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WO2021010920A1 - A stable composition comprising tetracyclin and tretinoin for topical acne treatment - Google Patents

A stable composition comprising tetracyclin and tretinoin for topical acne treatment Download PDF

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Publication number
WO2021010920A1
WO2021010920A1 PCT/TR2020/050574 TR2020050574W WO2021010920A1 WO 2021010920 A1 WO2021010920 A1 WO 2021010920A1 TR 2020050574 W TR2020050574 W TR 2020050574W WO 2021010920 A1 WO2021010920 A1 WO 2021010920A1
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Prior art keywords
tretinoin
weight
amount
pharmaceutical composition
composition
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Ceased
Application number
PCT/TR2020/050574
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French (fr)
Inventor
Mehmet Koray GÜRBÜZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Assos Ilac Kimya Gida Ueruenleri Ueretim Ve Ticaret AS
Original Assignee
Assos Ilac Kimya Gida Ueruenleri Ueretim Ve Ticaret AS
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Publication of WO2021010920A1 publication Critical patent/WO2021010920A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • 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
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents

Definitions

  • the present invention relates to the preparation of a stable topical composition effective in the treatment of acne containing the active substance of tetracycline and tretinoin.
  • Said composition is characterized by being stable in water- free environments.
  • Acne vulgaris also known as pimple, is a skin disease characterized by blisters, comedones (blackheads), inflammatory blisters in severe cases, inflammatory lesions, nodules and cysts located in the hair follicle. Symptoms related to acne vulgaris mostly occur on the face, upper part of the body and back, where the sebaceous glands are dense.
  • Topical antibiotics are one of the most effective drugs against Propionibacterium acnes bacteria, which is one of the factors affecting acne formation. Erythromycin, tetracycline, doxycycline and clindamycin, which are among the topical antibiotics, are widely used in the treatment of acne and are especially effective in mild and moderate inflammatory acne. Apart from these, fucidic acid, mupirocin, oxytetracycline, nadifloxazin, polymycin are used.
  • Creams with retinoids can be used alone or in combination with other acne medications.
  • the first option in acne with comedones is topical retinoids such as retinoic acid, tretinoin, isotretinoin and adapalene.
  • Tetracycline hydrochloride ointment is an antibiotic that acts against skin infections caused by bacteria. It prevents bacteria from growing and reproducing on the skin. It penetrates into acute pimples with red-pink blisters that have formed (purulent) or have just begun to form and dries the inflammation. 100 grams of ointment contains 3.0g Tetracycline hydrochloride.
  • Tretinoin prevents the formation of acne lesions, stimulates the follicular epithelium and accelerates the proliferation of non-adherent keratinocytes. These free horn-like cells are discharged to the skin surface with sebum. These horn-like cells cannot cling together and form a plug. Thus, formation of new acne lesions is prevented.
  • Tretinoin also helps in the expulsion of comedones, micro-cysts that cause retention in the follicle. Apart from the superficial desquamation of the epidermis, tretinoin also acts deep within the follicle. These free horn-like cells stimulate the proliferation of cells, preventing the adhesion of these cells and thus the formation of plugs, while also excreting micro-cysts and comedones.
  • US2010029765 relates to the topical combination of tretinoin and lincomycins, lincomycin derivatives, erythromycin, erythromycin derivatives, tetracycline, tetracycline derivatives and their acceptable salts, esters or prodrugs.
  • antibiotic is clindamycin or an acceptable salts thereof.
  • composition prepared in oily ointment base is superior in terms of stability compared to the hydrophilic ointment base.
  • the major degradation products of tetracycline are 4-epithetracycline (4-ETC), 4- epianhydrotetracycline (4-EATC) and anhydrotetracycline (ATC) compounds.
  • Isotretinoin has been accepted as the critical impurity for tretinoin.
  • Hydrocarbon-based ointment bases are intended as the oil phase in the composition of the composition of the invention.
  • This group of ointment bases are not soluble in water, washed with water and do not contain water. They do not absorb water, they are emollient and occlusive. They are suitable for hydrolysis -prone drugs because they are oleaginosis (oily).
  • Such oily ointment bases are petrolatum, solid paraffin, plastibase, beeswax, spermaceti, carnauba wax, and white petrolatum is chosen as oily ointment base for the composition.
  • Medium chain triglycerides were chosen as the solvent in the composition.
  • Medium chain triglycerides also known as "Caprylic/Capric Triglyceride, Octanoic/Decanoic Acid Triglyceride, MCT Coconut Oil" contains saturated fatty acids with C8 and CIO carbon.
  • Medium chain triglycerides have a variety of commercial products that can be used as a solvent in topical preparations such as Kollisolv® MCT (formerly known as Myritol® 318 PH).
  • the composition may contain colouring agents. Titanium dioxide is used as a colouring agent in the composition of the invention. Apart from titanium dioxide, iron oxides can be present in the composition.
  • the present invention is an easily applicable combination of tetracycline and tretinoin that allows the active ingredients to be formulated without stability issues.
  • the object of the invention is to obtain a stable tetracycline and tretinoin topical combined composition to be used in the treatment of acne.
  • Tetracycline and tretinoin topical combined composition has been developed in oily ointment base in accordance with its intended use in the treatment of acne.
  • the amount of tetracycline is approximately 3% by weight (w/w) and the amount of tretinoin is approximately 0.5% by weight (w/w).
  • the amount of white petrolatum in the composition is 50 to 70%, preferably 60 to 70%, more preferably 65-70% by weight (w/w).
  • the amount of medium chain triglyceride used as solvent in the composition is 20 to 40%, preferably 20 to 30% by weight (w/w).
  • the amount of titanium dioxide used as a colouring agent in the composition is 4 to 8%, preferably 5 to 7%, more preferably approximately 6% by weight (w/w).
  • iron oxides can be present in the composition in less than 1% by weight (w/w).
  • composition comprises:
  • compositions of the present invention can be formulated with one or more pharmaceutically acceptable excipients.
  • the composition may comprise pharmaceutically acceptable excipients such as viscosity enhancers, penetration enhancers, surfactants, antimicrobial preservatives, antioxidants, chelate compounds, fragrances in addition to ointment bases, solvents and colouring agents.
  • the topical combined composition of the stable tetracycline and tretinoin, which is the present invention, is for use in the treatment and prevention of acne.
  • the clinical study of the composition is foreseen in the treatment of acne vulgaris under conditions of Good Clinical Practices (GCPs).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a pharmaceutical composition topically used for the treatment of acne, the amount of tetracycline is approximately 3% by weight (w/w), the amount of tretinoin is approximately 0.5% by weight (w/w) and it comprises white petrolatum as oily ointment base, medium chain triglyceride as a solvent.

