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WO2002040029A2 - Adduits de corticosteroides comprenant des polymeres polysaccharidiques naturels - Google Patents

Adduits de corticosteroides comprenant des polymeres polysaccharidiques naturels Download PDF

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Publication number
WO2002040029A2
WO2002040029A2 PCT/IB2001/002170 IB0102170W WO0240029A2 WO 2002040029 A2 WO2002040029 A2 WO 2002040029A2 IB 0102170 W IB0102170 W IB 0102170W WO 0240029 A2 WO0240029 A2 WO 0240029A2
Authority
WO
WIPO (PCT)
Prior art keywords
adduct
aqueous solution
water
solution
freeze
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2001/002170
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English (en)
Other versions
WO2002040029A3 (fr
Inventor
Piergiorgio Anzaghi
Rosanna Stefli
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.)
PHARMA BIOTECH Ltd
Original Assignee
PHARMA BIOTECH Ltd
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Filing date
Publication date
Application filed by PHARMA BIOTECH Ltd filed Critical PHARMA BIOTECH Ltd
Priority to AU2002212630A priority Critical patent/AU2002212630A1/en
Publication of WO2002040029A2 publication Critical patent/WO2002040029A2/fr
Publication of WO2002040029A3 publication Critical patent/WO2002040029A3/fr
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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention concerns adducts of natural polysaccharide polymers with active ingredient belonging to the class of corticosteroids having improved therapeutic efficacy.
  • Natural corticosteroids are steroidal molecules produced and released from the adrenal cortex, some of which possess a hormonal activity. Among these the glucocorticoids act on the metabolism of the carbohydrates, lipids and proteins. Approximately 95% of the circulating hormone is bound to a globulin synthesized in the liver, while the remainder is available to realize its effects on target cells in which it binds to intracellular receptors. The macromolecular complex thus formed is then transported into the nucleus and interacts with the chromosomal constituents.
  • the number of natural and synthesized glucocorticoids, and esters thereof is constantly increasing.
  • the properties for which they find greatest application are their anti-inflammatory and immunosuppressor effect.
  • the former is due to the increase in neutrophils and the decrease in lymphocytes, monocytes, eosinophils and basophils, but it is also due to the lower release of histamine from the basophils, and to the reduction of bacterial toxins and quinines involving a decrease in the capillary permeability.
  • the control of rejection is caused by the decreased release of antigen from the implanted tissue and by the delayed vascularization.
  • they are frequently used in the case of anaphylactic reactions, in asthma, in tissue and ligament inflammations, in rejections and in dermatological disorders.
  • Such properties have stimulated the research and development of synthesized steroids of different strength and action duration depending on the therapy to be performed.
  • They can reduce the production of antibodies and considerably increase the production of acid and pepsin in the stomach, causing peptic ulcers.
  • the glucocorticoids used as anti-inflammatories are not, in any case, able to cure the pathological process, therefore its administration should be reduced to a minimum because of the widespread toxic effects that are dose-dependent.
  • the Applicant has now surprisingly found some adducts of corticosteroids with polysaccharide polymers, characterized in that the percentage of said corticosteroids in the adduct is between 40 and 80% in weight as regards the total weight of the adduct.
  • the adducts according to the present invention are in powder form or in aqueous solution that preferably contains them in a concentration of between 0.2 and 20% by weight calculated on the total weight of the aqueous solution.
  • the present invention further relates to the process for preparing the aforesaid adducts which, in particular, comprises the following steps: a) preparing the solution of the polysaccharide polymer in water in a percentage of between 20 and 60% by weight on the total weight of the adduct and adding afterwards the corticosteroid in salified form, so that the adduct concentration in the final aqueous solution is preferably comprised between the aforesaid intervals; b) filtering the aqueous solution thus obtained, thereby achieving the adduct in aqueous solution form; c) removing water thereby obtaining the adduct in powder form according to the present invention.
  • An additional object of the present invention are pharmaceutical compositions containing the adducts object of the present invention in association conjunction with suitable excipients and/or diluents.
  • adducts are described formed by of a cortisonic active ingredient bound to a natural and biocompatible polysaccharide, these substance being able to interact without forming covalent and ionic bonds.
  • the selected drugs are the water soluble esters of hydrocortisone, methylprednisolone, betamethasone and of dexamethasone, preferably used are hydrocortisone 21-emisuccinate, methylprednisolone 21-emisuccinate and methylprednisolone 21 -phosphate, betamethasone 21 -phosphate and the dexamethasone 21 -phosphate.
