WO1999033471A1 - A gel-form pharmaceutical preparation - Google Patents

A gel-form pharmaceutical preparation Download PDF

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Publication number
WO1999033471A1
WO1999033471A1 PCT/FI1998/001000 FI9801000W WO9933471A1 WO 1999033471 A1 WO1999033471 A1 WO 1999033471A1 FI 9801000 W FI9801000 W FI 9801000W WO 9933471 A1 WO9933471 A1 WO 9933471A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrocortisone
gellant
gel
formulation according
cellulose
Prior art date
Application number
PCT/FI1998/001000
Other languages
French (fr)
Inventor
Kirsi Katila
Veli-Matti Lehtola
Pertti Rantala
Original Assignee
Leiras Oy
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Leiras Oy filed Critical Leiras Oy
Priority to EP98962440A priority Critical patent/EP1047430A1/en
Priority to AU17607/99A priority patent/AU1760799A/en
Publication of WO1999033471A1 publication Critical patent/WO1999033471A1/en

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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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/38—Cellulose; Derivatives 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the invention relates to a corticosteroid-containing pharmaceutical preparation intended for topical use.
  • Corticosteroids constitute a large group of compounds with a pregnene or pregnadiene backbone and with versatile medical uses. In particular they are used topically as anti-inflammatory dermatological medicines.
  • Examples of corticosteroids on the market include hydrocortisone, dexamethasone, betamethasone, methylprednisolone, prednisolone, prednisone, beclomethasone, fludrocortisone, triamsinolone, desonide, fluprednidene, clobetasone, alclomethasone, momethasone, desoxymethasone, fluosinonide, budesonide and fluosinolone .
  • ester-form glucocorticoids such as betamethasonide propionate
  • Carbomer i.e. carboxyvinyl polymer
  • Hydrocortisone gels are not available on the market. Attempts to prepare a hydrocortisone gel by using conventional gellants such as Carbomer polymer have failed owing to the poor stability of hydrocortisone.
  • a corticosteroid-containing pharmaceutical formulation according to the invention is characterized in that the formulation has been brought to gel form by means of a gellant, the gellant being hydroxyalkyl cellulose.
  • the corticosteroid may be any pharmaceutically acceptable corticosteroid.
  • the corticosteroid is hydrocortisone.
  • the hydroxyalkyl cellulose used as the gellant is hydroxyethyl cellulose or hydroxypropyl cellulose, in particular hydroxyethyl cellulose.
  • the solvent used is preferably a mixture of water and a lower alcohol, such as ethanol or propanol.
  • a mixture of water and ethanol or of water and isopropanol is especially preferable .
  • Glycerol or propylene glycol is preferably added to the formulation in order to prevent skin drying caused by the alcohol (ethanol).
  • alcohol ethanol
  • some oil component such as Cetiol SN (cetearyl- isononanoate)
  • suitable perfumes and preservatives include methylparahydroxybenzoate, propyl- parahydroxybenzoate and benzyl alcohol.
  • hydrocortisone-containing gel batches I, II, III and IV were prepared. Batches I and II were prepared on a laboratory scale (1000 g/batch) and batches III and IV were prepared on an industrial scale (150 kg/batch). The soft gels were packed into polyethylene tubes. The stability of the gels was monitored for 18 months (batch I), 12 months (batch II) and 3 months (batches III and IV).
  • the gels were prepared as follows: HEC was added to a mixture of water and ethanol (containing only a portion of the ethanol) while stirring, and the mixture was allowed to gel. Thereafter the glycerol was added while stirring. The balance of the ethanol was added while stirring. Thereafter the active ingredient was added to the gel while stirring.
  • the batches were stored at a relative humidity of 60 %.
  • the temperature was 25 °C (batches I, III and IV) and respectively 20 °C (batch II).
  • the amount of degradation products may be at maximum 5 %, the amount of hydrocortisone should be 9.0 - 11.0 mg/g, and the pH should be 5 - 8.5.
  • hydrocortisone gel formulations A, B, C and D were prepared, in which the gellant used was carboxyvinyl polymer Carbomer 980 or Carbomer 940, or polymer Stabileze R QM, which is a copolymer of methylvinyl ether and maleic acid anhydride, cross- bridged with 1 , 9-decadiene .
  • These gellants yield a very low pH value (the pH of a 1 % aqueous dispersion of Carbomer polymer is 2.5 - 3.0), and therefore sodium hydroxide was added to adjust the pH to the desired range.
  • the auxiliary compositions and hydrocortisone concentrations of the preparations are shown in Table 1, which also shows the stabilities of the preparations .
  • Table 1 shows that, already after three months of storage, a large quantity of degradation products of hydrocortisone had formed. After six months of storage the concentration of hydrocortisone degradation products in preparations A, B and D clearly exceeded the guideline values (guideline value at maximum 5 % ) , and the concentration of degradation products in preparation C was also very high (4 %).

