WO1980001242A1 - Galenical preparation - Google Patents

Abstract

The preparations for oral application comprise a coating resistant to gastric juice and a core comprise of an ergot alkaloid and of a sterile ester. The preparations are characterized by an improved and enhanced release of the active principle and a higher efficiency. The core may be comprised of a solid solution of the ergot alkaloid. The coating resistant to the gastric juice may be covered with an outer layer of the active principle.

Description

New pharmaceutical preparations

The invention relates to pharmaceutical preparations for oral application of ergot alkaloids which are characterized by a prolonged action and good bioavailability.

It is undisputed in the medical community that in many cases a single daily application of a drug is preferable to a multiple daily application. This can generally be achieved with so-called "retard systems", by delaying and delaying the release of the active ingredient, and is aimed at extending the therapeutic effect. In the area of ergot therapy, however, retardation with classic systems, e.g. with a matrix system or with the help of microcapsules, each brings about a considerable reduction in bioavailability.

It is also known that ergy compounds are acid stable, i.e. are not broken down in gastric juice and that the absorption of ergot alkaloids takes place predominantly in the intestinal tract. One would then also not expect that the bioavailability of ergot alkaloids can be influenced favorably by means of a stomach-resistant coating.

It is therefore surprising that not only a significant increase in the duration of action of an ergot alkaloid can be envisaged with the help of an enteric coating, but also that the total bioavailability of the active ingredient is significantly improved if the cores provided with an enteric coating and the ergot alkaloide also include a polyalkoxyalkylene -Sterol ether included.

The invention therefore relates, more specifically, to a preparation provided with an enteric coating for oral application, the core of which is an ergot alkaloid and contains a polyalkoxyalkylene sterol ether.

The preparations are obtained according to the invention by providing a core which contains an enteric coating in ergot alkaloid and a polyalkoxyalkylene sterol ether (hereinafter referred to as sterol ether).

The term "core" encompasses any mixture of an ergot alkaloid and a sterol ether, optionally with other physiologically compatible auxiliaries, which can be covered with a stomach-resistant coating. It follows that the term "core", in the broadest sense, not only tablets, pellets and granules, but also capsules, e.g. Soft gelatin capsule or hard gelatin capsule filled with a liquid or wax-like mixture of an ergot alkaloid, a sterol ether and optionally pharmacologically acceptable excipients. Such capsules can then be coated with an enteric film, for example analogously to known methods. If tablet cores are used, they preferably have a hardness of approximately 10 to approximately 70N.

After application of the enteric coating, the pellets or granules can be used as such or in capsules, e.g. Hardgelatin capsules are filled. Suitable forms of use of the preparations according to the invention are therefore tablets, pellets, granules or capsules.

The term "ergot alkaloids" encompasses natural ergot alkaloids such as ergotamine, ergocristin, α-ergocryptin, β-ergocryptin and ergocornin, synthetic or semi-synthetic derivatives thereof such as ergovalin, dihydroergotoxin (also known as co-dergocrin) and dihydroergotamine in free form or in the form their salts with pharmacologically acceptable organic or inorganic acids such as methanesulfonic acid, maleic acid, tartaric acid or hydrogen chloride. The active ingredients to be administered in particular are compounds of the formula I

worin R₁ für Wasserstoff oder Halogen,

where R _{1 is} hydrogen or halogen,

R _{2 represents} hydrogen or an alkyl group with 1-4 carbon atoms, isopropyl, sec-butyl, isobutyl or benzyl,

R _{4 represents} methyl, ethyl or isopropyl, represents hydrogen, and represents hydrogen or methoxy, or

R ₅ and R ₆ together form a further bond or mixtures thereof.

If R _{1 is} halogen, it is preferably bromine.

Particularly preferred embodiments of the present invention contain dihydroergotamine, bromocryptin or dihydroergotoxin in free form or preferably in salt form as the active ingredient.

