhang, 33 years old, had vulvar itching for several days, which tended to become more and more itchy and accompanied by more and more small red rashes. She used dipyridamole gel (gel example 1) once each morning and evening after cleaning her vulva with clean water. After using it for 7 consecutive days, she reported that the antipruritic effect was good and lasted for a long time. She was cured after 7 days, indicating that the dipyridamole gel had certain anti-inflammatory and antibacterial effects, and also showed good compliance for patients with gynecological inflammation.
  • Case 1 Patient Liang, 46 years old, a teacher, often suffered from pharyngitis, dry throat, hoarseness, itching and occasional throat swallowing pain. He then insisted on trying the dipyridamole gel of the present application (gel embodiment 5), evenly applied it on the external skin of the affected area, once in the morning and once in the evening, for 2 months. Feedback: the symptoms of itchy throat were significantly improved, hoarseness and pain were also significantly improved, and the number of attacks was greatly reduced after discontinuation of use.
  • Case 1 Patient Zhang, female, 5 years old, was infected with hand, foot and mouth disease. Small blisters appeared on her hands, neck and face.
  • the dipyridamole cream of the present application (cream example 1) was applied externally to the affected area, once in the morning and evening, for 7 days. The rash and blisters disappeared, and the patient recovered without any adverse reactions.
  • Case 2 Qi, male, 13 years old, had an obvious round red patch with a diameter of about 3 cm on his face, slightly scaly at the border, and itchy. He was diagnosed with fungal infection by the hospital. He applied dipyridamole cream (cream example 7) on time once in the morning and evening. After a follow-up visit, he was informed that the condition was significantly relieved and the antipruritic effect was outstanding after the fourth day of application of the cream. After continuous medication for 1 month, the symptoms disappeared and the skin was completely healed.
  • dipyridamole cream cream example 7

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Abstract

Sont divulguées l'utilisation de dipyridamole et une préparation de celui-ci dans la prévention et le traitement de maladies allergiques et/ou inflammatoires. Dans la présente demande, l'inventeur trouve pour la première fois qu'une utilisation externe de dipyridamole peut efficacement prévenir, aider au traitement ou traiter des maladies allergiques et/ou inflammatoires, telles que la conjonctivite allergique, la rhinite allergique, l'urticaire allergique, l'acné rosacée et l'acné, et des préparations externes telles qu'une crème de dipyridamole et un gel de dipyridamole sont développées et obtenues en conséquence, qui font rapidement effet, ont un effet de traitement remarquable, sont supérieures à un médicament positif commun, ont une sécurité élevée dans le corps humain, ne présentent pas d'effets secondaires à la fois dans des expériences humaines et animales, et peuvent être largement appliquées à n'importe quelle peau du corps humain, en particulier une peau à haute sensibilité telle que le visage. De plus, en optimisant une formule, il a été découvert que l'ajout d'éther monoéthylique de diéthylène glycol et de polyéthylène glycol-7-stéarate peut améliorer significativement la perméabilité du dipyridamole et les effets de traitement et de prévention de celui-ci sur des maladies.
PCT/CN2023/135865 2022-12-16 2023-12-01 Dipyridamole pour prévenir et traiter des maladies allergiques et/ou inflammatoires et sa préparation Ceased WO2024125322A1 (fr)

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