  • Hydrocortisone 21-emisuccinate can be administered intramuscularly and intravenously at doses of 100-500 mg/die.
  • the acetate or butyrate type esters are only limited to topical use since they are insoluble.
  • Methylprednisolone as such is orally administered, in the form of 21-emisuccinate, parenterally with attack doses of 20-40 mg/die, whereas as an acetate ester it is used for slow release injectable forms and for cutaneous applications.
  • Betamethasone 21 -phosphate is used parenterally at doses of 1.5-4 mg.
  • dipropionate, valerate, valeroacetate and benzoate it is insoluble and therefore cannot be used for injectable purposes.
  • Dexamethasone is a powerful analogue of cortisol and depending on the ester used it is available for systemic or topical use.
  • dexamethasone 21- phosphate is administered by intramuscular or intravenous parenteral route in doses of 4-8 mg/die or for cutaneous, ophthalmological and otorhinolaryngological use in percentages of 0.1-0.2%.
  • the percentage of corticosteroids and in particular glucocorticoids is preferably 60% calculated on the total adduct weight.
  • the natural polysaccharide polymers dextrans, inulin and, for oral preparations maltodextrins of pharmaceutical grade are preferred.
  • Dextrans are polymers formed by linear chains of ⁇ -D - glucose molecules and present very different molecular weights, ranging from 1000 Dalton (dextran 1) to 110000 Dalton (dextran 110) and do not undergo enzymatic degradation. Hydrophilia and therefore the solubility in water decreases by increasing the molecular weight. Dextrans with molecular weights lower than 4000 are completely excreted in the urine within 48 hours, while those having higher molecular weights remain in circulation for longer periods of time. The dextrans of from 4 to 70 are preferred in the present invention.
  • Maltodextrins are formed by a branched polymer of maltose and dextrins in which the D-glucose units are mainly bound by ⁇ bond (1-4), but also ⁇ (1-6) in the branched sections. They have molecular weights varying between 900 and 9000 Dalton. Also inulin is a natural linear structure polysaccharide consisting of fructose molecules with a molecular weight of 5000, it does not undergo enzymatic degradation and is excreted in the urine, so that it is used in the medical field as a diagnostic means of renal functionality. The selected natural polysaccharides are therefore biocompatible and inert and therefore their adducts with glucocorticoids. In particular, dextran 5 and inulin were used in the present invention.
  • the preparation of the adducts envisages the solution of the polymer in water, in a percentage of between 20 to 60% as regards the total of the adduct, and the subsequent addition of the corticosteroid in salified form, allowing the hydrophilic interaction of hydroxylic groups of the active principles with those of the numerous polymer.
  • hydrogen type bonds are formed weaker than covalent or ionic type bonds (Remington's Pharmaceutical Science 18 th ed. p. 186).
  • the polymer and the drug are dissolved in distilled water in the presence of buffers and preservatives if necessary, filtering is performed to obtain a clear solution.
  • the solvent is removed from the adduct through a process of freeze-drying or nebulization (spray drier) obtaining the adduct in solid form.
  • freeze-drying or nebulization spray drier
  • nebulization spray drier
  • the solution is filtered, with filters of 0.1 to 0.2 ⁇ m porosity, then placed in depyrogenated and sterilized phialoids in a sterile environment, and preferably freeze-dried.
  • the solution is thus able to be quickly reconstituted with the addition of an aqueous solvent such as w.f.p. water or physiological solution.
  • Distilled water is used for the preparation of oral forms and the solution is filtered on filters of 0.45 ⁇ m porosity.
  • the solvent is removed preferably through nebulization, as a solid and a porous adduct is obtained, suitable for the preparation of oral use pharmaceutical forms, such as tablets, capsules and granules.
  • the adducts in the form of aqueous solutions according to the present invention can be prepared with a process that in particular comprises the following steps: a') dissolving the active ingredient in distilled water, b') filtering the aqueous solution coming from the previous step, c') removing water, preferably by freeze-drying, from the product obtained in the previous step, d') reconstituting the aqueous solution by the addition of water or other w.f.p. solvent., in which the polysaccharide polymer is dissolved, so that the concentration of the adduct in said aqueous solution is preferably between 0.2 and 20% in weight.
  • an adduct with a low molecular weight polysaccharide can increase the solubility of a poorly soluble corticosteroid and accordingly, if orally administered its bioavailability.
  • an adduct with a high molecular weight polysaccharide can prolong the time the drug remains in circulation and therefore its effect.
  • the presence of reduced doses of active ingredient reduces the toxicity with equal anti-inflammatory activity.
  • the adducts of the present invention are obtained with simple, quick and economic processes if compared to the traditional synthetic approaches, which envisage the formation of a covalent bond between the corticosteroid and the polymer, and therefore they also result less expensive.