Description

A STABLE COMPOSITION COMPRISING TETRACYCLIN AND TRETINOIN FOR
TOPICAL ACNE TREATMENT
Technical Field
The present invention relates to the preparation of a stable topical composition effective in the treatment of acne containing the active substance of tetracycline and tretinoin. Said composition is characterized by being stable in water- free environments.
Prior Art
Acne (acne vulgaris), also known as pimple, is a skin disease characterized by blisters, comedones (blackheads), inflammatory blisters in severe cases, inflammatory lesions, nodules and cysts located in the hair follicle. Symptoms related to acne vulgaris mostly occur on the face, upper part of the body and back, where the sebaceous glands are dense.
Retinoids and antibiotics can be applied topically in the treatment of acne. Topical antibiotics are one of the most effective drugs against Propionibacterium acnes bacteria, which is one of the factors affecting acne formation. Erythromycin, tetracycline, doxycycline and clindamycin, which are among the topical antibiotics, are widely used in the treatment of acne and are especially effective in mild and moderate inflammatory acne. Apart from these, fucidic acid, mupirocin, oxytetracycline, nadifloxazin, polymycin are used.
Creams with retinoids can be used alone or in combination with other acne medications. The first option in acne with comedones is topical retinoids such as retinoic acid, tretinoin, isotretinoin and adapalene.
Tetracycline hydrochloride ointment is an antibiotic that acts against skin infections caused by bacteria. It prevents bacteria from growing and reproducing on the skin. It penetrates into acute pimples with red-pink blisters that have formed (purulent) or have just begun to form and dries the inflammation. 100 grams of ointment contains 3.0g Tetracycline hydrochloride.
Tretinoin prevents the formation of acne lesions, stimulates the follicular epithelium and accelerates the proliferation of non-adherent keratinocytes. These free horn-like cells are discharged to the skin surface with sebum. These horn-like cells cannot cling together and form a plug. Thus, formation of new acne lesions is prevented.
Tretinoin also helps in the expulsion of comedones, micro-cysts that cause retention in the follicle. Apart from the superficial desquamation of the epidermis, tretinoin also acts deep within the follicle. These free horn-like cells stimulate the proliferation of cells, preventing the adhesion of these cells and thus the formation of plugs, while also excreting micro-cysts and comedones.
US2010029765 relates to the topical combination of tretinoin and lincomycins, lincomycin derivatives, erythromycin, erythromycin derivatives, tetracycline, tetracycline derivatives and their acceptable salts, esters or prodrugs. Specifically indicated antibiotic is clindamycin or an acceptable salts thereof.
Description of the Invention
The suitability of oily or hydrophilic ointment base has been investigated as the carrier matrix that will preserve the combined topical preparations containing Tetracycline approximately 3% by weight (w/w) and tretinoin approximately 0,5% by weight, in a stable way during the shelf life under room conditions.
As a result of the researches, it has been seen that the composition prepared in oily ointment base is superior in terms of stability compared to the hydrophilic ointment base.
The major degradation products of tetracycline are 4-epithetracycline (4-ETC), 4- epianhydrotetracycline (4-EATC) and anhydrotetracycline (ATC) compounds. Isotretinoin has been accepted as the critical impurity for tretinoin.
Detailed Description of the Invention
