JPS643846B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides pharmaceutical compositions for oral administration of ergot alkaloids, which are distinguished by a prolonged effect and a good bioavailability of the active agent. It is undisputed among medical experts that under many circumstances it is preferable to administer a drug once a day instead of multiple times a day. This is accomplished in "delay systems" by delaying the release of the active agent with the aim of providing a long-term therapeutic effect. In the field of ergot therapy, it has been found according to the present invention that delaying with traditional systems, such as with the aid of matrix systems or microencapsulation, always causes a significant reduction in the overall bioavailability. . It is also known that ergot alkaloids are stable in the presence of acids, which means that they do not degrade in gastric fluids and that absorption of ergot alkaloids occurs primarily in the intestinal tract. Therefore, enteric coated drugs containing ergot alkaloids cannot be expected to provide improved bioavailability. Therefore, when the coated core contains polyoxyalkylene sterol ether in addition to ergot alkaloids, not only the period of action of ergot alkaloids is sufficiently extended, but also the overall bioavailability is greatly improved. It is surprising that this was observed with the help of enteric coatings. Accordingly, the present invention more particularly provides a composition for oral administration, wherein the core of the composition contains a specific ergot alkaloid and a specific polyoxyalkylene sterol ether in a specific ratio, and the coating surrounding the core is an enteric coating. solid enteric coated compositions in unit dosage form for. The present invention also provides a method for producing the composition according to the present invention by enterically coating a core as described above consisting of an ergot alkaloid and a polyoxyalkylene sterol ether (hereinafter referred to as sterol ether). do. The "core" consists of a mixture of ergot alkaloids and sterol ethers, which may be admixed with physiologically acceptable substances if desired, and which can be surrounded by an enteric coating. In a broad sense,
The "core" is not only a tablet, pellet or granule, but also a capsule (e.g. a soft or hard gelatin capsule filled with a liquid or waxy mixture of ergot alkaloids, sterol ethers and optionally pharmaceutically acceptable substances). It may also consist of agents). Such capsules may then be enteric coated, for example, in a conventional manner.
If a tablet core is used, it is preferred that it has a hardness of about 10-70N. The pellets or granules may be used as is or filled into capsules, for example hard gelatin capsules, after being enterically coated. The preferred use of the composition according to the invention is therefore as tablets, pellets, granules or capsules. "Ergot alkaloids" refers to synthetic or semi-synthetic derivatives of natural ergot alkaloids (e.g. ergotamine, ergocristine, α-ergocributine, β-ergocributine and ergocornine) (e.g. ergovaline, dihydroergotoxine (as cordergocline) also known) and dihydroergotamine in its free base form or in its acid addition salt form with pharmaceutically acceptable organic or inorganic acids (methanesulfonic acid, maleic acid, tartaric acid or hydrochloric acid). The activator of interest is the formula [In the formula, R ₁ is C _1-4 alkyl _, R ₂ is isopropyl, sec-butyl, isobutyl or benzyl,
R ₃ is methyl or isopropyl. ] or a mixture thereof. Particularly preferred compositions of the invention contain as active agent dihydroergotoxine or dihydroergotamine in free base form or preferably in acid addition salt form. Preferred sterol ethers for use in the compositions of the invention have a hydrophilic-lipophilic balance value (HLB group number) of about 10-20, especially 12-16. The ethers include ethers of lanosterol, dihydrocholesterin and especially cholesterin,
or mixtures of such ethers are preferred. In particular, sterol ethers are sterols etherified with 9 to 30 alkylene oxide units. The hydroxy groups of the terminal alkylene units of such sterol ethers may be partially or completely acylated, for example by acyl residues of aliphatic carbon acids (eg acetyl). Particular preference is given to sterol ethers etherified with ethylene oxide and/or propylene oxide units. Sterol ethers are obtained in conventional manner by etherification of sterols with corresponding amounts of epoxides and, if necessary, acylation of the resulting alcohols. The ether is partially available on the market, ie marketed by the company Amerchol under the trade name Solulan. Examples of Solulan types that are commercially available and suitable for use in compositions according to the invention are:
