KR830001642B1 - Method for preparing oral composition of ergot alkaloids - Google Patents

Abstract

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Description

Method for preparing oral composition of ergot alkaloids

The present invention relates to a method for preparing an oral herbal composition of ergot alkaloids characterized by continuous effects and high in vivo efficiency of the active ingredient.

In many cases, it is indisputable among medical professionals that taking a drug once a day is preferable to taking several times a day. This can be achieved by delaying the release of the active ingredient for a longer lasting therapeutic effect with a so-called delay system. In erectile therapy, delays by systems, such as matrix systems or microencapsulation, greatly reduce total in vivo efficiency.

The ergot alkaloids are acid-stable, meaning that they are not degraded in gastric juice, and the absorption of ergot alkaloids occurs mainly in the intestine. Therefore, it was not expected that the efficiency in vivo would be increased when the drug containing ergot alkaloid was coated on enteric skin. However, when the coated nucleus contains polyalkoxy alkylenesterol ethers in addition to the ergot alkaloids, enteric skin treatment not only prolongs the erect alkaloids but also greatly enhances the total in vivo efficiency, which is surprising. .

Accordingly, the present invention provides a solid enteric coating composition, in unit dosage form, particularly for oral administration, wherein the nucleus of the composition contains ergot alkaloids and polyalkoxyalkylene esters.

The present invention also provides a method for preparing a composition according to the present invention, by avoiding enteric nuclei containing ergot alkaloids and polyalkoxy alkylenesterol ethers (hereinafter referred to as esterol ethers).

A "nucleus" consists of a mixture with ergot alkaloids and sterol ethers, a mixture further containing physiologically unfavorable substances that can be enteric avoided if necessary. "Nuclear" in the broad sense includes soft or hard gelatin capsules filled with tablets, pellets or granules as well as capsules, for example liquid or waxy mixtures of ergot alkaloids, sterol ethers and any pharmaceutically unfavorable substance. . Such capsules can also be enteric-coated in a conventional manner. When tablet cores are used, they preferably have a hardness of about 10 to about 70N.

Pellets or granules are used as is after enteric bark or for filling hard gelatin capsules, for example. The composition according to the invention is suitably applied in tablets, pellets, granules or capsules.

“Ergot alkaloids” are natural ergot alkaloids, such as ergotamine, ergocristine, α-ergocrtin, β-ergocrtin and ergocortin, ergovalin, dihydro ergotoxin (known as co-dergoclean) and Synthetic or semisynthetic derivatives, such as dihydro ergotamine, are included in free base form or acid salts with pharmaceutically nontoxic organic or inorganic acids, such as methanesulfonic acid, maleic acid, tartaric acid or hydrochloric acid.

Particularly advantageous active substances for use in the present invention are the compounds of formula (I) or mixtures thereof.

In the above formula,

R ₁ is hydrogen or halogen,

R ₂ is hydrogen or alkyl of 1 to 4 carbon atoms,

R ₃ is isopropyl, secondary-butyl, isobutyl or benzyl

R ₄ is methyl, ethyl or isopropyl,

R ₅ is hydrogen

R ₆ is hydrogen or methoxy or R ₅ and R ₆ together form an intimate bond.

Bromine is preferred when R ₁ is halogen.

Particularly preferred compositions of the present invention are those containing dihydroergotoxine, bromocriptine or dihydroergotamine as active substances in free base form, or preferably in acidic salted form.

Preferred hydrophilic-lipophilic balances of sterol ethers for use in the compositions of the present invention are from about 10 to about 20, in particular 12 to 16. They are preferably lanosterol, dihydrocholesterine in particular ethers of cholesterine or mixtures of such ethers. Particularly suitable sterol ethers are sterols etherified with alkylene oxide units on average from 8 to 75, preferably from 9 to 30. The hydroxy groups of the terminal alkylene units of these sterolethers may be partially or completely acylated, for example, the acyl residues of aliphatic carboxylic acids such as acetyl are also acylated. Especially preferred are sterol ethers etherified with ethylene oxide and / or propylene-oxide units.

