HK1117044B - Stabilisation of glucocorticoid esters with acids - Google Patents

Description

Stabilization of glucocorticoid esters with acids

The invention relates to a non-aqueous pharmaceutical formulation comprising a glucocorticoid ester and an acid, and to the stabilization of the glucocorticoid ester in the formulation by the acid.

Since its synthetic preparation, glucocorticoids have been used in human and veterinary medicine for the treatment of infectious diseases. Chronic systemic administration leads to the so-called cushing's syndrome due to excessive blood levels of corticosteroids, manifested as full moon face, steroid acne, central obesity, hyperemia, cutaneous stretch marks (purple lines of the skin), essential hypertension, weakness, endocrine mental syndromes, osteoporosis, diabetes, impotence, menstrual disorders or menoxenia, hirsutism and hirsutism in women. In addition, there is an increased risk of infection or potential exacerbation of infection, gastric ulceration, and prolonged wound healing. Muscle, skin, and adipose tissue may atrophy due to catabolic effects. The risk of thrombosis increases.

In order to maintain low systemic exposure to glucocorticoids, local application of the active substance directly to the lesion site was attempted. Thus, the amount is only about 1-10% of the systemically administered dose. Skin inflammation is usually treated by topical administration of semi-solid (ointments, creams, gels) or liquid pharmaceutical forms (suspensions, emulsions, solutions) in which the glucocorticoid is dissolved or dispersed.

Besides glucocorticoids, glucocorticoid esters are also known.

Esterification of the hydroxyl groups on C17 and/or C21 increases the glucocorticoid activity. Higher lipophilicity allows easier cell entry. Simultaneously improving the stimulation to the skin. Thus, hydrocortisone is a weak glucocorticoid, whereas hydrocortisone-17-butyrate is a strong glucocorticoid. The same effect can also be seen with the following glucocorticoids: dexamethasone such as dexamethasone-21-acetate, betamethasone, and betamethasone-17-valerate.

Glucocorticoid esters are more or less sensitive to hydrolysis and are in this way converted into the corresponding corticosteroids which are less active and not esterified. This hydrolysis process occurs naturally, especially for topical pharmaceutical forms formulated in aqueous form. However, even in formulations that do not contain water, hydrolysis cannot be completely ruled out due to the absorption of water vapor from the surrounding environment. While packages that use moisture barrier properties tend to fail in view of aesthetic or economic considerations.

It is feasible to stabilize the corticoid esters by adjusting the pH in the weak acid range. Hydrolysis is inhibited at this time compared with the strongly acidic and neutral to alkaline pH ranges (Anderson BD et al, stratages in the design of solution-stable, water-soluble precursors I: a physical-organic reaction to pro-entity selection of 21-esters of cortico-acids, J.Pharm.Sci.74(4), 365-.

Also in powders containing corticoid esters, stabilization can be achieved by the addition of organic acids (Teijin Ltd., Powder pharmaceuticals for the purpose of treatment of organic cavity disorders, stabilizing steric inhibition of and organic acids stabilizers, JP 60028923; Teijin Ltd., Powder formulations for the purpose of coordination of branched lipids for the purpose of nasal mucosa application, JP 60032714). The above powder formulations contain significant amounts of water, which is introduced by other adjuvants, such as cellulose ethers. In addition, other water may be absorbed by the moisture of the ambient air. It is thus hypothesized that the pH of the aqueous layer subsequently attached to the powder particles is altered by the addition of acid and thereby stabilizes the corticosteroid ester.

The change of the aqueous pH by addition of organic or inorganic acids is of course only possible in the case of the aqueous or water-containing preparations described above. It has now surprisingly been found that glucocorticoids can also be stabilized against hydrolysis by adding an acid to the non-aqueous solution or dispersion medium, although the acid cannot be separated into the solution or dispersion medium.

The present invention therefore relates to a non-aqueous, fluid pharmaceutical formulation comprising at least one glucocorticoid ester and at least one acid.