For example: a 1 mole of cholesterin (Solulan C-24) with 24 moles of ethylene oxide b 1 equivalent of lanolin alcohol (Solulan 16) with about 16 equivalents of ethylene oxide c 1 equivalent of lanolin alcohol (Solulan 25) with about 25 equivalents of ethylene oxide ) d Partial acetyl of 1 equivalent of lanolin alcohol (Solulan PB-10) obtained by alkoxylation with about 10 equivalents of propylene oxide and e ethoxylated with about 10 equivalents of ethylene oxide. (Solulan 98) and f a fully acetylated derivative of 1 equivalent of lanolin alcohol ethoxylated with about 9 equivalents of ethylene oxide (Solulan 97). "About" in a) to f) above means that the number of donated equivalents of ethylene oxide or propylene oxide is an average value, that is, a certain sterol ether has more or fewer ethyleneoxy groups or propyleneoxy groups. shows. Lanolin alcohol is known as wool wax alcohol (Handbuch der Kosmetika und
Riechstoffe, Ed.2, 1950, Vol.I, page 1101
(Janistyn), a mixture of cholesterin, cyhydrocholesterin and lanosterol. "Enteric coatings" prevent the release of the active agent in the stomach and are sufficiently degraded in the intestinal tract (by contact with near-neutral or alkaline intestinal fluids) to allow absorption of the active agent through the walls of the intestinal tract. consisting of a pharmaceutically acceptable coating that provides a Various in vitro tests for determining whether a coating is classified as an enteric coating are published in national pharmacopeias. More specifically, the "enteric coating" according to the present invention can be combined with artificial gastric fluid such as HCl with a pH of 1.2 to 36-38
Refers to a coating that remains intact on contact at 0.degree. C. for at least 1 hour, such as 2 hours, and then disintegrates in 30 minutes in an artificial intestinal fluid, such as a KH ₂ PO ₄ buffer solution at PH 6.8. The thickness of the coating may vary and depends, among other things, on its permeability in water and acids and on the desired retardation effect. Generally, a satisfactory result is 5-100μ
m, preferably with a coating thickness of 20 to 80 μm. The coating is suitably selected from high molecular weight polymers. Suitable polymers are, for example, those described by Hagers Handbuch der
Pharmazeutischer Praxis, Ed.4, Vol.7a, pages 739-742 and 776-778 (Springer Verlag,
1971) and Remington's Pharmaceutical
Sciences, Ed. 13, pages 1689-1691 (Mack
Publ. Co., 1970) and consist of, for example, cellulose ester derivatives, cellulose ethers, acrylic resins (eg methyl acrylate copolymers) and copolymers of maleic and phthalic acid derivatives. Preferred films are made from cellulose acetate phthalate, copolymers derived from methyl acrylic acid and its esters containing at least 40% methyl acrylic acid, and especially hydroxypropyl methyl cellulose phthalate. An example of a suitable cellulose acetate phthalate is the commercial product CAP (Eastman Kodak,
Rochester N.Y., USA). Examples of suitable hydroxypropyl methylcellulose phthalates are:
The market products are HP50 and HP55 (Shin-Etsu, Tokyo, Japan). Since a coating consisting essentially of CAP degrades at a higher PH than, for example, a coating consisting essentially of KP50, the release of active agent from a composition provided with the former coating will be lower than that of a composition provided with the latter coating. It will probably be even slower than if it were from . In this way, by appropriate selection of the coating, a retarding effect can be obtained taking into account the nature of the activator in an optimal manner. The method according to the invention may be carried out in a manner analogous to known methods using enteric coatings. Coated tablets, pellets or granules can be produced by, for example, spraying the core with an enteric coating solution. Suitable solvents for enteric coatings include, for example, organic solvents (e.g. alcohols such as ethanol,
a ketone such as acetone, a halogenated hydrocarbon such as CH ₂ Cl ₂ , or a mixture of such solvents (eg ethanol/acetone = 1:1).