이란 상품명으로 시판되고 있다.Sterol ethers are obtained by conventional methods of etherifying the sterols in epoxide equivalents and optionally acylating the obtained alcohols. Some of them are from Solutan

It is marketed under the trade name Iran.

Commercially available solutans suitable for use in the compositions according to the invention are obtained by the following alkoxylation.

C_24)a) Alkoxylation of 1 mole of cholesterol to about 24 moles of ethylene oxide (solutane

C_24)

16)b) alkoxylation of 1 equivalent of tanolin alcohol with about 16 equivalents of ethylene oxide (solutan

16)

25)c) alkoxylation of about 25 equivalents of tanolin alcohol with ethylene oxide (solutan

25)

16)d) alkoxylation of about 1 equivalent of tanolin alcohol with about 75 equivalents of ethylene oxide (solutan

16)

PB-10)e) alkoxylation of about 1 equivalent of tanolin alcohol with about 10 equivalents of propylene oxide (solutan

PB-10)

98)f) partially acetylated derivatives of tanroline alcohol equivalent to one equivalent of ethoxylated with about 10 equivalents of ethylene oxide (solutan

98)

97)g) 1 equivalent of lanolin alcohol fully acetylated derivative (solutane) ethoxylated with about 9 equivalents of ethylene oxide

97)

The term "about" in paragraphs a) to g) above means that the number of equivalent ethylene oxide or propylene oxide equivalents is average, i.e. some sterol ethers have more and others sterol ethers have less ethyleneoxy- or propyleneoxy-groups. It is present.

Larolin alcohols are also known as wool fat alcohols (Handbuch der kosmetita and Riechstoffe, 2nd edition 1950, Vol. 1, p. 1101 (yanistin) and are a mixture of cholesterine, dihydrocholesterine and tanosterol.

“Enteric bark” refers to a pharmaceutically toxic coating that prevents the release of the active ingredient into the stomach and is sufficiently disintegrated in the intestine by contact with an almost neutral or alkaline intestinal fluid to allow the active ingredient to be absorbed through the intestinal wall. Several in vitro tests for determining encapsulation are listed in the Pharmacopoeia of each country.

In particular, enteric skin according to the present invention is present in the gastric fluid such as hydrochloric acid at pH 36 to 38 ° C. at a temperature of at least 1 hour, for example, 2 hours, and is treated with KH ₂ PO ₄ buffer solution at pH6.8. The film disintegrates within 30 minutes of the same artificial intestinal fluid.

The thickness of the coating can be varied, inter alia, depending on the permeability in water and acid and the desired delay effect. In general, satisfactory results are obtained by coating the film to a thickness of 5 to 100 μm, preferably 20 to 80 μm. The coating material is appropriately selected from macromolecular polymers. Suitable polymers are described in Hagers Handbuch der Pharmazeutischer Praxis, 4th Ed. Vol. 7a, pages 739 to 742, 776 to 778 (Springer Verlag, 1971) and Renington's Pharmaceutical Sciences, 13th, Ed., P. 1689 to1691 (Mack Publ. Co., 1970)], cellulose ester derivatives, cellulose Acrylic resins such as ethers, methylacrylate copolymers and copolymers with maleic and phthalic acid derivatives.

Preferred coatings are cellulose acetate phthalate, copolymers derived from methylacrylic acid containing at least 40% methylacrylic acid and esters thereof, and in particular hydroxypropyl methylcellulose phthalate. Examples of suitable cellulose acetate phthalates are commercially available CAP (Eastman) products. kodak, Rochester NY, USA). Examples of suitable hydroxyl propyl methylcellulose phthalate are commercially available HP50 and HP 55 (Shinetsu, Tokyo, Japan).

Since the coating made of CAP disintegrates at a higher pH than the coating made of HP 50, the release of the active ingredient from the composition made of the former coating can be more pronounced than in the composition made of the latter coating. In this way, the coating material can be properly selected to obtain a delay effect considering the characteristics of the active ingredient included in the optimum method.

