JPH0566367B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to enterally applied pharmaceutical agents.

BACKGROUND OF THE INVENTION It is known that the bioavailability of orally or intravenously applied pharmaceutical agents is often unsatisfactory. Recently, therefore, attempts have been made to improve the bioavailability of drug active substances by enteral application. So, for example, West German patent application publication no.
No. 3,131,610 describes an enteral preparation of glycerin trinitrate. However, this application
For the enteral application of water-soluble slightly solid drugs, the diffusion rate of the active substance in this type of application is unsuitable.

Means for Solving the Problems In contrast, the application agents according to the invention are also very suitable for the enteral application of only slightly water-soluble solid drug active substances.

Pharmaceutical active substances dissolved in the gel include, for example, analgesic-antirheumatic agents with ulcerative side effects, antibiotics, ergot compounds, β-receptor blockers, prostaglandins, prostacyclins, cardioactive glycosides, pharmacological agents. It is possible to use sex peptides or in particular steroid hormones.

Suitable sedative-antirheumatic agents are, for example, phenylbutazone, oxyphenylbutazone, Indomethacin, Naproxen, Ibuprofen and the like.

Suitable antibiotics are inter alia penicillin, tetracycline or streptomycin.

Suitable β-receptor blockers are, for example, Pindolol, Mepindolol or Propranolol.

Suitable prostaglandins or prostacyclins are, for example, Iloprost or Nileprost.

Suitable cardioactive glycosides are, for example, digitalis glycosides or strophanthosides.

Suitable pharmaceutically active peptides include, inter alia
Gonadotropic peptides such as LHRH (luteinizing hormone releasing hormone).

Suitable steroid hormones are in particular estrogens, gestagens, androgens or anabolic hormones, such as estradiol and its esters, namely valerate, benzoate or undecyl ester, estrogens such as ethinylestradiol, norethisterone acetate, levo Norgestrel (Levonorgestrel), Chlormadinone Acetate,
gestogens, testosterone and its esters (propionate esters,
androgens such as undecylate ester, etc.) and anabolic agents such as metandrostenolone, Nandrolon and its esters.

The amount of drug active substance contained in the application agent naturally depends on its effectiveness and on its absorbability and must be ascertained in the customary manner in each individual case.

A well-water soluble drug agent can be dissolved in a gel consisting of water and a thickening agent.

Since the application agent according to the invention is intended in particular for the enteral application of drug active substances that are poorly soluble in water, the gel used for dissolving the active substance is
It consists in particular of a thickener, a high-boiling organic solvent of no physiological concern and optionally water.

The optionally aqueous solvent must be sufficiently lipophilic to dissolve the drug active substance;
On the other hand, it must also have sufficient hydrophilicity to enable the desired active substance transport. Suitable solvents are, for example, dimethylformamide or especially polyhydric alcohols or polyhydric ethers. Examples of polyhydric alcohols or polyhydric ethers include: ethylene glycol, propylene glycol, glycerin, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, dimethyl isosorbide (=
3,6-dimethoxy-furo[3,2-b]furan), diethylene glycol and its ether (“Ro¨mpp”, Dr.Otto-Albrecht Neumu¨ller:
Ro¨pps Chemie Lexikon, 7th edition, 1972,
Franckh′sche verlagshandlng Stuttgart,
Bundesrepubrik Deutschland, 814815) or polyethylene glycol with a molecular weight up to 600 (“Ro¨mpp”, 27502751). The hydrophilicity of the solvent can be increased by adding water. On the other hand, the hydrophilicity of the solvent is increased by the addition of non-polar oils, such as esters of long-chain fatty acids known under the name Cetiol ^(R) .

The application agent according to the invention may, of course, contain anhydrous solvents only if the thickener necessary for gel formation is swellable, for example carboxymethyl cellulose in dimethyl isosorbitol. good. In other cases, water must be added to the solvent in such an amount that swelling of the thickener is possible.

As thickeners (“Ro¨mpp” 3792) the swelling agents which are customary for gel formation in galenic preparations are used. Thickeners include, for example: natural organic thickeners such as agar, gelatin, gum arabic, pectin, etc., modified organic natural substances such as carboxymethyl cellulose or cellulose ethers, or polyesters. Fully synthetic organic thickeners such as acrylic compounds, vinyl polymers or polyethers. Particularly advantageous thickeners are, for example, Carbopol ^(R) .
or carboxymethylcellulose.

The thickener is placed in such a way that the resulting gel is no longer flowable.