It is advantageous to add softeners such as di-n-butyl phthalate to such solutions. Advantageously, the core is warmed to 25-40°C, for example by heated air at 40-70°C, before spraying. To avoid core sticking, the spraying process is preferably interrupted at predetermined time intervals and the cores are then warmed up again. The spray pressure may be varied over a wide range, and generally satisfactory results are obtained with a spray pressure of about 1 to 1.5 bar. However, it is also possible to carry out without interrupting the spraying process, for example by automatically adjusting the spray amount as a factor of the exhaust air and/or the temperature of the core. The enteric coated compositions of the present invention have the advantageous property that, after oral administration to humans, maximum concentrations of active agent in the plasma are obtained after about 4 to 6 hours. In contrast, the first peak after administration of conventional compositions, for example tablets, is already reached after 0.5 to 1 hour. The therapeutic effects of the compositions of the invention are also illustrated by measuring the concentration of active agent (and metabolites) in excreted urine. Maximum concentrations in urine have been found approximately 6 hours after administration. In contrast, when administering conventional compositions, this maximum is achieved in about 2 hours. In addition, the plasma levels after administration of the composition according to the invention are between 6 and 24 hours after use and are higher than after administration of conventional compositions, eg tablets. This is illustrated by the area under plasma level (AUC), which is a measure of the superior bioavailability of the compositions of the present invention. Thus, the compositions of the present invention exhibit a therapeutically desirable delayed effect with excellent bioavailability, thus allowing treatment with a single unit dose per day. The compositions of the invention, particularly tablets, may be further covered by other drug layers. This outer layer contains, in addition to active agents such as ergot alkaloids, carriers and/or fillers that are soluble or dispersible in gastric fluids (e.g. talc, microcrystalline cellulose,
magnesium stearate, mannitol, polyvinylpyrrolidone, etc.). Such compositions may be used, for example, when rapid onset of activity is required. The high initial concentration of ergot alkaloids in the blood is maintained by sustained release from the core in the intestinal tract. The optimum weight ratio of ergot alkaloid:sterol ether in the core depends to a large extent on the physical properties of the sterol ether contained, the adjuvant used, and the type and size of the composition.
The amount of the abovementioned sterol ethers of the Solulan 16, Solulan 25 and Solulan C-24 types is likewise limited in view of their waxy nature. However, generally satisfactory results are 1:2 to 1:
8, preferably obtained when employing an ergot alkaloid:sterol ether weight ratio of 1:4. A range of 1:2 to 1:8 is particularly preferred when the core is present in the form of a solid solution of the ergot alkaloid, especially when polyvinylpyrrolidone is used as solid solvent. The core contains the usual excipients (e.g. binders, lubricants,
fillers and disintegrating agents). Suitable fillers for making tablet cores are, for example, calcium carbonate silica gel, sodium carbonate, lactose, starch, talc. Suitable granulating and disintegrating agents are, for example, starch and alginic acid. Suitable binders are, for example, starch and gelatin, and suitable lubricants are stearic acid and talc. The use of the core in solid solution form is a special embodiment of the invention. Such a core may be prepared as follows. An ergot alkaloid, a sterol ether, and a pharmaceutically acceptable polymer that is at least partially soluble in the aqueous medium are mixed, particularly polyalkylene glycols, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinyl acetate, or mixtures thereof. Suitable polyalkylene glycols range from 200 to
20000, preferably 4000-15000, more preferably
Includes polyethylene glycol, polypropylene glycol and copolymers thereof, with a molecular weight of 6000-13000. Non-crosslinked poly(N-vinyl) by “polyvinylpyrrolidone”
Means pyrrolidone-2, 10,000 to 100,000, preferably 11,500 to 40,000, more preferably 20,000 to
A molecular weight of 30,000 is preferred. The copolymer of vinylpyrrolidone and vinyl acetate contains 60wt% vinylpyrrolidone and 40wt% vinyl acetate,
It preferably has a molecular weight of 30,000 to 100,000, more preferably 40,000 to 90,000. When desired stabilizers such as acids, preferably methanesulfonic acid, maleic acid and tartaric acid are added to adjust the PH of the composition, the preferred PH range of the composition is PH4-6, preferably PH4-5. It is. The weight ratio of ergot alkaloid:sterol ether:pharmaceutically acceptable polymer may vary widely, but generally preferred results are from 1:2 to 8:
Obtained in a ratio of 0.1-10, preferably 1:2-5:0.1-5. To produce the solid solution according to the invention, the polymer is used in solid form. If certain polymers used are liquid at room temperature, for example polyalkylene glycols with a molecular weight of about 200,
Such polymers cannot be used alone, but may be used in conjunction with polymers that are solid at room temperature. The above components are dissolved in a suitable solvent, for example in a lower alcohol such as ethanol or methanol or in chloroform, at 30-70°C, preferably at 40°C.