The preparation according to the invention is carried out in a manner similar to the known method in the application of enteric skin.

In the preparation of enteric-coated economies, felt or granules, nuclei are sprayed with enteric-coated solutions.

Suitable solvents for enteric skin include organic solvents such as alcohols such as ethanol, ketones such as acetone, halogenated hydrocarbons such as CH ₂ Cl _2, or mixtures of such solvents such as ethanol / acetone (1: 1). Softeners such as di-n-butylphthalate are usually added to this solution.

Conveniently, the nucleus is warmed before spraying to 25 ° C. to 40 ° C. with hot air from 40 ° to 70 ° C. It is desirable to stop the spraying process at regular time intervals and to re-warm the nucleus to prevent the nucleus from sticking. Spray pressures can vary widely and generally achieve satisfactory results with spray pressures of about 1 to about 1.5 bar. However, it is possible without stopping the spraying, for example, the automatic control of the spraying volume with respect to the temperature of the exhaust air and / or the nucleus.

When the enteric skin composition of the present invention is orally administered to humans, the highest peak concentration of the active substance is reached after about 4 to 6 hours, compared to the initial peak after 0.5 to 1 day after administration of a common composition such as a tablet Has the advantage.

The delaying effect of the release of the composition of the present invention is also explained by measuring the concentration of the active substance (and metabolite) in the urine. Usually, the composition reaches the highest concentration about 2 hours after administration, whereas the highest concentration in urine is reached almost 6 hours after administration.

In addition, the blood concentration after administration of the composition according to the invention is higher than when administration of a composition, such as a tablet, usually between 6 and 4 hours. This is described in terms of blood concentration curve area (AUC), which speaks to the excellent biomaterial efficiency of the compositions of the present invention.

Therefore, the composition of the present invention exhibits excellent in vivo efficiency as well as therapeutically desirable delaying effect, and as a result, can be used once daily.

The compositions of the invention, in particular tablets, may again be encased. This outer layer may contain, in addition to active ingredients such as ergot alkaloids, extenders and / or fillers that are dissolved or dispersed in gastric juice, such as talc, microcrystalline cellulose, magnesium stearate, mannitol, polyvinylpyrrolidine, and the like. Such compositions are used when rapid action is required. Release from the nucleus in the intestine continues slowly and long, maintaining the initial high blood levels of the ergot alkaloids.

16, 솔루란

25 및 솔루란

C-24형의 상기 언급한 스테롤 에테르 양은 그들의 왁스와 같은 성질에 좌우된다.Among the nuclei, the optimum weight ratio of ergot alkaloid and sterol ether is mainly related to the physical properties of the sterol ethers involved, the auxiliaries used, the form and size of the composition. Soluran

16, soluran

25 and soluran

The abovementioned amounts of sterol ethers of type C-24 depend on their wax-like properties.

However, generally satisfactory results are obtained when the weight ratio of ergot alkaloid and sterol ether is from 1: 1 to 1:24, preferably from 1: 2 to 1: 8, in particular 1: 4. The range of 1: 2 to 1: 8 is preferred when the nucleus is in the form of a solid solution of ergot alkaloids and in particular when polyvinylpyrrolidone is used as the solid solvent.

The nucleus may be mixed with matrix excipients such as binders, suspending agents, fillers and disintegrants. Suitable fillers for the preparation of tablet cores include silica gel potassium carbonate, sodium carbonate, lactose, starch, talc, starch and alginic acid as appropriate granulation and disintegrating agents, starch and gelatin as suitable binders, stearic acid as There is talc.

The use of a solid solution nucleus is a special embodiment of the present invention. Such nuclei can be produced as follows.

Pharmaceutical toxic polymers which dissolve ergot alkaloids, sterol ethers and maximally in part in an aqueous medium, in particular polyalkylene glycols, copolymers of polyvinylpyrrolidone, vinylpyrrolidone and vinyl acetate, or mixtures thereof Mix together.

