FI84696C - FOERFARANDE FOER FRAMSTAELLNING AV EN INDOMETACININNEHAOLLANDE SALVAKOMPOSITION. - Google Patents

Description

84696

The present invention relates to a process for preparing an ointment composition containing indomethacin.

Ointments, oils or Vaseline were previously commonly used as the basis for ointment bases, all of which, however, have the disadvantage that they are oily and leave a greasy feeling on the skin. The biggest drawback, however, is that they have only a limited ability to deliver the active ingredient to the skin.

Oil / water or water / oil type emulsions are also commonly used as a base for ointment bases, which in addition to the fat or oil component may contain e.g. emulsifier, stabilizer, preservatives and water. However, these known skin care products have the disadvantage that they or the active ingredients contained in them do not penetrate the skin quickly enough or to a sufficient extent, so that their therapeutic effect is called into question.

Recently, the importance of the composition of the ointment bases and the manufacturing technique have been emphasized in the sense that they can significantly affect the bioavailability of the active ingredient incorporated therein. It has become increasingly apparent that the rate of dissolution or release of the active ingredient from the preparation plays an important role in this respect, and that even minor changes in composition or manufacturing technique can greatly affect these properties. It is the ability of the ointment base to deliver the active ingredient that is the primary contribution to the performance of the ointment base containing the active ingredient.

. · **. The use of penetration enhancers as active ingredients in topical formulations has also been extensively studied. Typical of such compounds or groups of compounds are 2,84696 alkyl alkyl sulfoxides, saturated fatty acid alkyl esters, unsaturated fatty acid alkyl esters, and 1-alkyl-azacycloheptan-2-ones, typically represented by 1-n-dodecyl, ie-n-dodecyl.

EP patent application 104037 describes an anti-inflammatory and analgesic composition containing clidanac in which it is proposed to improve the absorption of the active ingredient by adding e.g. Azone in an amount of 0.3 to 10% by weight.

EP patent application 0129285, in turn, describes a pharmaceutical topical composition which, in addition to the active ingredient, including indomethacin, contains a two-component mixture of N- (2-hydroxyethyl) pyrrolidone and a "cell shell disrupting compound". As one such latter compound, oleic acid has been proposed.

Transdermal Controlled Systemic Medications, Marcel Dekker, Inc., New York and Basel, 1987, has also investigated the use of various penetration enhancers in transdermal delivery systems, e.g., drug: patches. However, according to this publication, the concomitant use of Azone and oleic acid in the tape portion of the patch did not significantly promote the penetration of drugs, including indomethacin, into the skin.

It has now surprisingly been found that an ointment containing indomethacin can be prepared, from which indomethacin is well released and from which the penetration of indomethacin into the skin can be substantially improved. This object is achieved by using as a cream base a well-defined definition of the specific constituents of the substance and in particular its emulsifier system. ·. composition, together with specific indomethacin penetration enhancers.

3,84696

The invention thus relates to a process for preparing an indomethacin ointment composition, wherein the ointment base of the composition is an oil-in-water type emulsion ointment having an aqueous hydrophilic phase and a fat phase containing as a waxy component - a saturated fatty alcohol having from 14 to 24 carbon atoms - esters of saturated fatty acids having from 16 to 24 carbon atoms with alcohols having from 8 to 20 carbon atoms and / or their mono-, di- or triglycerides in an amount of from 4 to 25% by weight, and - as an oily component - from 16 to 24 carbon atoms unsaturated fatty acid ester with an alcohol having 8 to 20 carbon atoms, in an amount of 4 to 10% by weight, and that the hydrophilic phase of the cream contains a hygroscopic substance in an amount of 6 to 12% by weight, the cream emulsifier containing two different degrees of ethoxylation, 14 to 24% by weight. a mixture of fatty alcohols containing a carbon atom, a total of 2-10 pa indomethacin penetration enhancer contains 1-n-dodecyl-: azacycloheptan-2-one and oleic acid in combination in the fat phase in each case in an amount of 1-5% by weight, said% by weight being calculated on the total weight of the composition .