Glucocorticoid esters are typically esters of glucocorticoids and organic acids, such as esters with carboxylic acids or carbon compounds. Preferably, the hydroxyl groups on C17, or C21 of the corticoid are esterified, it also being possible for both hydroxyl groups to be esterified. The acid component of the esters comes, for example, from saturated fatty carboxylic acids having up to 10, preferably up to 8, particularly preferably up to 6, carbon atoms. The following esters may be mentioned by way of example: acetate, propionate, butyrate, valerate, hexanoate, pivalate. Aceponat refers to a mixed propionate-acetate diester, and butyrate refers to a mixed butyrate-acetate diester. Also, esters derived from heterocyclic substituted carboxylic acids, such as furoate esters, are contemplated. Also suitable are mixed carbonates, which are obtained by introducing alkoxycarbonyl groups, preferably having 1 to 6 carbon atoms, of which ethoxycarboxyl groups are mentioned by way of example.

Examples of glucocorticoid esters are alclometasone propionate (Aclomeasonproprionat), betamethasone dipropionate, betamethasone valerate, clobetamethasone propionate, fluocinolone butyrate, clocortolone caproate, clocortolone pivalate, dexamethasone acetate, diflucortolone valerate, flumethasone pivalate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, fluticasone propionate, hydrocortisone butyrate, hydrocortisone propionate (hydrocortisone acetate), hydrocortisone acetate, hydrocortisone dipropionate (hydrocortisone), methylprednisolone acetate, mometasone furoate, prednisone ester and prednisolone acetate.

Fluid preparations are to be understood here as meaning, for example, solutions, suspensions, emulsions and the like, which can also have a semisolid consistency at higher viscosities (e.g. ointments, creams, gels and the like).

Non-aqueous formulations contain a matrix consisting of an organic solution or dispersion. Non-aqueous formulations within the scope of the present invention may also contain up to 1% (M/V), preferably up to 0.5% (M/V) of water, such as: in some cases the feed material itself contains a small amount of water. ("% (M/V") means the mass of the relevant substance in g per 100 ml of finished preparation).

The formulations of the invention may contain protic or aprotic solvents or dispersants, or a mixture of the two forms.

Mention may be made, as protic solvents or dispersants:

mono-or polyhydric alcohol: examples of monohydric alcohols are propanol, isopropanol, ethanol, butanol, isobutanol, 2-hexadecanol, benzyl alcohol, tetrahydrofurfuryl alcohol and octanol. Examples of polyols are glycerol, diethylene glycol, polyethylene glycol and 1, 2-propanediol.

The formulations of the present invention preferably contain an aprotic solvent or dispersant. The following are mentioned in particular:

alkanes such as hexane, paraffin and dioctyl cyclohexane.

Ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone.

Amides such as 2-pyrrolidone and N-methylpyrrolidone.

Mono-, di-and triglycerides (esters made with fatty acids and glycerol), for example, coconut oil caprylate/caprate, glyceryl monolinoleate, glyceryl monooleate, glyceryl ricinoleate, medium chain triglycerides, cottonseed oil, peanut oil, almond oil, sesame oil, olive oil, sunflower oil, safflower oil, rapeseed oil, glycerol-monostearate, glycerol distearate and soybean oil.

Esters prepared from fatty acids and monohydric alcohols, for example, 2-octyldodecyl myristate, cetearyl ethylhexanoate, cocodecyl oleate, decyl oleate, ethyl oleate, isohexadecyl palmitate, isopropyl myristate, isopropyl palmitate, isostearyl isostearate, octyl palmitate, octyl stearate, and erucyl ester (Oleylerucat).

Esters prepared from fatty acids and propylene glycol, for example, propylene glycol caprylate/caprate, propylene glycol dinonoate, propylene glycol laurate, and propylene glycol monocaprylate.

Other fatty acid esters are, for example, dibutyl adipate, dioctyl carbonate (dicaprylyl carbonate), diethyl hexyl carbonate, cyclic carbonates, for example propylene carbonate.