Suitable polyalkylene glycols include polyethylene glycol and polypropylene glycol and their copolymers having a molecular weight of 200 to 20,000, preferably 4000 to 15,000, more preferably 6000 to 13,000. Polyvinylpyrrolidone suitably means noncross-linked poly (n-vinyl) pyrrolidone-2 having a molecular weight between 10,000 and 100,000 and preferably 11,500 to 40,000 more preferably 20,000 to 30,000. The copolymer of vinylpyrrolidone and vinyl acetate preferably contains 60% vinyl pyrrolidone by weight and 40% vinyl acetate, and preferably has a molecular weight of 30,000 to 100,000 and more preferably 40,000 to 90,000.

If desired, stabilizers such as acids such as metalsulfonic acid, maleic acid and tartaric acid are preferably added to adjust the pH of the composition. The preferred pH range of the composition is pH 4-6, preferably pH 4-5.

The weight ratio of ergot alkaloid and sterol ether and pharmaceutically toxic polymer can vary widely, but is generally from 1: 1 to 10: 0.1 to 10, especially from 1: 2 to 8: 0.1 to 10, more preferably 1: Satisfactory results are obtained when 2 to 5: 0.1 to 5.

In preparing the solution according to the invention, the polymer is used in solid form. If one of the polymers used is a liquid at room temperature (eg polyalkylene glycols having a molecular weight of about 200), such polymers are not used alone but in combination with polymers that are solid at room temperature.

The abovementioned components are dissolved by stirring at a temperature of 30 ° to 70 ° C., preferably 40 to 60 ° C., in a suitable solvent such as, for example, a lower alcohol such as ethanol or methanol or chloroform, and the solvent is evaporated in vacuo at the same temperature. Remove it. In preparing the solution, it is also possible to add only a part of the polymer and the additional components and to add the remainder while evaporating the solvent. The resulting clear solution is allowed to solidify at room temperature (15 ° C. to 25 ° C.), and the solid solution or dispersion is ground into fine powder and suitably vacuum dried at 30 ° C. to remove all solvents.

The solid solution (composition core) obtained by the above method is mixed with a pharmaceutical-adhesive non-toxic diluent or weighting agent by a known method, and sterol ether is optionally added so that the total amount of the sterol ether of the nucleus is preferably within the above range.

The following examples illustrate the invention. All temperatures are in degrees Celsius.

Example 1

C-24) 및 22g의 분산 실리카겔로 구성된 정제핵을 회전하는 피막팬(pan)내에서 50°의 더운 공기로 10분동안에 30°로 가열한다. 분무피스톨을 써서 정제핵의 에탄올과 아세톤의 혼합액(1 : 1)내의 하이드록시프로필메틸셀룰로스 프탈레이트 (HP 50) 5.4g 및 디-n-부틸프탈레이트 1.35g 용액으로 1내지 1.5바의 분무압에서 간격분무 피막업을 사용하여 분무하고, 얻어진 장용피정을 건조시킨다.75 g of cholesterine (soluran) ethoxylated with 3 g of dihydro ergotamine, approximately 24 ml of ethyl oxide

C-24) and 22 g of dispersed silica gel were heated to 30 ° for 10 minutes with 50 ° hot air in a rotating pan. Using spray gun, interval of 5.4 g of hydroxypropylmethylcellulose phthalate (HP 50) and 1.35 g of di-n-butylphthalate in a mixture of ethanol and acetone of tablet cores (1: 1) are separated at a spray pressure of 1 to 1.5 bar. Spraying is carried out using a spray coating industry, and the obtained enteric coating is dried.

Example 2

25) 75g을 사용하여 실시예 1과 유사하게 수행한다.Instead of 77 g of cholesterine ethoxylated with about 24 moles of ethylene oxide, lanolin alcohol ethoxylated with about 24 moles of ethylene oxide (soluran

25) Perform similarly to Example 1 using 75 g.