The gel containing the drug active substance forms the inner layer of the application according to the invention, whereas the outer layer of the application consists of a crosslinked silicone elastomer. As a silicone elastomer, especially addition-crosslinked
RTV systems are used, which are condensation-crosslinked
This does not exclude that RTV systems may also be used.
Two component systems (Ullmanns Encyklopedie der
technischer Chemie, 4th edition, Volume 21 (1982
(2013), entry “Silicone” (see page 511 et seq.) is advantageous. Such a two-component system consists, for example, of: 1-10% by weight of polydimethylhydrogensiloxane with an average molecular weight of 300-2000 2,4,6,8-tetramethyl-2,4,6,8
-tetravinyl-cyclotetrasiloxane
1-10% by weight platinum catalyst 10-100ppm and average molecular weight 3000-
20000 vinyl endcapped polydimethylsiloxane.

Usually two components are formed, the first component containing a polydimethylhydrogen siloxane and a portion of vinyl end-capped polydimethylsiloxane.

The second component contains the remainder of the vinyl endcapped polydimethylsiloxane, 2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane and catalyst.

Suitable platinum catalysts include, for example, 2,4,6,8-
Tetramethyl-2,4,6,8-tetravinyl-
Cyclotetrasiloxanyl platinum.

polydimethylhydrogensiloxane, vinyl endcapped polydimethylsiloxane and 2,4,
By changing the quantitative ratio of 6,8-tetramethyl-2,4,6,8-tetravinylsiloxane and changing the chain length of polymethylhydrogensiloxane and vinyl end-capped polydimethylsiloxane, the crosslinked molecular length of the silicone elastomer can be changed. can be varied within a wide range. This makes it possible, according to the invention, to produce enteral applications of drug active substances with very different diffusion coefficients and thus to prepare them in such a way that an optimum release rate of the active substance is achieved.

The degree of crosslinking can be determined by measuring the crosslinking index by dividing the empirically determined molecular weight between the crosslinking points (=network chain length) by the molecular weight of one siloxane unit. Empirical verification of the molecular weight between cross-linking points is provided by Treloar's publication: The Physics of Rubber Elasticity: Clarendon.
Press Oxford), 1975, p. 142.

In general, it is advantageous to choose silicone elastomers with a crosslinking index of 20 to 500, in particular for steroid hormones silicone elastomers with a crosslinking index of 50 to 250.

For the preparation of the application according to the invention, the component mixture is intimately mixed with 1/3 to 3 parts by weight of the gel containing the drug active substance, so that the gel phase has a droplet size of about 5 μ to 500 μ. Make it distributed, and 0.5~
It is cured at 40-100°C so that a 5 mm thick sheet results.

The transport of the active substance from the application agent according to the invention (hereinafter referred to as "system") through its outer interface in the direction of the film is caused by a concentration gradient Cis/Cas (Cis=
(internal concentration of Cas system, external concentration of Cas system), interface A,
Written as a function of time t, concentration Cis and diffusion coefficient D: Qt=f(A, t, Cis, D).

This macroscopic consideration also applies to the microscopic consideration of the gel/silicone interface within the system. Due to the interface A' of the internal layer to the external phase, the active substance diffuses in the direction of the external interface of the system due to the concentration gradient.

The diffusion coefficient D′ of the active substance in the external layer, the length l of the diffusion path and the size A′ of the interface between the internal and external phases determine the active substance transport inside the system: q _t = f(A', t, l, D').

The size A' depends on the droplet distribution in the system and can be easily adjusted by process parameters. Therefore, the ratio
By varying A'/A over a wide range, for example from 25 to 500, the active substance release of the system can be varied.

Furthermore, the general functional formula: Qt=f(A'/A, t,
Cis, D′/D), the emission modification is the diffusion coefficient D′(=
It becomes clear that this can be achieved by changing the diffusion (diffusion within the system). Varying the diffusion coefficient D' is achieved by the intended composition of the silicone rubber phase.

As the degree of crosslinking increases, the "free volume" in the network decreases and the diffusion resistance increases.

The easy tunability of factors A' and D' gives rise to a significant advantage over other systems: these are mutually independent quantities for regulating the release of the active substance.

To produce a plaster, for example, small disks of the application agent according to the invention are cured onto an aluminium-coated support sheet, the support sheet is provided with an adhesive around the application agent and sealed with a protective sheet. I can do it.

The following examples are used to illustrate the invention.

Examples Example 1 (A) Preparation of active substance-containing gel phase: 87% with 22.55 g of dimethyl diglycol
300 mg of estradiol-17-valerianate are dissolved in a mixture consisting of 22.55 g of glycerin and 5.64 g of distilled water. The solution is thickened with stirring at room temperature with ^Carbopol® 9341.13 g. For complete gel formation as well as adjustment of the physiological PH ratio, adjust the pH to 5.0 with approximately 1N caustic soda solution.