Dissolve by stirring at a temperature of ~60 °C. The solvent may be removed by evaporation under reduced pressure at the same temperature. In preparing the solution, it is possible to add only some of the polymer and additional components, or to add the remaining components, if any, during evaporation of the solvent. The resulting clear solution is left to solidify at room temperature (15-25 °C), then the solid solution or dispersion is ground to a fine powder and suitably dried under reduced pressure at 80 °C to remove all traces of solvent. do. The solid solution (core of the composition) obtained according to the above method is then treated with a pharmaceutically acceptable diluent or carrier, optionally an additional amount of sterol ether (wherein the total amount of sterol ether in the core is as given above). (should be within the specified range) and formulated by known methods. Next, the present invention will be specifically explained with reference to Examples. Reference Example 1 3 g of dihydroergotamine, 75 g of cholesterin ethoxylated with about 24 moles of ethylene oxide (Solulan C-24), and dispersed silica gel
Tablet cores consisting of 22 g are heated to 30° C. for 10 minutes with heated air at 50° C. in a repeatedly rotating coating pan. The tablet cores were then sprayed with a spray pistol and 5.4 g of hydroxypropyl methyl cellulose phthalate (HP50) and G-n-
A solution of 1.35 g of butyl phthalate in a 1:1 ethanol/acetone mixture is sprayed at a spray pressure of 1 to 1.5 bar using a conventional interval spray coating method. The coated tablets thus obtained are dried. Reference Example 2 The same procedure as Reference Example 1 is carried out, except that lanolin alcohol (Solulan25) ethoxylated with about 25 equivalents of ethylene oxide is used instead of 75 g of cholesterin ethoxylated with about 24 moles of ethylene oxide. . Example 1 Tablets coated with a core in solid solution form: - Dihydroergotoxine methanesulfonate 15
g, 1.05 g of Solulan C-24, 33.98 g of polyvinylpyrrolidone (average molecular weight 25000), and 250 ml of methanol are placed in a round bottom flask. Attach the flask to a rotary evaporator and rotate at a bath temperature of 60 °C until the flask contents reach 60 °C. During this time a clear solution is obtained. The bath temperature is maintained at 60° C. and the solvent is evaporated under reduced pressure until the residue has a syrupy consistency. Decant the residue into an evaporation dish and leave to solidify at room temperature for 2 hours. Heat the solid residue in a vacuum oven at 30°C, approx.
0.001316 atm, dried for about 12 hours, ground into fine powder and dried again. 26.8 g of the resulting solid solution is then mixed with the following adjuvant until a homogeneous mixture is obtained. Silicon dioxide (Aerosil 200, Degussa)
1.0 g Polyvinylpyrrolidone (cross-linked) 8.0 g Corn starch 20.0 g Talc 30.0 g Solulan C-24 30.0 g Cellulose powder (Elcema G250) 42.0 g Lactose 122.0 g The mixture is then pressed into 140.0 mg tablet cores in the usual manner ( hardness 10~32N). Cellulose acetate phthalate (CAP), in which the obtained cores are sprayed with the following solution in the same manner as in Reference Example 1, until the cores are coated with a mixture of about 10 mg of cellulose acetate phthalate/d-n-butyl phthalate per core.