The sterol ethers according to the invention preferably have an average HLB value (hydrophylic-lipophilic balance = hydrophilic-lipophilic equilibrium value) of approximately 10 to approximately 20, in particular 12 to 16. They are preferably ether of lanosterol, dihydrocholesterol and, in particular, of cholesterol or mixtures of such Ether. Particularly suitable sterol ethers are sterols which are etherified with an average of 8 to 75, preferably an average of 9 to 30, alkylene oxide equivalents. The hydroxy substituent of the last alkylene part of such sterol ethers can optionally be partially or completely acylated, for example with an acyl residue of an aliphatic carboxylic acid such as acetyl.

Sterol ethers which are etherified with ethylene oxide or propylene oxide are particularly preferred.

Analogously to known methods, the sterol ethers can be obtained by etherification of the sterol with the appropriate amount of epoxide and, if appropriate, subsequent acylation of the hydroxy ethers thus obtained.

Some of them are commercially available and are sold, among others, by the Amerchol company under the name Solulan ^® . Examples of Solulan ^® types that are commercially available and in the preparations according to the invention

Can be used are those which are obtained by alkoxylation of a) 1 mol of cholesterol with an average of 24 mol of ethylene oxide (Solulan ^® C-24) b) 1 equivalent of lanolin alcohols with an average of 16 equivalents of ethylene oxide (Solulan ^® 16) c) 1 equivalent of Lanolin alcohols with an average of 25 equivalents of ethylene oxide (Solulan ^® 25) d) 1 equivalent of lanolin alcohols with an average of 75 equivalents of ethylene oxide (Solulan ^® 75) e) 1 equivalent of lanolin alcohols with an average of 10 equivalents of propylene oxide (Solulan ^® PB-10) or through f) partial acetylation of the reaction product of

1 equivalent of lanolin alcohols with an average of 10 equivalents of ethylene oxide (Solulan ^® 98) g) complete acetylation of the reaction product of 1 equivalent of lanolin alcohols with an average of 9 equivalents of ethylene oxide (Solulan ^® 97).

The term "average" in connection with the specification of the equivalent amount of alkylene oxide which can be converted or is converted per mole of sterol means that the stated amount represents an average value, i.e. that a mixture of sterol ethers may be present, some of which carry more, and some less alkyleneoxy groups.

Lanolin alcohols are also known as wool fatty alcohols (Handbook of Cosmetics and Fragrances, 2nd Ed. 1950, Vol. I, page 1101 (Janistyn) and are a mixture of cholesterol, dihydrocholesterol and lanosterol, among others.

The expression "enteric coating" includes any pharmacologically acceptable coating which prevents the release of the active ingredient in the stomach when the preparation passes through the stomach and which is sufficiently disintegrated in the intestinal tract (through contact with the approximately neutral to alkaline intestinal juices) to allow the active ingredient to be absorbed by the Allow walls of the intestinal tract.

A number of in vitro tests have been described in the pharmacopoeia of various countries, which make it possible to determine whether a coating is gastro-resistant.

More specifically, the expression gastric juice-resistant coating in the sense of the invention comprises a coating which remains intact for at least 1 hour, for example 2 hours, in artificial gastric juices such as a hydrogen chloride solution of pH 1.2 and at a temperature of 36 to 38 ° C. and which subsequently remains in artificial intestinal juices, for example in a pH 6.8 buffered solution with KH ₂ PO ₄ , is dissolved within 30 minutes. The thickness of the film depends on Degree of permeability of the film for water and acid and the desired retarding effect. In general, satisfactory results are obtained with a film thickness of 5-100 μm and in particular of 20-80 μm. The film expediently consists of a macromolecular polymer.

Suitable polymers are listed, for example, in Hager's Handbook of Pharmaceutical Practice, 4th edition, vol. 7a, pages 739-742 and 776-778, and in Remingtons' Pharmaceutical Sciences, 13th edition, pages 1689-1691, and include in particular cellulose ester derivatives, Cellulose ethers, acrylic resins, such as methacrylate copolymers, and copolymers of maleic acid and derivatives of phthalic acid.

Preferred films are made from cellulose ethers such as cellulose acetate phthalate or hydroxypropylmethyl cellulose phthalate, and from copolymers of methacrylic acid and its esters, which contain at least 40% methacrylic acid. An example of a suitable cellulose acetate phthalate is CAP (trade name), marketed by Eastman Kodak, Rochester N.Y., USA. Examples of suitable hydroxypropylmethyl cellulose phthalates include the commercial products HP50 and HP55 distributed by Shinetsu, Tokyo, Japan.