Alkoxylated alcohols (ethers prepared from polyethylene glycol and alcohols) such as polyethylene glycol monododecyl ether, polyethylene glycol cetyl ether, polyethylene glycol hexadecylstearyl ether (Ceteareth), polyethylene glycol stearyl ether, diethylene glycol monoethyl ether and dipropylene glycol monomethyl ether.

Other ethers, such as dioctyl ether and octyl dodecanol.

Silicone oils, for example, polydimethylsiloxane and cetyl polydimethylsiloxane (Cetylidimethicon).

Particularly preferred are formulations of the present invention which are free of protic solvents and dispersants. These acids can be dissolved or dispersed in the solvents mentioned. Preferably, the acid is dissolved in a solvent.

Organic or inorganic acids are suitable as acids.

Examples of inorganic acids are hydrochloric acid, sulfuric acid, sulfurous acid and phosphoric acid.

Examples of organic acids are saturated aliphatic monocarboxylic acids having up to 18 carbon atoms, such as formic acid, acetic acid, propionic acid, butyric acid, lauric acid, palmitic acid, stearic acid, mono-or polyunsaturated aliphatic monocarboxylic acids having up to 18 carbon atoms, such as oleic acid or sorbic acid, aliphatic hydroxycarboxylic acids having up to carbon atoms, such as citric acid, tartaric acid, lactic acid; dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, or adipic acid; ketocarboxylic acids such as oxaloacetic acid; aromatic carboxylic acids such as benzoic acid or phthalic acid; organic sulfonic acids such as methanesulfonic acid; cycloaliphatic carboxylic acids, such as ascorbic acid.

The acid is preferably used at a concentration of 0.01 to 10% (M/V), more preferably 0.05 to 5% (M/V), and particularly preferably 0.05 to 1% (M/V).

The above formulations may also include other additional substances and auxiliary substances which are generally pharmaceutically acceptable. Mention may be made, as examples:

● preservative substances, such as phenols, (cresols, parabens, e.g. methyl paraben, propyl paraben, etc.), aliphatic alcohols (benzyl alcohol, ethanol, butanol, etc.), quaternary ammonium compounds (benzalkonium chloride, cetylpyridinium chloride).

● antioxidants, for example, sulfites (sodium sulfite, sodium metabisulfite), organosulfides (cystine, cysteine, cystamine, methionine, thioglycerol, thioglycolic acid, thiolactic acid), phenols (tocopherol, also known as vitamin E and vitamin E-TPGS (d- α -tocopheryl polyethylene glycol-1000-succinate), butyl hydroxyanisole, butyl hydroxytoluene, gallic acid derivatives (propyl, octyl, and dodecyl gallate).

● wetting or emulsifying agents, for example, fatty acid salts, fatty alkyl sulfates, fatty alkyl sulfonates, linear alkylbenzene sulfonates, fatty alkyl polyglycol ether sulfates, fatty alkyl polyglycol ethers, alkylphenol polyglycol ethers, alkyl polyglycosides, fatty acid N-methylglucamines, polysorbates, sorbitan fatty acid esters, lecithins and poloxamers.

● pharmaceutically acceptable coloring materials such as ferric oxide and carotenoid.

● As spreading agents there may be used, in particular, hexyldodecanol, decyl oleate, dibutyl hexanoate, polydimethylsiloxane, glyceryl ricinoleate, octyldodecanol, octyl stearate, propylene glycol dinonylate, preferably isopropyl myristate and isopropyl palmitate.

● penetration enhancers improve transdermal administration of drugs and are known in principle from the prior art (see, e.g., Dermatopharmazie, Chapter 6, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 2001). Mention may be made, as examples of spreading oils, of isopropyl myristate, propylene glycol pelargonate, silicone oils or their copolymers with polyethers, fatty acid esters (such as oleyl oleate), triglycerides, fatty alcohols and linseed (Linolen). DMSO, N-methylpyrrolidone, 2-pyrrolidone, dipropylene glycol monomethyl ether, octyldodecanol, oleyl macrogol glyceride, or propylene glycol laurate may also be used.