90.0g D-n-butyl phthalate 22.5g Acetone 240.0g Ethanol 21.0g Dichloromethane 526.5g 900.0g The core remains intact even after being treated with artificial gastric juice of PH=1.2 for 1 hour, so the resulting coated tablet is resistant to gastric juice. It has resistance to The decomposition time in artificial intestinal fluid is
1 hour or more at PH5.5, 23-28 minutes at PH6.0, and
12 to 16 minutes at pH 6.8. Example 2 616 g of ethanol with 140.0 g of hydroxypropyl methylcellulose phthalate (HP50) and 28 g of di-n-butyl phthalate in a 140 mg tablet core.
and acetone 616 g mixture solution as in Example 1, except that the cores were coated with a mixture of hydroxypropyl methylcellulose phthalate/d-n-butyl phthalate (ratio 10:2) at about 9 mg per core. implement. Example 3 Dihydroergotoxin methanesulfonate 4
Example 1
You can get it in the same way. This solid solution is then mixed with the following ingredients. Silicon dioxide 0.5g Polyvinylpyrrolidone (average molar amount 2000)
4.0g Cornstarch 10.0g Talc 15.0g Solulan16 15.0g Cellulose powder (Elcema G250) 21.0g Lactose 61.1g This mixture is pressed into 140.0mg tablets. The resulting tablet cores are then sprayed as in Example 2 until each core is coated with about 10 mg or about 15 mg of the hydroxypropyl methylcellulose phthalate/d-n-butyl phthalate mixture. Similar to the method of the above examples, the tablets listed in Table 1 below are obtained. In the case of Ib and Ic (see Table 1), the tablet core is in solid solution form.

[Table] Example 12 Tablet with drug outer layer (coated tablet): - a (dihydroergotamine mesylate 8.0 g,
26.8 g of a solid solution (composed of 0.6 g of Solulan C-24 and 18.2 g of polyvinylpyrrolidone) was mixed with 1.0 g of highly dispersed silica gel and cross-linked polyvinylpyrrolidone.
8.0g, cornstarch 20g, Solulan C-24
47.4g, cellulose powder 42.0g, lactose
A core is produced in the same manner as in Example 1 by mixing 104.8 g and 30.0 g of talc until the mixture becomes homogeneous. The mixture is then pressed into 140.0 mg cores. b. Spray the resulting cores with a solution of 140.0 g of hydroxypropyl methylcellulose phthalate and 28.0 g of di-n-butyl phthalate in a mixture of 616 g of ethanol and 616 g of acetone until the cores are coated with approximately 10 mg per tablet. c Dihydroergotamine mesylate 4.0g, dispersed silica gel 4.0g, magnesium stearate 6.0g, cellulose powder 166.8g, talc 40.0
The drug outer layer is prepared by mixing 191.2 g of cornstarch, 191.2 g of calcium hydrogen phosphate, and 848.0 g of calcium hydrogen phosphate until the mixture is homogeneous. This mixture was then pressed into coated tablets (of Example 12b) having a total weight of 530.0 mg per tablet.
A tablet with a drug outer layer is manufactured. Example 13 Analogously to Examples 1 to 12, 4 mg of dihydroergovaline or 4 mg of dihydroergonine are used instead of dihydroergotoxine or dihydroergotamine, and tablets containing the corresponding ergot alkaloid as active agent are obtained. Example 14 Clinical Trial: - The composition according to Example 2 was compared with a solid solution of dihydroergotoxin mesylate and tartaric acid (composition A) and a conventional composition of dihydroergotoxin mesylate (composition B). Each person for the study received 4 mg of dihydroergotoxin mesylate. The results are listed in the table below.