As a CAP film only goes into solution at a higher pH than e.g. an HP50 film, the administration form provided with CAP film will have a comparatively longer lasting effect. In this way, by suitable choice of the coating, a retardation can be achieved which optimally takes into account the properties of the active ingredient used

The method according to the invention can be carried out analogously to methods known for applying a coating. For the production of coated tablets, pellets or granules, one proceeds, for example, by spraying the cores with a solution of the film-forming material.

Suitable solvents for the film-forming material are, for example, organic solvents, for example an alcohol such as ethanol, a ketone such as acetone, a halogenated hydrocarbon such as CH ₂ Cl ₂ or solvent mixtures such as ethanol / acetone 1: 1. A plasticizer such as di-n-butyl phthalate is expediently added to the solution.

The cores are expediently heated to 25 to 40 ° C. before spraying, for example by means of warmer air from 40 to 70 ° C. In order to avoid sticking of the cores, the spraying process is advantageously interrupted at certain time intervals and the cores warmed up again. The spray pressure can vary, generally good results are obtained with a spray pressure of 1 to 1.5 bar. However, the spraying process can also be carried out without interrupting the working process, for example by automatically regulating the spray quantity as a function of the exhaust air or core temperature.

The forms according to the invention provided with an enteric coating are characterized in that after po administration to humans, the maxima of the active substance concentration in the plasma are only reached about 4-6 hours after the application, while the initial peak after administration of a normal tablet already after 0. 5 - 1 hour occurs. The retarding effect achieved is also evident in the determination of the amount excreted in the urine: after application of the form according to the invention, the maximum rate of excretion with urine is shifted from about 2 to 6 hours compared to a normal tablet. In addition, the plasma levels after application of Form according to the invention between 6 and 24 hours higher than after application of a normal tablet. This is based on the area under the plasma level (AUC) and is a measure of the excellent bioavailability which is achieved with the preparations according to the invention.

The dosage form according to the invention accordingly leads to a therapeutically desired sustained release effect, which allows a single application per day. This increases the patient's comfort of use and the level of safety.

The forms provided with an enteric coating, in particular the tablets, can additionally be coated with an outer layer of active substance. In addition to an active ingredient, this outer active ingredient layer contains e.g. an ergot alkaloid that is soluble or dispersible in the gastric juices and / or fillers, such as talc, microcrystalline cellulose, magnesium stearate, mannitol, polyvinylpyrrolidone, etc. In this case, the active ingredient is rapidly absorbed through the stomach walls, initially having a high concentration of the active ingredient in the bloodstream is achieved. The level of the active substance blood level is maintained by the delayed release of the active substance from the tablet core in the neutral or alkaline juices of the intestinal tract.

The optimal weight ratio of ergot alkaloid: sterol ether in the cores depends to a large extent on the physical properties of the sterol ether, the auxiliaries used and the type and size of the chosen administration form.

Thus, the above-mentioned example, sterol ethers of the type ^® Solulan 16, Solulan 25 and Solulan ^{® ®} C-24 is not due to its waxy nature in unlimited Quantity tablettable.

In general, however, good results are obtained with an ergot alkaloid: sterol ether weight ratio of 1: 1 to 1:25, in particular 1: 2 to 1: 8, preferably 1: 4. The range 1: 2 to 1: 8 is particularly preferred if the cores are used in the form of a solid solution of ergot alkaloid, in particular if polyvinylpyrrolidone is used as the solid solvent.

Depending on requirements, other auxiliaries such as binders, lubricants, fillers and wetting agents are processed in the cores.

The use of the cores in the form of their solid solution is a special embodiment of the invention. To produce such cores, e.g. as follows:

An ergot alkaloid is mixed with a sterol ether and a pharmaceutically acceptable polymer which is at least slightly soluble in an aqueous medium, in particular one or more polyalkylene glycols. Polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate or a mixture thereof.