The process according to the invention is characterized in that - the components of the fat phase are melted together and the emulsifiers, Azone and oleic acid are dissolved in a mixture heated to a maximum of about 75 ° C, - the temperature of the hydrophilic phase containing the hygroscopic substance is adjusted to a maximum of about 75-77 ° C, the aqueous phase is added to the fat phase and the mixture is emulsified and homogenized by uniform cooling at. 1 ° C / 1 minute to 1 ° C / 5 minutes while vigorously stirring until the temperature has dropped to 50-55 ° C and a 4 84696 homogeneous emulsion has formed, stirring is continued at reduced intensity until the temperature has dropped, suitably to room temperature, and indo-metazine is added.

The exact chemical name of indomethacin is 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetic acid and is well known e.g. as an anti-inflammatory, antipyretic and analgesic agent (cf. Merck Index 10th Edition, 1983, No. 4852). Indomethacin can be used according to the invention both as the free acid or a suitable salt thereof.

The waxy saturated fatty alcohol used in the cream composition is in particular a fatty alcohol having 16 to 18 carbon atoms, such as cetyl and stearyl alcohol, especially cetyl alcohol. In the preparation according to the invention, the fatty alcohol acts as a non-ionizable thickener and stabilizer, as well as an emulsion conditioner. Fatty alcohol also acts as a solution mediator for the active ingredient. In addition, fatty alcohols have a water-retaining effect and, by law, prevent the mass effect contained in the preparation; decomposition of fatty acid esters.

The preferred ester equilibrium stabilizing concentration is: about 4% fatty alcohol by total weight of the composition.

The ointment composition contains, as a waxy binder, esters and glycerides of saturated fatty acids, such as stearic and palmitic acid, in an amount of about 4-25, especially about 8.5-10.5%, based on the total weight of the composition.

Binding agents maintain the homogeneity of the formulation and prevent more liquid components from seeping out or "sweating" out during prolonged storage at higher temperatures. Preferably, no more than a sufficient amount of binder is used in the preparation to prevent visible expulsion of the co-solvent used in the preparation, for example glycerol, at elevated temperature. Excess binding agent is not desirable as this will unnecessarily dilute the other agents and their effect. If the concentration of the binder is not carefully balanced with the other components, the stability of the preparation will deteriorate after one or more repeated solidification and liquefaction cycles.

Mono-, di- and tri-glycerides of stearic and palmitic acids have proven to be particularly preferred binders.

The best binding is achieved, especially in the case of fatty acid esters, if the binding agent and the fatty alcohol, as well as the fat group of the other components, have the same or almost the same number of carbon atoms.

The oily component used in the preparation may be an ester of an unsaturated fatty acid which resembles the skin's own fats, thus acting as a emollient. Particularly preferred are oleic acid esters, such as: oleic acid decyl ester, which is non-irritating to the skin and well: tolerable, as well as chemically stable, and oleic acid oleyl ester.

The amount of oil component used in the preparation is about 4-10%, especially 4-6% based on the total weight of the composition. Emollients give the cream softness and a pleasant feeling and make the cream cosmetically suitable. They also maintain the homogeneity of the mixture around the environment. at temperatures where the waxy fatty alcohol is solid. In addition, they improve the plasticity of the mixture as well as the even distribution of the active ingredient used.

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In addition to the above-mentioned components, the fat part of the preparation may also contain a small amount, up to a maximum of 3, and preferably only 1% by weight of hydrocarbon-type wax, petrolatum and / or paraffin, preferably white wax, which together with the emollient component forms a petrolatum-like product. easier to apply and less greasy. White wax forms a film that covers the skin and prevents water from evaporating.

In the preparation, attention has been paid above all to the choice of emulsifiers. Non-ionic surfactants are less irritating and less toxic than ionic ones, and are much more compatible with the other components of the formulation.

The emulsifier mixture used in the preparation contains two fatty alcohols having 16 to 18 carbon atoms and different degrees of ethoxylation, whereby the number of ethylene oxide groups can vary widely, e.g. in the range of 5 to 30 ethylene oxide groups, but suitably in the range of 12 to 20. Ethoxylated saturated fatty alcohols, especially cetyl stearyl alcohols (a mixture of cetyl and stearyl alcohols), have proven to be quite advantageous.