The agents of the invention are generally suitable for use in humans and animals. Preferably for use in agriculture and for breeding domestic animals, zoos, laboratories and laboratory animals, animal management of pets and animal breeding, in particular mammals.

For example, cattle, horses, sheep, pigs, goats, camels, buffalo, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals, such as mink, chinchilla, racoon, and birds, such as chickens, geese, turkeys, ducks, pigeons, ostrich, and the like. Examples of preferred agricultural livestock are cattle, sheep, pigs and chickens.

Laboratory and experimental animals include dogs, cats, rabbits, and rodents, such as mice, rats, guinea pigs, and hamsters.

Pets include dogs, cats, horses, rabbits, rodents such as golden hamsters, guinea pigs, mice, but also reptiles and amphibians and birds for domestic and zoo rearing.

The formulations of the invention can in principle be administered in all customary ways, for example parenterally, orally or, in particular, topically (for example transdermally).

Examples

Example 1: dexamethasone acetate-210.05 g, clotrimazole 0.5g and X g acid were dissolved in 931g of medium chain triglycerides (Miglyol 812). 0.114g of Pradofloxacin trihydrate and 1.8g of highly disperse silica (Aerosil 200) were then dispersed therein under vigorous stirring. The suspension is then stirred to homogeneity using a rotor-stator stirrer.

Example 1 a: 0.1g sorbic acid

Example 1 b: 0.2g sorbic acid

Example 1 c: 0.5g sorbic acid

Example 1 d: 0.1g stearic acid

Example 1 e: 0.2g stearic acid

Example 1 f: 0.5g stearic acid

Example 1 g: 0.1g propionic acid

Example 1 h: 0.2g propionic acid

Example 1 i: 0.5g propionic acid.

Stabilization of dexamethasone acetate was studied by storage at 25 ℃, 40 ℃ and 50 ℃ over 6 weeks. Figure 1 shows that the formation of dexamethasone decomposition products can be reduced in a concentration-dependent manner by the acid used.

Example 2: 0.1g betamethasone valerate-21 and 0.2g propionic acid were dissolved in 940g propylene glycol caprylate/caprate (Miglyol 840). 2.0g of hydrophobic, highly dispersed silica (Aerosil R974) were then dispersed therein with stirring, and the suspension was then homogenized with a rotor-stator stirrer. Finally, colorless, slightly turbid liquid is obtained.

Example 3: 0.5g hydrocortisone acetate and 0.5g stearic acid were dissolved in 850g isopropanol. A colorless, clear liquid was finally obtained.

Legend:

FIG. 1: dexamethasone acetate in examples 1a-1f of the invention decomposed to dexamethasone upon storage for 6 weeks.

Claims (9)

1. A non-aqueous fluid pharmaceutical formulation comprising at least one glucocorticoid ester and at least one acid, said formulation being free of protic solvents and dispersants.

2. The formulation of claim 1, wherein the acid is used at a concentration of 0.01-10%.

3. The formulation as claimed in any of the preceding claims, wherein formic acid, acetic acid, propionic acid, butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, sorbic acid, citric acid, oxaloacetic acid, tartaric acid, methanesulphonic acid, lactic acid or ascorbic acid is used as acid.

4. The formulation of claim 3, wherein sorbic acid, stearic acid or propionic acid is used as the acid.

5. The formulation of claim 4, wherein sorbic acid is used as the acid.

6. A formulation according to any preceding claim, wherein the glucocorticoid ester is esterified at C17 and C21.

7. The formulation according to any of the preceding claims, wherein dexamethasone acetate or betamethasone valerate is used as glucocorticoid ester.

8. Use of a formulation according to claim 1 in the manufacture of a medicament for topical application.

9. Use of the formulation of claim 1 for the preparation of a veterinary drug.