Suitable polyalkylene glycols include inter alia polyoxyethylene or polyoxypropylene polymers and their copolymers with a molecular weight of 200 to 20,000, in particular 4,000 to 15,000, preferably 6,000 to 13,000. Polyvinylpyrrolidone means uncrosslinked poly-nvinylpyrrolidone-2 compounds with molecular weights of 10,000 to 100,000, in particular 11,500 to 40,000, preferably 20,000 to 30,000. The copolymers of vinyl pyrrolidone and vinyl acetate preferably consist of approximately 60 parts by weight of vinyl pyrrolidone and 40 parts by weight of vinyl acetate and preferably have a molecular weight of 30,000 to 100,000, in particular 40,000 to 90,000. If desired, additives requiring stability, such as acids, in particular methanesulfonic acid, maleic acid, tartaric acid, are added. The preferred pH of the preparation is between 4 and 6, in particular between 4 and 5. The weight ratio ergot alkaloid: sterol ether: to polyalkylene glycols and / or polyvinylpyrrolidone and / or copolymers of vinyl acetate and vinylpyrrolidone used can vary between wide limits; in general, however, good results are achieved with ratios which vary between 1: 1-10: 0.1-10, in particular between 1: 2-8: 0.1-10, preferably between 1: 2-5: 0.1-5 .

The polymers are used in solid form to prepare the solid solution. If one of the polymers, for example a polyalkylene glycol with a molecular weight of about 200, which is liquid at room temperature, is used to produce the solid, it goes without saying that this is not used alone, but together with a solid polymer.

The above-mentioned constituents are dissolved in a suitable solvent, for example a lower alcohol, for example ethanol or methanol or chloroform, with stirring and heating to temperatures of 30 to 70 ° C., preferably 40 to 60 ° C., a clear solution being obtained . The solvent is then removed in vacuo at temperatures from 30 to 70 ° C., preferably 40 to 60 ° C. It is possible that only part of the polyalkylene glycol and / or polyvinylpyrrolidone and / or copolymer of vinyl acetate or the other additives is used in the preparation of the solution, and the remaining amount is added while the solution is evaporated. The resulting clear liquid is allowed to solidify at room temperature (15-25 ° C). The product obtained is ground to a fine powder and in vacuo at about 30 ° C. dried until the solvent is completely removed.

The solid solution obtained by the above process (core of the administration form) is processed together with pharmacologically acceptable auxiliaries and, if appropriate, further portions of the sterol ether in a manner known per se. The proportion of sterol ether added here, but also during the previous operation, should overall remain within the numerical limits above.

The following examples illustrate the invention. Temperatures are given in degrees Celsius.

example 1

Tablet cores consisting of 3 g dihydroergotamine, 75 g cholesterol (Solulan ^® C-24) ethoxylated with approx. 24 mol ethylene oxide and 22 g disperse silicic acid are in a coating pan with repeated turning of the cup, by means of supply air from 50 ° for 10 minutes to approx. 30 ° warmed. The tablet cores are then covered with a. Solution of 5.4 g of hydroxypropylmethyl cellulose phthalate (HP-50) and 1.35 g of di-n-butyl phthalate in an ethanol / acetone mixture 1: 1, using a hand spray gun and at a spray pressure of 1-1.5 bar, by means of known interval spraying method, sprayed. The coated tablet cores thus obtained are then dried.

Example 2

The procedure is analogous to Example 1, but tablet cores are used which contain instead of 75 g of ethoxylated cholesterol with approx. 24 mol of ethylene oxide, 75 g of lanolin alcohols ethoxylated with 25 equivalents of ethylene oxide.

Example 3: Tablet core in the form of a solid solution

Into a flask of 1 liter. Volume 15 g of dihydroergotoxine methanesulfonate, 1.05 g ^® Solular C-24 and 33.95 g of polyvinylpyrrolidone (average. Mol. Wt. 25,000) and Given 250 ml of methanol. The flask is connected to a rotary evaporator. At a bath temperature of 60 ° C, the contents are heated to approx. 60 ° C with the piston rotating. This creates a clear solution. The solvent is evaporated at a reduced pressure and a bath temperature of 60 ° C. until the residue has reached a syrup-like consistency. This mass is placed in an evaporation dish and kept at room temperature for about 2 hours. This is followed by drying in a vacuum drying cabinet at 30 ° C, approx. 1 torr., Approx. 12 hours, grinding and drying. 26.8 g of the powder produced are then mixed with the following auxiliaries

Silicon dioxide 1.0 g (Aerosil ^® 200, Degussa)

Polyvinyl pyrrolidone 8.0 g

(networked)

Corn starch 20.0 g

Talc 30.0 g Solulan ^® C-24 30.0 g

Cellulose granules 42.0 g

Milk sugar 122.0 g and then compressed to tablets of 140.0 mg (hardness 10-32N) in a manner known per se.