Hydrocarbon-based ointment bases are intended as the oil phase in the composition of the composition of the invention. This group of ointment bases are not soluble in water, washed with water and do not contain water. They do not absorb water, they are emollient and occlusive. They are suitable for hydrolysis -prone drugs because they are oleaginosis (oily). Such oily ointment bases are petrolatum, solid paraffin, plastibase, beeswax, spermaceti, carnauba wax, and white petrolatum is chosen as oily ointment base for the composition.
Medium chain triglycerides were chosen as the solvent in the composition. Medium chain triglycerides, also known as "Caprylic/Capric Triglyceride, Octanoic/Decanoic Acid Triglyceride, MCT Coconut Oil", contains saturated fatty acids with C8 and CIO carbon. Medium chain triglycerides have a variety of commercial products that can be used as a solvent in topical preparations such as Kollisolv® MCT (formerly known as Myritol® 318 PH).
The composition may contain colouring agents. Titanium dioxide is used as a colouring agent in the composition of the invention. Apart from titanium dioxide, iron oxides can be present in the composition.
The present invention is an easily applicable combination of tetracycline and tretinoin that allows the active ingredients to be formulated without stability issues.
The object of the invention is to obtain a stable tetracycline and tretinoin topical combined composition to be used in the treatment of acne.
Tetracycline and tretinoin topical combined composition has been developed in oily ointment base in accordance with its intended use in the treatment of acne.
In a preferred embodiment of the invention, the amount of tetracycline is approximately 3% by weight (w/w) and the amount of tretinoin is approximately 0.5% by weight (w/w).
In a preferred embodiment of the invention, the amount of white petrolatum in the composition is 50 to 70%, preferably 60 to 70%, more preferably 65-70% by weight (w/w).
In another preferred embodiment of the invention, the amount of medium chain triglyceride used as solvent in the composition is 20 to 40%, preferably 20 to 30% by weight (w/w). In another preferred embodiment of the invention, the amount of titanium dioxide used as a colouring agent in the composition is 4 to 8%, preferably 5 to 7%, more preferably approximately 6% by weight (w/w). In addition, iron oxides can be present in the composition in less than 1% by weight (w/w).
In another preferred embodiment of the invention, the composition comprises:
Figure imgf000005_0001
The compositions of the present invention can be formulated with one or more pharmaceutically acceptable excipients. The composition may comprise pharmaceutically acceptable excipients such as viscosity enhancers, penetration enhancers, surfactants, antimicrobial preservatives, antioxidants, chelate compounds, fragrances in addition to ointment bases, solvents and colouring agents. The topical combined composition of the stable tetracycline and tretinoin, which is the present invention, is for use in the treatment and prevention of acne. The clinical study of the composition is foreseen in the treatment of acne vulgaris under conditions of Good Clinical Practices (GCPs). It has been confirmed by accelerated stability studies that the composition containing the oily ointment base subject to the invention is more stable than the water based ointment base. The stability results of the compositions containing hydrophilic ointment base and oily ointment base are presented below. Table 1. Oily Ointment Based Unit Formula:
Figure imgf000006_0001
Table 2. Stability Study of Oil Based Unit Formula at 25°C,60% RH
Figure imgf000006_0002
Table 3. Hydrophilic Ointment Based Unit Formula:
Figure imgf000006_0003
Figure imgf000007_0001
Table 4. Stability Study of Water Based Unit Formula at 25°C,60% RH
Figure imgf000007_0002
Clinical study of the developed stable oil-based composition is planned for products containing two mono active ingredients.