Abstract

The invention relates to a pharmaceutical formulation which contains a corticosteroid and a solvent. According to the invention the formulation is brought to gel form by using a gellant which is a hydroxyalkyl cellulose, in particular hydroxyethyl cellulose or hydroxypropyl cellulose.

Description

A GEL-FORM PHARMACEU ICAL PREPARATION
The invention relates to a corticosteroid-containing pharmaceutical preparation intended for topical use.
Corticosteroids constitute a large group of compounds with a pregnene or pregnadiene backbone and with versatile medical uses. In particular they are used topically as anti-inflammatory dermatological medicines. Examples of corticosteroids on the market include hydrocortisone, dexamethasone, betamethasone, methylprednisolone, prednisolone, prednisone, beclomethasone, fludrocortisone, triamsinolone, desonide, fluprednidene, clobetasone, alclomethasone, momethasone, desoxymethasone, fluosinonide, budesonide and fluosinolone .
Common forms of preparations include solutions, ointments, creams and liniments. Certain ester-form glucocorticoids , such as betamethasonide propionate, have also been prepared as a gel in which Carbomer, i.e. carboxyvinyl polymer, has been used as the gellant.
Hydrocortisone gels are not available on the market. Attempts to prepare a hydrocortisone gel by using conventional gellants such as Carbomer polymer have failed owing to the poor stability of hydrocortisone.
We have now observed, surprisingly, that by using hydroxyalkyl cellulose, in particular hydroxyethyl cellulose, as the gellant, very stable corticosteroid gels are obtained.
The characteristics of the invention are given in Claim 1.
A corticosteroid-containing pharmaceutical formulation according to the invention is characterized in that the formulation has been brought to gel form by means of a gellant, the gellant being hydroxyalkyl cellulose.
The corticosteroid may be any pharmaceutically acceptable corticosteroid. Preferably the corticosteroid is hydrocortisone.
According to a preferred embodiment, the hydroxyalkyl cellulose used as the gellant is hydroxyethyl cellulose or hydroxypropyl cellulose, in particular hydroxyethyl cellulose.
The solvent used is preferably a mixture of water and a lower alcohol, such as ethanol or propanol. A mixture of water and ethanol or of water and isopropanol is especially preferable .
Glycerol or propylene glycol is preferably added to the formulation in order to prevent skin drying caused by the alcohol (ethanol). For this purpose it is also possible to add some oil component, such as Cetiol SN (cetearyl- isononanoate) . It is also possible to add suitable perfumes and preservatives. Examples of suitable preservatives include methylparahydroxybenzoate, propyl- parahydroxybenzoate and benzyl alcohol.
The invention is described in greater detail with the help of the following, non-limiting examples.
Example 1
Hydrocortisone gels in which hydroxyethyl cellulose (HEC) is used as the gellant
Four hydrocortisone-containing gel batches I, II, III and IV were prepared. Batches I and II were prepared on a laboratory scale (1000 g/batch) and batches III and IV were prepared on an industrial scale (150 kg/batch). The soft gels were packed into polyethylene tubes. The stability of the gels was monitored for 18 months (batch I), 12 months (batch II) and 3 months (batches III and IV). The gels were prepared as follows: HEC was added to a mixture of water and ethanol (containing only a portion of the ethanol) while stirring, and the mixture was allowed to gel. Thereafter the glycerol was added while stirring. The balance of the ethanol was added while stirring. Thereafter the active ingredient was added to the gel while stirring.
Gel compositions (mg/g):
Batches I, Batch II III and IV
Hydrocortisone 10.00 10.00
Hydroxyethyl cellulose 15.00 15.00 Glycerol (99.5 %) 60.00
Ethanol (96 %) 500.00 500.00
Purified water 415.00 475.00
Stability tests:
The batches were stored at a relative humidity of 60 %. The temperature was 25 °C (batches I, III and IV) and respectively 20 °C (batch II).
According to the objective, the amount of degradation products may be at maximum 5 %, the amount of hydrocortisone should be 9.0 - 11.0 mg/g, and the pH should be 5 - 8.5. Results:
Batch I
Period of storage Degradation Hydrocortisone PH months products % mg/g
Beginning of test 0.6 10.2 7.5
3 months 0.7 10.1 5.8
7 2.3 10.1 5.7
12 " 1.9 10.1 5.7
18 " 1.9 9.5 5.7
Batch II
Period of storage Degradation Hydrocortisone PH months products % mg/g
Beginning of test *) *) *)
12 months 2.2 10.3 5.6
*) not determined
Batch III
Period of storage Degradation Hydrocortisone pH months products % mg/g
Beginning of test 0.6 10.3 6.6
3 months 0.7 9.8 6.8
Batch IV
Period of storage Degradation Hydrocortisone pH months products % mg/g
Beginning of test 0.55 10.2 7 3 months 0.8 10.2 7 The results show that all of the batches remained well within the guideline values as regards hydrocortisone concentration, hydrocortisone degradation products and pH .
Example 2
Hydrocortisone gels in which Carbomer or Stabileze polymer was used as the gellant
For the sake of comparison, four hydrocortisone gel formulations A, B, C and D were prepared, in which the gellant used was carboxyvinyl polymer Carbomer 980 or Carbomer 940, or polymer StabilezeR QM, which is a copolymer of methylvinyl ether and maleic acid anhydride, cross- bridged with 1 , 9-decadiene . These gellants yield a very low pH value (the pH of a 1 % aqueous dispersion of Carbomer polymer is 2.5 - 3.0), and therefore sodium hydroxide was added to adjust the pH to the desired range. The auxiliary compositions and hydrocortisone concentrations of the preparations are shown in Table 1, which also shows the stabilities of the preparations .
Table 1 shows that, already after three months of storage, a large quantity of degradation products of hydrocortisone had formed. After six months of storage the concentration of hydrocortisone degradation products in preparations A, B and D clearly exceeded the guideline values (guideline value at maximum 5 % ) , and the concentration of degradation products in preparation C was also very high (4 %).
The examples given above clearly show that highly stable hydrocortisone gels are obtained by using hydroxyethyl cellulose as the gellant. Although test results have not been presented, it can be assumed that corresponding results would be obtained also with respect to other corticosteroids and when using other hydroxyalkyl celluloses, in particular hydroxypropyl cellulose. Table 1
Figure imgf000008_0001
Figure imgf000008_0002
The above embodiments of the invention are only examples of the implementation of the idea of the invention. For a person skilled in the art it is clear that the various embodiments of the invention may vary within the claims presented below.

Claims

1. A pharmaceutical formulation comprising a corticosteroid and a solvent, characterized in that the formulation has been brought to gel form by using a gellant, the gellant being a hydroxyalkyl cellulose.
2. A formulation according to Claim 1, characterized in that the corticosteroid is hydrocortisone.
3. A formulation according to Claim 1 or 2, characterized in that the hydroxyalkyl cellulose is hydroxyethyl cellulose or hydroxypropyl cellulose.
4. A formulation according to Claim 1, 2 or 3 , characterized in that the solvent is a mixture of water and a lower alcohol .
5. A formulation according to any of the above claims, characterized in that the corticosteroid is hydrocortisone, the gellant is hydroxyethyl cellulose, and the solvent is a mixture of water and ethanol .
6. A formulation according to Claim 5, characterized in that it additionally contains glycerol.
7. A formulation according to Claim 5 or 6 , characterized in that it additionally contains propylene glycol.
8. A formulation according to Claim 5, characterized in that it contains approx. 0.1 % by weight hydrocortisone and 1 - 2 % by weight hydroxyethyl cellulose.
PCT/FI1998/001000 1997-12-23 1998-12-21 A gel-form pharmaceutical preparation WO1999033471A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP98962440A EP1047430A1 (en) 1997-12-23 1998-12-21 A gel-form pharmaceutical preparation
AU17607/99A AU1760799A (en) 1997-12-23 1998-12-21 A gel-form pharmaceutical preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI974610 1997-12-23
FI974610A FI974610A0 (en) 1997-12-23 1997-12-23 Pharmaceutical preparations in gelform