Example 3

Enteric retreat with a solid solution nucleus

C-24 1.05g, 폴리비닐피롤리돈 (평균 분자량 25,000) 33.95g 및 250ml의 메탄올을 1l 환저 플라스크에 넣는다. 풀루스크를 회전 증발기에 부착시키고 의 욕온에서 플라스크 내용물의 온도가 60°에 도달할 때까지 계속 회전시키는데, 이때쯤이면 맑은 용액이 얻어진다.15 g of dihydro ergotoxin methanesulfonate, solulan

1.05 g of C-24, 33.95 g of polyvinylpyrrolidone (average molecular weight 25,000) and 250 ml of methanol are placed in a 1 l round bottom flask. The pulllusk is attached to a rotary evaporator and kept rotating at a bath temperature of until the temperature of the flask contents reaches 60 °, at which point a clear solution is obtained.

The bath temperature is maintained at 60 ° and the solvent is evaporated under reduced pressure so that the residue has a syrupy viscosity. The residue is poured into an evaporator and solidified at room temperature for 2 hours.

The solid residue is dried in a vacuum oven of about 1 Torr at 30 ° C. for about 12 hours, ground to fine powder and dried again.

26.8 g of the solid solution thus obtained is mixed with the following auxiliaries.

C-24 30.0gSilicium Dioxide 1.0g Solulan

C-24 30.0 g

200, 데구사) 셀룰로스 과립 42.0g(Aeroroom

200, degussa) cellulose granules 42.0 g

Polyvinylpyrrolidone (crosslinked) 8.0 g (Elsema G 250)

Corn Starch 20.0g Lactose 122.0g

Talc 30.0 g

Once a homogeneous mixture is obtained, it is compressed into 140.0 ng tablet cores (hardness of 10 to 32 N) by a conventional method.

The resulting nucleus is sprayed with the following solution, similar to Example 1, and coated with about 10 mg of cellulose acetate phthalrace / di-n-butylphthalate mixture per nucleus.

Cellulose Acetate Phthalate (CAP) 90.0g Ethanol 21.0g

Di-n-butylphthalate 22.5 g dichloromethane 526.5 g

Acetone 240.0 g 9000.0 g

The enteric retreat obtained in this way is resistant to gastric juice because the nucleus remains intact even after 1 hour treatment with artificial gastric juice of pH 1.2. Decomposition time in artificial intestine at pH 5.5 is over 1 hour, between 23 and 28 minutes at pH 6.0 and between 12 and 16 minutes at pH6.8.

Example 4

140 mg tablet cores were sprayed in a similar manner to Example 3 with a solution of 140.0 g of hydroxy propyl methylcellulose phthalate (HP 50), 28 g of di-n-butylphthalate in 616 g of 616f and 616 g of acetone, about 9 mg of hydroxypropyl methyl per nucleus. The film is coated with a cellulose phthalate mixed solution (ratio 10: 2).

Example 5

16 0.3g, 폴리비닐 피롤리돈 9.1g (평균분자량 2000)의 고형용액을 얻는다.Similar to Example 3, dihydro ergotoxine methanesulfo neat 4 g, solutan

16 0.3 g and 9.1 g of polyvinyl pyrrolidone (average molecular weight 2000) are obtained.

This solid solution is mixed with the following ingredients and compressed into 140.0 mg tablets.

16 15.0gSilium Dioxide 0.5g Solulan

16 15.0 g

Polyvinylpyrrolidone (average molecular weight 2000) 400 g cellulose powder (cell sema G 250) 21.0 g

Corn Starch 10.0g Lactose 61.1g

Talc 15.0 g

The tablet nuclei thus obtained are sprayed similarly to Example 4, and each nucleus is coated with about 10 mg or about 15 mg of hydroxylpropyl methylcellulose phthalate / di-n-butylphthalate mixture.

Similar to the method described in the above examples, the tablets obtained in Table 1 below are obtained.