Table: The significance of the differences observed between the composition of Example 2 and Composition B was calculated according to the Student's T-test (P ^* <0.05, P ^** <0.01, P ^*** <
0.001). The good retardation effect and excellent bioavailability of the compositions according to the invention are clearly demonstrated by the values in the table above. On the other hand, testing of commercial compositions of dihydroergotoxine delayed according to conventional methods revealed a clearly inferior bioavailability (60-70% of composition B). Similar tests with other compositions according to the invention give equally good results. However, commercial compositions of dihydroergotamine retarded by conventional methods have shown bioavailability that is approximately 30-40% inferior to that found with the corresponding non-retarded controls.

Claims (1)

[Scope of Claims] 1. A pharmaceutical composition for oral administration comprising a core,
The above core is (i) [In the formula, R ₁ is C _1-4 alkyl _, R ₂ is isopropyl, sec-butyl, isobutyl or benzyl, and R ₃ is methyl or isopropyl. ] or a mixture thereof; and (ii) a polyoxyalkylene sterol ether having 9 to 30 alkylene oxide units, the weight ratio of (i):(ii) being 1:2 to 1:8; , a composition coated with an enteric coating. 2. The composition according to claim 1, wherein the ergot alkaloid is dihydroergotamine. 3. The composition according to claim 1, wherein the ergot alkaloid is dihydroergotoxin. 4 Polyoxyalkylene sterol ether is
A composition according to any one of claims 1 to 3 having a hydrophilic-lipophilic balance of 10 to 20. 5 Polyoxyalkylene sterol ether is
5. A composition according to claim 4 having a hydrophilic-lipophilic balance of 12-16. 6. The composition according to any one of claims 1 to 5, wherein the sterol moiety of the polyoxyalkylene sterol ether is lanosterol, dihydrocholesterin and/or cholesterin. 7. The composition according to any one of claims 1 to 6, wherein the polyoxyalkylene sterol ether is a sterol etherified with ethylene oxide or propylene oxide. 8. The enteric coating according to any one of claims 1 to 7, wherein the enteric coating is selected from cellulose ester derivatives, cellulose ethers, acrylic resins, or derivative copolymers of maleic acid and phthalic acid. Composition. 9. Claim 8, wherein the enteric coating consists of cellulose acetate phthalate.
Compositions as described in Section. 10. The composition of claim 9, wherein the enteric coating comprises hydroxypropyl methylcellulose phthalate. 11. The composition of claim 8, wherein the enteric coating consists of methyl acrylic acid and its esters containing at least 40% methyl acrylic acid. 12. A composition according to any one of claims 1 to 11, wherein the enteric coating comprises a softener. 13. The composition according to claim 12, wherein the softener is di-n-butyl phthalate. 14. The composition according to any one of claims 1 to 13, which is in the form of a tablet, granule, pellet or capsule. 15 The core of the composition contains an ergot alkaloid and a polyoxyalkylene sterol ether, the coating surrounding the core is an enteric coating,
A composition according to claim 1, which is a solid enteric coated composition in the form of a unit dosage tablet for oral administration, characterized in that the core is in solid solution form. 16. The composition according to claim 15, wherein the core contains polyalkylene glycol, polyvinylpyrrolidone, and/or vinylpyrrolidone, and/or a copolymer of vinylpyrrolidone and vinyl acetate as solid solvent. 17. The composition according to claim 16, wherein the weight ratio of ergot alkaloid: polyoxyalkylene sterol ether: solid solvent in the core is 1:2 to 8:0.1 to 10. 18. The composition according to claim 17, wherein the weight ratio is 1:2 to 5:0.1 to 5. 19. A composition according to any one of claims 15 to 18, wherein the core contains a stabilizer. 20. The composition according to claim 19, wherein the core is stabilized by adjusting its pH to 4 to 6 with an acid.