The tablet cores obtained in this way are analogous to Example 1 with a solution of

Cellulose acetate phthalate (CAP) 90.0 g di-n-butyl phthalate 22.5 g

Acetone 240.0 g

Ethanol 21.0 g

Dichloromethane 526.5 g

900.0 g sprayed until the tablet cores with about 10 mg of the mixture of cellulose acetate phthalate and di-n-butyl phthalate are coated per tablet core.

The tablets obtained in this way are enteric-resistant, ie the cores remain unharmed after 1 hour of treatment with artificial gastric juices of pH-1 _f 2.

The intestinal juice disintegration time is longer than 60 minutes at pH 5.5 and between 23-28 minutes at pH 6.0 and between 12 to 16 minutes at pH 6.8.

Example 4

The procedure is analogous to Example 3, but the tablet cores of 140 mg are sprayed with a solution of 140 g of hydroxypropylmethyl cellulose phthalate (HP-50) and 28 g of di-n-butyl phthalate in a mixture of 616 g of ethanol and 616 g of acetone until the cores are mixed with 9 , 0 mg of the mixture of hydroxypropyl methyl cellulose phthalate and di-n-butyl phthalate (weight ratio 10: 2) are coated per tablet core.

Example 5

Analogously to Example 3, a solid solution of 4 g of dihydroergotoxin methanesulfonate, 0.3 g of Solulan (R) 16 and 9.1 g

Polyvinyl pyrrolidone (average mol. Weight 25,000) produced.

The powder thus obtained is then mixed with the excipients

Silicon dioxide 0.5 g

Polyvinyl pyrrolidone 4.0 g

(average mol. weight 2,000)

Corn starch 10.0 g

Talc 15.0 g

Solulan ^® 16 15.0 g

Cellulose powder 21.0 g

Milk sugar 61.1 g

mixed and compressed into tablets of 140.0 mg.

The tablet cores obtained in this way are then sprayed analogously to Example 4 until the cores contain approximately 10 mg or about 15 mg of the mixture of hydroxypropyl methyl cellulose phthalate and di-n-nutyl phthalate are coated per tablet core.

Analogously to the processes described in the examples above, the tablets obtained are summarized in Table I below.

If Ib or Ic (see table) are used, the tablet cores are in the form of a solid solution.

Beispiel 14 : Herstellung von Manteltabletten

Example 14: Production of coated tablets

a) 26.8 g of solid solution (containing 8.0 g of dihydroergotamine mesilate, 0.6 g of Solulan ^R

C-24 and 18.2 g polyvinyl pyrrolidone) together with 1.0 g highly disperse silicon dioxide, 8.0 g cross-linked polyvinyl pyrrolidone, 20 g corn starch, 47.4 g Solulan ^R C-24, 42.0 g cellulose granules, 104.8 g Lactose and 30.0 g talcum are mixed to a homogeneous mass and this mixture is pressed to cores of 140.0 mg full weight.

b) The cores obtained according to a) are sprayed in a suitable apparatus with a solution of 140.0 g of hydroxypropylmethyl cellulose phthalate and 28.0 g of di-n-butyl phthalate in a mixture of 616 g of ethanol and 616 g of acetone until an amount of solids is applied an average of 10.0 mg per tablet, which gives the kernels a stomach-resistant coating.

c) To produce the casing mass, 4.0 g of dihydroergotamine mesilate together with 4.0 g of highly disperse silicon dioxide, 6.0 g of magnesium stearate, 166.8 g of cellulose powder, 40.0 g of talc, 191.2 g of corn starch and 348.0 g of calcium hydrogen phosphate processed into a homogeneous mixture. This mixture is pressed together with the coated cores obtained according to paragraph to coated tablets of full weight 530.0 mg.