Claims

1) A pharmaceutical composition topically used for the treatment of acne, wherein the amount of tetracycline is approximately 3% by weight (w/w), and the amount of tretinoin is approximately 0.5% by weight (w/w), and it comprises white petrolatum as an oily ointment base.
2) Pharmaceutical composition according to Claim 1, wherein the amount of white petrolatum is 50 to 70% by weight (w/w).
3) Pharmaceutical composition according to Claim 2, wherein the amount of white petrolatum is 60 to 70% by weight (w/w).
4) Pharmaceutical composition according to any of the preceding claims, comprising medium chain triglyceride as a solvent.
5) Pharmaceutical composition according to Claim 4, wherein the amount of medium chain triglyceride as solvent is 20 to 40% by weight (w/w). 6) Pharmaceutical composition according to Claim 5, wherein the amount of medium chain triglyceride as a solvent is 20 to 30% by weight (w/w).
7) Pharmaceutical composition according to any of the preceding claims, comprising white petrolatum as oily ointment base, medium chain triglyceride as a solvent, wherein said composition has impurities of 4-ETC less than 3.0%, 4-EATC less than 1.0%, ATC less than 1.0% and impurity of isotretinoin less than 3.0% after being stored under 25°C60% conditions for at least 6 months.
PCT/TR2020/050574 2019-07-12 2020-07-03 A stable composition comprising tetracyclin and tretinoin for topical acne treatment Ceased WO2021010920A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2019/10426 2019-07-12
TR2019/10426A TR201910426A2 (en) 2019-07-12 2019-07-12 STABILITY FORMULATION WITH TETRASYCLIN AND TRETINOIN FOR TOPICAL ACNE TREATMENT

Publications (1)

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WO2021010920A1 true WO2021010920A1 (en) 2021-01-21

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5037655A (en) * 1990-04-18 1991-08-06 Giovanoni Richard L Method of stabilizing tretinoin
US20100029765A1 (en) * 2008-07-30 2010-02-04 Ranbaxy Labortories Limited Topical aqueous composition comprising tretinoin
US20160287614A1 (en) * 2013-11-20 2016-10-06 Lupin Limited Stable Pharmaceutical Formulation(s) of Tetracycline Antibiotic

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5037655A (en) * 1990-04-18 1991-08-06 Giovanoni Richard L Method of stabilizing tretinoin
US20100029765A1 (en) * 2008-07-30 2010-02-04 Ranbaxy Labortories Limited Topical aqueous composition comprising tretinoin
US20160287614A1 (en) * 2013-11-20 2016-10-06 Lupin Limited Stable Pharmaceutical Formulation(s) of Tetracycline Antibiotic

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
IPEK EROGLU ET AL.: "Liposome Based Combination Therapy for Acne Treatment", JOURNAL OF LIPOSOME RESEARCH, 26 June 2019 (2019-06-26), DOI: 10.1080/08982104.2019.1630646 *

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