Publications (1)

Publication Number Publication Date
WO1999033471A1 true WO1999033471A1 (en) 1999-07-08

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ID=8550206

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FI1998/001000 WO1999033471A1 (en) 1997-12-23 1998-12-21 A gel-form pharmaceutical preparation

Country Status (5)

Country Link
EP (1) EP1047430A1 (en)
AU (1) AU1760799A (en)
DK (1) DK200200342U3 (en)
FI (1) FI974610A0 (en)
WO (1) WO1999033471A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7862552B2 (en) 2005-05-09 2011-01-04 Boston Scientific Scimed, Inc. Medical devices for treating urological and uterine conditions
US8277780B2 (en) 2005-05-27 2012-10-02 Taro Pharmaceutical North America, Inc. Stable liquid desoximethasone compositions with reduced oxidized impurity
US8617578B2 (en) 2003-08-22 2013-12-31 L'oreal Compositions containing topical-active agents and pentyleneglycol

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3899580A (en) * 1972-06-30 1975-08-12 Merck & Co Inc Anti-inflammatory topical gel
US4267173A (en) * 1979-11-05 1981-05-12 Schering Corporation Use of 6β-fluoro-7α-halogenocorticoids as topical anti-inflammatories and pharmaceutical formulations useful therefor
US4604384A (en) * 1982-06-24 1986-08-05 Smith Robert A Pharmaceutical gel composition
WO1988009174A1 (en) * 1987-05-21 1988-12-01 Schering Corporation Steroid lotion
US4866050A (en) * 1988-04-27 1989-09-12 Ben Amoz Daniel Ultrasonic transdermal application of steroid compositions
US5110809A (en) * 1988-03-21 1992-05-05 Bristol-Myers Squibb Company Antifungal gel formulations

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3899580A (en) * 1972-06-30 1975-08-12 Merck & Co Inc Anti-inflammatory topical gel
US4267173A (en) * 1979-11-05 1981-05-12 Schering Corporation Use of 6β-fluoro-7α-halogenocorticoids as topical anti-inflammatories and pharmaceutical formulations useful therefor
US4604384A (en) * 1982-06-24 1986-08-05 Smith Robert A Pharmaceutical gel composition
WO1988009174A1 (en) * 1987-05-21 1988-12-01 Schering Corporation Steroid lotion
US5110809A (en) * 1988-03-21 1992-05-05 Bristol-Myers Squibb Company Antifungal gel formulations
US4866050A (en) * 1988-04-27 1989-09-12 Ben Amoz Daniel Ultrasonic transdermal application of steroid compositions

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8617578B2 (en) 2003-08-22 2013-12-31 L'oreal Compositions containing topical-active agents and pentyleneglycol
US7862552B2 (en) 2005-05-09 2011-01-04 Boston Scientific Scimed, Inc. Medical devices for treating urological and uterine conditions
US8277780B2 (en) 2005-05-27 2012-10-02 Taro Pharmaceutical North America, Inc. Stable liquid desoximethasone compositions with reduced oxidized impurity
US8715624B2 (en) 2005-05-27 2014-05-06 Taro Pharmaceuticals North America, Inc. Stable liquid desoximethasone compositions with reduced oxidized impurity

Also Published As

Publication number Publication date
AU1760799A (en) 1999-07-19
FI974610A0 (en) 1997-12-23
DK200200342U3 (en) 2003-02-28
EP1047430A1 (en) 2000-11-02

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