: A particularly good drug-releasing effect is obtained by using about 3% by weight of an emulsifier mixture with a 1: 1 ratio of cetylstearyl alcohol containing; . about 12 moles of ethylene oxide, and cetyl stearyl alcohol containing about 20 moles of ethylene oxide. The weight ratio of emulsifier to oil component is preferably * · "- about 1: 2.

: Emulsifiers act not only as surfactants but also as a "body" for the cream, i.e. they give a semi-solid creamy form to a preparation in which the aqueous phase is considerably larger than the fat phase, which makes the price of the cream favorable.

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Emulsifiers are generally used for manufacturing reasons, but have also been found in some cases to promote percutaneous adsorption. In the preparation according to the invention, emulsifiers have also been used to reduce the fat content of the preparation, while at the same time maintaining the oily properties of the preparation as well as easy spreadability.

The hydrophilic part of the preparation, i.e. the aqueous part, consists in a known manner of water and a hygroscopic substance such as glycerol, propylene and polyethylene glycol, sorbitol, urea, preferably glycerol.

The total concentration of the hygroscopic substance and the oil component in the preparation should preferably be greater than 10% by weight of the composition.

The hygroscopic substance slows down the evaporation of water and forms a protective layer on the skin after most of the water has evaporated off the skin. The retention of this layer on the skin is increased by the viscosity of the hygroscopic substance.

. The preparation may additionally contain conventional additives, “V such as preservatives and perfumes.

/. * The pH of the preparation is about 5-7, especially about 5, which corresponds to: the pH of the skin itself, and is unfavorable for microbial growth.

In the preparation according to the invention, the amount of indomethacin may vary, for example in the range from 1 to 20% by weight. Typically, the ointment contains 5% by weight of indomethacin.

Since the emulsifiers used are heat sensitive, it is important that the temperature of the fat phase does not become too high, with the addition of upper limit emulsifiers being about 75 ° C.

β 84696 At this stage, care must also be taken to ensure that the emulsifiers dissolve well. The temperature of the hydrophilic phase in the addition step is preferably approximately the same as or slightly higher than that of the fat phase. After the addition, the temperature is lowered, for example at a rate of about 1 ° C / 1 minute and at the same time with stirring, for example using a so-called dissolver and a paddle mixer. To form the emulsion, the stirring power is increased, for example using a colloid mill, while allowing the temperature to continue to drop evenly. Vigorous stirring is stopped when a cream-type emulsion is formed, and this occurs at a temperature in the range of about 50-55 ° C, usually 53-54 ° C. Stirring is then continued more calmly, for example with a paddle mixer alone, until the cream has reached room temperature. The calculated amount of indomethacin is then added.

As has already become apparent from the foregoing, the release of the active ingredient from the ointment and its penetration are also influenced by the composition of the ointment base, and by appropriately selecting the components of the ointment base, the release and penetration properties of the ointment can be optimized.

. In addition, it has been found that the ointment base, the ingredients of which and their amounts are carefully balanced with each other, can significantly promote the release and penetration of the active ingredients into the skin, as will be shown below.

However, this is particularly evident when the active ingredient is indomethacin and Azo-ne and oleic acid dissolved in the fat phase of the ointment are used in combination with indomethacin.

Such an ointment base is an oil-in-water type emulsion cream having an aqueous hydrophilic phase and a fat phase, the fat phase containing as a waxy component - a saturated fatty acid having 14 to 24 carbon atoms in an amount of 3 to 6% by weight, and 9,84696 to 16% by weight. Esters of saturated fatty acids having 24 carbon atoms with alcohols having 8 to 20 carbon atoms or their mono-, di- or triglycerides in an amount of 4 to 25% by weight, and as an oily component - ester of an unsaturated fatty acid having 16 to 24 carbon atoms with an alcohol having 8 to 20 carbon atoms , in an amount of 4 to 10% by weight, and that the hydrophilic phase of the ointment contains a hygroscopic substance in an amount of 6 to 12% by weight, the ointment containing, as emulsifier, a mixture of two fatty alcohols having 14 to 24 carbon atoms with different degrees of ethoxylation. 10% by weight, and wherein all percentages are by weight of the total weight of the ointment base.