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

TABLE 1

* HPMCP = Hycipropyl Methylcellulose Phthalate (1) The nuclei of these tablets were compressed to have a hardness of 50 to 60N.

Example 14

Outer coated tablets

C-24 0.6g 및 폴리비닐피롤리돈 18.2g으로 이루어짐)을 1.0g의 고분산 실리카겔, 교차 결합 폴리비닐피롤리돈 8.0g, 옥수수 전분 20g, 솔루탄

C-24 47.4g, 셀룰로스 과립 42.0g, 락토스 104.8g 및 탈크 30.0g과 함께 혼합하여 균일하게 함으로써 핵을 제조한다. 혼합물을 140mg의 핵으로 타정한다.a) Solid solution similar to Example 3. 27.8 g (8.0 g dihydro ergotamine mesylate, soluran

Consisting of 0.6 g of C-24 and 18.2 g of polyvinylpyrrolidone), 1.0 g of highly dispersed silica gel, 8.0 g of cross-linked polyvinylpyrrolidone, 20 g of corn starch, solutan

Nuclei are prepared by mixing together and homogenizing with 47.4 g of C-24, 42.0 g of cellulose granules, 104.8 g of lactose and 30.0 g of talc. The mixture is compressed into 140 mg of nuclei.

b) The nucleus thus obtained is sprayed with a solution of 140.0 g of hydroxypropyl methylcellulose phthalate and 28.0 g of di-n-butylphthalate in a mixed solution of 616 g of ethanol and 616 g of acetone, and coated at about 10 mg per tablet.

c) The outer layer is a uniform mixture of 4.0 g of dihydro ergotamine mesylate with 4.0 g of dispersed silica gel, 6.0 g of magnesium stearate, 266.8 g of cellulose powder, 40.0 g of talc, 191.2 g of corn starch, and 348.0 g of calcium hydrogen phosphate. To prepare.

This mixture is compressed with enteric coating (according to Example 14b) to prepare tablets with an outer layer of total amount of 530.0 mg per one.

Example 15

Similar to Examples 1 to 14, using 4 mg of dihydro ergovalin or 4 mg of dihydro ergonin and 4 mg of bromocriptine, instead of dihydro ergotoxin or dihydro ergotamine, the corresponding ergot alkaloids were prepared as active ingredients. To obtain a tablet containing.

Example 16

Clinical trial

The composition according to Example 4 was compared with the solid solution of dihydro ergotoxin mesylate and tartaric acid (composition A) and the known composition of dihydro ergotoxin methylate (composition B).

Individuals were given 4 mg of dihydro ergotoxine mesylate, respectively.

The results are described in the following table.

The significance of the difference shown between the composition of Example 4 and Composition B was calculated according to the Student T test (* P <0.05, ** P <0.01, and * P <0.001).

The excellent delaying effects and excellent in vivo efficiencies of the compositions according to the invention are clearly explained in the table above. On the other hand, in the case of commercial compositions of dihydro ergotoxin delayed by conventional methods, it can be seen that the in vivo efficiency (60 to 70% of composition B) is clearly deteriorated.

Similar tests with other compositions according to the invention also show good results. However, commercially available compositions of dihydro ergotamine delayed by known methods exhibited in vivo efficiencies of about 30 to 40 percent compared to the in vivo efficiencies of nondelayed counterparts.

Claims (1)

The nucleus of the composition is characterized by incorporating a compound of formula (I) or a mixture thereof in polyalkoxy cyalkylenesterol ether, forming a nucleus, and then applying an enteric coat to the nucleus, wherein the nucleus of the composition contains the ergot alkaloid of formula (I) Method for producing a fixed enteric skin composition in the form of an oral unit dosage form. Wherein R ₁ is hydrogen or halogen, R ₂ is hydrogen or C _1-4 alkyl, R ₃ is isopropyl, secondary-butyl, isobutyl or benzyl and R ₄ is methyl, ethyl or isopropyl and R ₅ Is hydrogen and R ₆ is hydrogen or methoxy or R ₅ and R ₆ together form an additional bond.