  • dextran 5 4 g are dissolved under strong shirring in 40 ml of w.f.p. water and maintained at 55°C, by means of a thermostat. 7.7 g of hydrocortisone emisuccinate acid are added salifying with 1.4 g of sodium bicarbonate and buffering to pH 7.35 with bibasic sodium phosphate. Then the final volume is adjusted to 60 ml with w.f.p. water and the solution, brought to room temperature of 20-25°C, is filtered with a 0.2 ⁇ m porosity sterilizing filter and placed in depyrogenated and sterilized vials, in a ratio of 3 ml/vial.
  • the vials containing the adduct solution of the previous example are finally placed in a freeze-dryer programmed to perform a freeze-drying cycle at the following temperatures: -33°C for 6 hours, -10°C for 5 hours, +25°C for 7 hours and +42°C for 10 hours; the vacuum is kept at 4.410 "2 mbar.
  • the liophylized adduct is compact, white in colour, and is readily soluble with the addition of 3 ml of w.f.p. water.
  • the hydrocortisone content by weight in the adduct, determined with the HPLC method described in example 1 is 59.6%
  • EXAMPLE 3 Preparation of the solution of the adduct: 50% methylprednisolone 21-emisuccinate - 50% dextran.
  • dextran 5 800 mg are dissolved in approx. 30 ml of w.f.p. distilled water and added with 1 g of buffered methylprednisolone sodium succinate, corresponding to 800 mg of methylprednisolone.
  • the solution is then brought to 40 ml, filtered with a 0.2 ⁇ m sterilizing filter, placed in vials a maintaining a filling of 1 ml for each vial.
  • EXAMPLE 4- Preparation of the solid adduct: 50% methylprednisolone 21- emisuccinate - 50% dextran.
  • the vials of the adduct prepared as described in example 3 are set in a freeze- dryer programmed to perform the freeze-drying cycle already described in example 2.
  • the liophylized dried substance is compact, titrated with the HPLC method described in example 3 and has a methylprednisolone content of 50.2%, and with the addition of 1 ml of w.f.p. water readily reconstitutes an injectable solution containing 20 mg of active ingredient.
  • EXAMPLE 5 Preparation of the solution of the adduct: 50% methylprednisolone 21-emisuccinate - 50% inulin. 1 g of buffered methylprednisolone sodium succinate, equal to 800 mg of methylprednisolone is dissolved in approx 50 ml of distilled w.f.p. water. The solution is then brought to 80 ml and filtered with a 0.2 ⁇ m sterilizing filter, placed in sterile and depyrogenated vials, maintaining a filling of 2 ml for each vial and freeze-dried as in example 2.
  • the freeze-dried adduct titrated with the HPLC method described in example 3, has a content in methylprednisolone of 50%.
  • 40 mg of adduct are constituted by 50% of active ingredient.
  • EXAMPLE 6 Preparation of the solution of the adduct: 60% dexamethasone 21- phosphate - 40% dextran.
  • dexamethasone 21 phosphate 50 mg of sodium metabisulphite, 50 mg of phenol and 32 mg of dextran 5 are solubilized in a volume of approx. 10 ml water
  • disodic dexamethasone 21 phosphate 48 mg dexamethasone 21 phosphate
  • the dexamethasone 21- phosphate titre is 60.12% by weight in the adduct solution.
  • Hydrocortisone 21-emisuccinate and the corresponding adduct of example 1 were administered to cats with an acute attack of bronchial asthma, following the protocol proposed by the veterinary therapeutic manual SCIVAC (SCIVAC Editions 1995, pp. 273-74).
  • EXAMPLE 9 In vivo activity of the adduct with 50% methylprednisolone 21- emisuccinate Methylprednisolone 21-emisuccinate and the corresponding 50% active ingredient adduct of example 3 were administered to dogs with an acute attack of bronchial asthma, following the protocol proposed by M. Gogny and O. Souille in "The cough and its treatment in carnivores," Summa, 8, 1994, pp. 15-18. Approx 4 years old hybrid dogs of male gender were treated. More precisely 4 dogs were intravenously injected with 3 mg/Kg of methylprednisolone suspension, and 4 dogs with 3 mg/Kg of adduct. In both groups the attack dose decreased to 1.5 mg/Kg in the two day maintenance period. Clinical recovery was observed in all subjects.
  • EXAMPLE 10- In vivo activity of the adduct with 60% dexamethasone 21- phosphate
  • the dexamethasone 21-phosphate and the corresponding adduct containing 60% of active ingredient of example 6 were administered to cats with an acute attack of bronchial asthma, following the protocol proposed by M. Gogny and O. Souille in the "The cough and its treatment in carnivores", Summa, 8, 1994, pp. 15-18. 9 common European cats of male gender, and of varying ages between 2 and 5 years were treated. More precisely, 4 cats were intravenously injected with 1 mg/Kg of dexamethasone 21-phosphate, and 5 cats with 1 mg/Kg of adduct. In both groups, the attack dose decreased to 0.5 mg/Kg in the two day maintenance period. Remission of the clinical symptomatology of the cough was observed in all subjects.
  • adducts of the present invention between corticosteroids and natural polysaccharide polymers have shown, in the in vivo activity tests in cats and dogs, a clinical efficacy comparable to that of the active ingredient alone, although they contain it in lower amounts, thus reducing the cost of the therapy.
  • this adduct is obtained with a quick economic process and which is suitable for the subsequent preparation of parenteral forms and, with suitable excipients also of oral forms for the treatment of various inflammatory states and of anaphylactic reactions in animals and humans.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)