With regard to the constituent components of the ointment base and their more precise definition, reference is made to what has been stated above in connection with the medicated ointment composition.

To prepare the ointment base as defined above - the ingredients of the fat phase are melted together and dissolved in a mixture heated to a maximum of about 75 ° C. "·. emulsifiers, V - the temperature of the hydrophilic phase containing the hygroscopic substance is adjusted to a maximum of about 75 to 77 ° C, - the aqueous phase is added to the fat phase and the mixture is emulsified: and homogenized by uniform cooling at * 1 ° C / 1 minute - 1 ° C / 5 minutes while vigorously stirring until the temperature has dropped to 50-55 ° C and a homogeneous emulsion has formed, after which stirring is continued at reduced stirring intensity.

. For a detailed description of the process steps, reference is made to the one described above in connection with the preparation of the pharmaceutical preparation, however, both the penetration enhancers and the drug addition steps are omitted from this process.

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The following are some examples of preparations according to the invention.

Example 1: The following ingredients were used as an ointment base to prepare a medicated ointment containing 5% indomethacin:

% By weight cetanol 4.00 oleic acid decyl ester 5.00 glycerol monostearate 9.50 white wax 1.00 cetyl stearyl alcohol + 12 moles of ethylene oxide 1.5 moles of cetyl stearyl alcohol + about 20 moles of ethylene oxide 1.5 methyl p-hydroxybenzoate 0.07 propyl p-hydroxybenzate 03 glycerol (85%) 8.00 pur. water ad 100. The fat phase was weighed into the vessel: glycerin monostearate, cetanol, oleic acid decyl ester and white wax. The mixture was heated on a water bath at about 75 ° C with occasional stirring until the solids melted. To their 75 ° C mixture were added emulsifiers and in each case 3% by weight of Azone and oleic acid. The second phase was weighed with the aqueous phase: water and .. · glycerol. To this, the preservatives were dissolved using short-term boiling to completely dissolve the solids. However, preservatives as well as emulsifiers are heat sensitive, so prolonged heating should be avoided.

When the temperature of both mixtures was 75 ° C, the aqueous phase was poured into a completely clear fat phase and the emulsion was homogenized. This was done by cooling to a uniform mass while stirring efficiently, initially using the highest speed of the homogenizer. The emulsion was completely homogenized at about 53-54 ° C, after which stirring was continued gently. After the ointment had cooled to room temperature, a uniform amount of indomethacin was mixed.

Example 2:

According to Example 1, a cream containing 5% indomethacin was prepared, the cream base of which had the following composition: stearyl alcohol 5.0 oleic acid oleyl ester 5.0 glycerol monostearate 5.0 white wax 1.0 cetyl stearyl alcohol + 25 moles of ethylene oxide 2.5 cetyl stearyl alcohol + 6 ethylene oxide . *. propylene glycol 8.0 methyl p-hydroxybenzoate 0.08 propyl p-hydroxybenzoate 0.02 / pur. water ad 100 - 'Experimental Part I.

: *: In the first part of the experiment, the properties of some known active ingredients commonly used in ointment bases were investigated. *. both from the ointment base used according to the invention and from some commercial ointment bases. The purpose of the experiment is to show that the combination and amounts of substances used in the ointment base generally have a beneficial effect on the release of drugs.

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The release from the creams was examined by in vitro dialysis. The drug was allowed to diffuse at 37 ° C through a semipermeable membrane from ointment to water. A hydrophilic, porous, polymeric cellulose film was used as the film. The film was tensioned in a glass cylinder with an inside diameter of 41 mm. The recipient of the released drug was 500 ml of water in a beaker. The water was kept in motion by a magnetic stirrer to prevent the formation of a liquid diffusion layer on the surface of the film, and the drug would be transported away as quickly as possible upon release, thus creating favorable conditions for release. The inner cylinder was attached to the plastic lid so that when the lid was placed on top of the beaker, the film was placed about 2 mm below the surface of the water. The beaker was immersed in a thermostated water bath at 37 ° C. The ointment base and drug were weighed on the film to a total of 2000 mg. The drug was mixed with the film into the ointment, and the ointment was applied as evenly as possible to the surface of the film. The drug diffused from the ointment into the water, which was sampled after a five-hour release test period.