Example 15

The procedure is analogous to that of Examples 1 to 14, and tablets containing the appropriate amount of ergot alkaloid as the active ingredient are obtained using 4 mg bromocryptine, 4 mg dihydroergovalin or 4 mg dihydroergonine instead of dihydroergotoxin or dihydroergotamine.

Example 16: Clinical Trials

The preparation was tested in a clinical trial Example 4 with a solid solution of dihydroergotoxin mesilate (A) and with a classic

Preparation of dihydroergotoxin mesilate (B) compared.

Each of the 12 treated subjects was treated with 4 mg dihydroergotoxin mesilate.

The result is summarized in Table II below.

Die gute Retardierung und Bioverfügbarkeit der erfindungsgemässen Zubereitung geht eindeutig aus der obigen Tabelle hervor. Anderseits zeigte ein sich im Handel befindliches Retard-Präparat von Dihydroergotoxin eine eindeutig schwächere Bioverfügbarkeit (60-70% der als Referenz verwendete Zubereitung B)

The good retardation and bioavailability of the preparation according to the invention is clearly shown in the table above. On the other hand, a commercially available slow-release preparation of dihydroergotoxin showed a clearly weaker bioavailability (60-70% of preparation B used as reference)

Experiments with the other preparations according to the invention give comparably good results. A commercially available sustained-release preparation of dihydroergotamine, on the other hand, also showed a 30 to 40% weaker bioavailability than the corresponding non-delayed reference.

Claims

Claims 1. Preparations for oral application provided with an enteric coating, the core of which contains an ergot alkaloid and a polyalkyxyalkylene sterol ether. 2. A preparation according to claim 1, wherein the ergot alkaloid is a compound of formula I.

where R _{1 is} hydrogen or halogen, R _{2 represents} hydrogen or an alkyl group 1-4 carbon atoms, R ₃ for isopropyl, sec-butyl, isobutyl or Benzyl, R _{4 is} methyl, ethyl or isopropyl, R ₅ for hydrogen, and R _{6 represents} hydrogen or methoxy, or - R ₅ and R ₆ together form a further bond, or is a mixture of compounds of the formula I. 3. A preparation according to claims 1 and 2, wherein the active ingredient is dihydroergotamine, dihydroergotoxin or bromoergocryptine. 4. A preparation according to any one of claims 1 to 3 wherein the sterol ether is a derivative of cholesterol, dihydrocholesterol or lanosterol which is etherified several times with ethylene oxide or propylene oxide. 5. A preparation according to claims 1 to 4 wherein the coating is a macromolecular polymer from the series cellulose ester derivatives, cellulose ethers, acrylic resins, copolymers of maleic acid with phthalic acid derivatives. 6. A preparation according to claim 5 wherein the coating is made of cellulose acetate phthalate. 7. A preparation according to claim 5 wherein the coating is made of hydroxypropyl methyl cellulose phthalate. 8. A preparation according to claims 1 to 7 wherein the weight ratio of the components contained in the core ergot alkaloid: sterol ether is between 1: 1 and 1:25. 9. A preparation according to claims 1 to 8 wherein the core is in the form of a solid solution. 10. A preparation according to claim 9, wherein the core contains one or more polyalkylene glycols and / or polyvinylpyrrolidone and / or a copolymer of vinylpyrrolidone and vinyl acetate. 11. A preparation according to claims 9 and 10 wherein the weight ratio ergot alkaloid: sterol ether: polyalkylene glycol and / or polyvinylpyrrolidone and / or copolymers of vinyl acetate and vinylpyrrolidone is 1: 1-10: 0.1-10. 12. A method for producing a preparation as described in the above claims, characterized in that a core containing an ergot alkaloid as an active ingredient and a polyalkoxyalkylene sterol ether is warped with an enteric coating. 13. The method according to claim 12, characterized in that the coating is applied analogously to known methods. 14. The method according to claim 13, characterized in that the cores are sprayed with a solution of the film-binding material. 15. The method according to claim 14, characterized in that the cores are heated to 25 to 40 ° C before spraying.