Abstract

L'invention concerne des adduits de polysaccharides naturels comprenant des médicaments corticostéroïdes sous forme de solutions aqueuses ou à l'état solide, sous forme de poudre. Ces adduits présentent une efficacité thérapeutique identique à celle de l'ingrédient actif seul utilisé dans les mêmes quantités. Ceux-ci présentent donc une toxicité inférieure pour une activé anti-inflammatoire égale. Ces nouveaux adduits sont obtenus par un processus de réalisation simple qui permet de réduire leur coût.
PCT/IB2001/002170 2000-11-17 2001-11-16 Adduits de corticosteroides comprenant des polymeres polysaccharidiques naturels Ceased WO2002040029A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002212630A AU2002212630A1 (en) 2000-11-17 2001-11-16 Corticosteroids adducts with natural polysaccharide polymers

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2000A002477 2000-11-17
IT2000MI002477A IT1319665B1 (it) 2000-11-17 2000-11-17 Addotti di corticosteroidi con polimeri polisaccaridici naturali.

Publications (2)

Publication Number Publication Date
WO2002040029A2 true WO2002040029A2 (fr) 2002-05-23
WO2002040029A3 WO2002040029A3 (fr) 2002-10-31

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PCT/IB2001/002170 Ceased WO2002040029A2 (fr) 2000-11-17 2001-11-16 Adduits de corticosteroides comprenant des polymeres polysaccharidiques naturels

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AU (1) AU2002212630A1 (fr)
IT (1) IT1319665B1 (fr)
WO (1) WO2002040029A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103705470A (zh) * 2014-01-06 2014-04-09 南通大学 一种负载甲强龙的纳米微球及其制备方法和应用
US9155700B2 (en) 2003-10-22 2015-10-13 Chiesi Farmaceutici S.P.A. Process for the preparation of pharmaceutical suspensions for inhalation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8904296D0 (sv) * 1989-12-21 1989-12-21 Pharmacia Ab Transdermal system
ES2059299T3 (es) * 1990-12-19 1997-10-01 Advanced Magnetics Inc Direccionado de agentes terapeuticos utilizando polisacaridos.
JP2920611B2 (ja) * 1995-12-11 1999-07-19 株式会社シーエーシー 皮膚炎の治療外用剤

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9155700B2 (en) 2003-10-22 2015-10-13 Chiesi Farmaceutici S.P.A. Process for the preparation of pharmaceutical suspensions for inhalation
CN103705470A (zh) * 2014-01-06 2014-04-09 南通大学 一种负载甲强龙的纳米微球及其制备方法和应用
CN103705470B (zh) * 2014-01-06 2015-06-17 南通大学 一种负载甲强龙的纳米微球及其制备方法和应用

Also Published As

Publication number Publication date
IT1319665B1 (it) 2003-10-23
WO2002040029A3 (fr) 2002-10-31
ITMI20002477A1 (it) 2002-05-17
AU2002212630A1 (en) 2002-05-27

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