. The ointment base used was the composition mentioned in Example 1, in which the amount of emulsifiers is 3%.

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The results were

table 1

Cream base Drug Amount released

Salicyl- Example 3% 29% acidic ointment

Aqualan® 3% 6%

Novalan 5% 10.8%

Apobase "14.6%

Ambilan "16.8%

Ultrabase "20.2% _Neribase__21.1%

Dequalinum Eg. cream 0.5% 47% chloride_Aqualan® _ ”__ 0% _

Camphor Eg. cream 10% 2.5% _Aqualan® _ "_ 0% _

Ketoprofen Ex. cream 5% 2.85% _Aqualan® _ "_ 0.8%

Fluphenamil Ex. ointment 5% 0.1%. . ·. acid_Aqualan® _ "_ 0% _ V Indomethacin Eg ointment 7.5% *) 10.6% _Aqualan®_7.5% *) _ 6.4% *) solvent phosphate buffer pH 9 .. · Reference products include Novala, Apobase, Ambilan, Ultra-base and Neribase commercial ointment bases commonly used for pharmaceuticals.

. *. From the experiments it can be stated that the ointment base according to Example 1 is very well suited as a base cream for drugs due to its good drug-releasing properties. The product is also physically soft and easy to apply due to its physical properties. For example, the degree of dispersion of an ointment containing 3% emulsifier mixture is good enough to keep the emulsion cream stable even during long-term storage. The pH of this ointment is about 5 corresponding to the pH of the skin and is detrimental to the growth of the microorganism.

II.

According to Example 1, medicated ointments containing varying amounts of Azone and / or oleic acid in the fat phase were prepared, and a medicated ointment was added to the corresponding ointment base, in which Azone and oleic acid were added directly to the base cream after preparation, leaving them completely in the aqueous phase. An ointment was also prepared without penetration enhancers but with 5% indomethacin.

Penetration of indomethacin through isolated human skin was studied with automated equipment that mimicked conditions in vivo. Tape treatment revealed how much indomethacin remained in the skin after the study. In in vivo studies, creams were applied to the dorsal skin of male Wistar rats; indomethacin was analyzed in plasma by a liquid chromatograph equipped with a fluorescence sensor. The assay was based on the conversion of indomethacin to a fluorescent metabolite.

: Penetration tests:: / The penetration test results are shown in the following table.

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Table 2

Parameters describing the penetration of indomethacin from ointments through human skin in vitro over 5 hours (n = 3).

Cream J »Kp Penetrate t-value (10“ 3 mg en-2 h-1) (10 “5 c · h" 1) (% ± SD) IND 4.67 9.34 3.75 t 0.21 A 3% S 5.13 10.25 * 4.97 ± 0.25 6.47 A 3% U 2.08 4.15 * 2.04 t 0.16 11.22 Ö 3% S 5.49 10, 98 3.99 ± 0.16 1.57 Ö 3% U 2.84 5.69 * 2.16 ± 0.23 8.84

AfcÖ 1% S 4.60 9.21 3.99 ± 0.12 1.72

Aiö 1% U 1.28 2.57 * 1.11 ± 0.24 14.34

Atö 3% S 9.43 18.85 * 9.73 ± 0.15 40.14

Aiö 3% U 2.89 5.79 * 2.35 ± 0.22 7.97 * p <0.05 c '* statistically significant difference at 5 l risk level compared to IND ointment A = Azone Ö = oleic acid

Js = average penetration rate Kp = permeability constant; The results show that the penetration rate * of indomethacin varies depending on whether the penetration-promoting compounds are located in the inner or fat phase (S) or in the outer phase (U) of the cream.

Indomethacin as such penetrated the base cream into the skin. through the receiving buffer solution for a total of about 25 μg / ·; · cm2 over five hours. When the ointment contained 3% Azone in the inner phase, the penetration improved slightly while it deteriorated when Azone was in the outer phase. For 3% oleic acid, the lumbar spine was approximately the same. However, a significant improvement is achieved with an ointment with 3% Azone and 3% oleic acid in the internal phase, the penetration rate of indomethacin is more than four times that of indomethacin ointment (IND) during the first half hour, cumulatively displaced, 64.5 yg / cm2 2.6-fold compared to indomethacin ointment.

Variations in the amount of indomethacin in the skin

The concentration of indomethacin in the stratum corneum and live epidermis was of interest for the study because it provided information on the effect of the ointment base on the amount of drug penetrating through the skin. In addition, the drug remaining in the skin sample was easy to determine. The dose of indomethacin that separated from the ointment and passed through the skin in five hours proved to be greater than the amount of drug remaining in the epidermis from the same preparation during that time. The results are shown in the accompanying Figure IA. Again, the effectiveness of the cream containing 3% Azone and 3% oleic acid in the internal phase is obvious.

Percutaneous ionization in vivo

Absorption of indomethacin from butter applied to rat skin; the blood in the others is illustrated in the accompanying Figure IB.

; It shows the concentration of indomethine in rat plasma after application of 5% drug cream to the animal's spine; . at 0.1 g / cm2 had elapsed 12 hours (n = 3). Again, an ointment containing 3% Azone and 3% oleic acid is the most effective, as this ointment absorbed almost ten times the amount of indomethacin ointment alone.

Claims (10)

A process for the preparation of an indomethacin-containing ointment composition, in which the ointment base of the composition is an oil-water emulsion having an aqueous hydrophilic phase and a fat phase, which contains the fatty phase as a waxy component - a saturated fatty alcohol having 14-24 carbon atoms in an amount 3 - 6% by weight, and - esters of saturated fatty acids of 16-24 carbon atoms with alcohols of 8-20 carbon atoms and / or their mono-, di- or triglycerides, in an amount of 4-25% by weight, and as an oil component - an ester of an unsaturated fatty acid of 16-24 carbon atoms with an alcohol of 8-20 carbon atoms, in an amount of 4-10 wt. %, wherein the ointment as emulsifier contains a mixture of two fatty alcohols having 14-24 * ·· carbon atoms and with different degrees of ethoxylation, in a total: amount of 2-10% by weight, and that the ointment base as the indomethacin's skin penetration enhancers contain in combination in the fat phase 1-n-dodecyl-azacycloheptan-2-one (Azone) and oleic acid each in an amount of 1-5% by weight, said weight% being calculated on the total weight of the composition, characterized in that - the components of the fat phase are melted together and in; . ·. their at most about 75 ° C heated mixture dissolves the emulsifiers, Azone and oleic acid, - the temperature of the hydrophilic phase containing the hydroscopic agent is adjusted to a maximum of about 75-77 ° C, - the aqueous phase is added to the fat phase and the mixture is emulsified and cooled to cool. at a rate of 1 ° C / 1 minute - 1 ° C / 5 minutes during simultaneous intensive mixing until the temperature drops to 50-55 ° C and a homogeneous emulsion is formed, mixing is continued at a reduced stirring rate until the temperature drops, preferably to room temperature, and the indomethacin is added. 2. A process according to claim 1, characterized in that the fat phase contains Azone and oleic acid each in an amount of about 3% by weight. 3. A process according to claim 1 or 2, characterized in that the fat alcohol used as an emulsifier contains 5-30 ethylene oxide moles, preferably 10-20 ethylene oxide moles. 4. A process according to claim 3, characterized in that the fatty alcohol contains 16-18 carbon atoms. Method according to claim 4, characterized by:. notwithstanding that the emulsifier is a mixture of 12 ethylene. ; oxide moles containing cetylstearyl alcohol and ethylene oxide: moles containing cetylstearyl alcohol. ; . 6. A process according to claim 5, characterized in that the mixture is a 1: 1 mixture. 7. A method according to claim 6, characterized in that the total amount of the emulsifier is 3% by weight of: -. the total weight of the ointment base. The method according to any of the preceding claims, characterized in that the indomethacin content is 1-IV 20 'preferably 5% by weight of the total weight of the salve. 9. A method according to claim 1, characterized in that the cooling rate is about 1 ° C / 2 minutes - 1 ° C / 4 minutes. 10. A process according to claim 9, characterized in that the ointment mixture is stirred intensively until the temperature reaches a value of about 53-54 ° C.