(B) Preparation of the silicone elastomer phase: In a hermetically sealable reaction vessel with a stirrer, 48.80 g of vinyl end-capped dimethylpolysiloxane (average molecular weight 6000), 2,4,
0.42 g of 6,8-tetramethyl-2,4,6,8-tetravinyl-tetracyclosiloxane and 2.99 g of polydimethylhydrogensiloxane with an average molecular weight of 350 to 500 and a platinum catalyst (2,
4,6,8-tetramethyl-2,4,6,8-
15 ppm of tetravinyl-tetracyclosiloxanyl platinum (in the form of a toluol solution) are mixed.

(C) Preparation of enteral application of estradiol-17-valerianate The gel phase prepared by (A) is added to the silicone elastomer phase and the mixture is stirred at 1250 rpm for 20 minutes under vacuum (100 Torr). . after that,
The dispersion obtained is cured for 1 hour at 60° C. in a disc-shaped sheet mold with a surface area of 10 cm and a depth of 1.5 mm.

Example 2 (A) Preparation of active substance-containing gel phase: 8.5 g dimethyl diglycol, 8.5 g Cetiol ^(R) HE, 4.0 g distilled water, 20 g 87% glycerin, 1.0 polyglycol (molecular weight 400).
500 mg of testosterone are dissolved in a mixture consisting of 3.0 ml of buffer solution with pH 9.0 and pH 9.0. The solution is thickened with 0.85 g of ^Carbopol® 934 with stirring.

(B) Preparation of the silicone elastomer phase: In a hermetically sealable reaction vessel with a stirrer, 51.37 g of vinyl end-capped dimethylpolysiloxane (average molecular weight 6000), 2,4,6,
0.93 g of 8-tetramethyl-2,4,6,8-tetravinyl-tetracyclosiloxane and
0.914 g of polydimethylhydrogensiloxane with an average molecular weight of 350-500 and a platinum catalyst (2,4,
15 ppm of 6,8-tetramethyl-2,4,6,8-tetravinyl-tetracyclosiloxanyl platinum (in the form of a toluene solution) are mixed.

(C) Preparation of enteral application of testosterone: The gel phase prepared by (A) is added to the silicone elastomer phase and the mixture is stirred at 1250 rpm for 20 minutes under vacuum (100 Torr). after that,
The dispersion obtained is cured for 1 hour at 60° C. in a disc-shaped sheet mold with a surface area of 10 cm and a depth of 1.5 mm.

Example 3 (A) Preparation of active substance-containing gel phase: 10.68 g of anhydrous glycerin, Cetiol ^(R)
In a mixture consisting of 49.9 g of HE and 8.93 g of distilled water,
Dissolve 0.8g of estradiol. This solution is thickened with 1.84 g of ^Carbopol® 934 while stirring. PH5.0 with approximately 1N caustic soda solution to improve gel structure and adjust physiological conditions.
Adjust to

(B) Preparation of the silicone elastomer phase: In a hermetically sealable reaction vessel equipped with a stirrer, 82.40 g of vinyl end-capped dimethylpolysiloxane (average molecular weight 6000), 2,4,6,
0.42 g of 8-tetramethyl-2,4,6,8-tetravinyl-tetracyclosiloxane and
2.99 g of polydimethylhydrogensiloxane with an average molecular weight of 350-500 and a platinum catalyst (2,4,
15 ppm of 6,8-tetramethyl-2,4,6,8-tetravinyl-tetracyclosiloxanyl platinum (in the form of a toluene solution) are mixed.

(C) Preparation of enteral application of estradiol: The gel phase prepared by (A) is added to the silicone elastomer phase and the mixture is stirred at 1250 rpm for 20 minutes under vacuum (100 Torr). after that,
The dispersion obtained is cured for 1 hour at 60° C. in a disc-shaped sheet mold with a surface of 10 cm and a depth of 0.9 mm.

Example 4 (A) Preparation of the active substance-containing gel phase: Polyglycol (molecular weight 6000) is added under mild heating (approximately 45° C.) into a mixture consisting of 5.0 g of distilled water, 5.0 g of anhydrous glycerin and 15.0 g of dimethyl diglycol. Dissolve 5.0g.

After cooling, microcrystalline Lisuride base
Mix 0.1g. 30% of the active substance remains insoluble.

Thicken the batch with 1.0g of Carbopol ^(R) 934 while stirring, and add approximately 1N-caustic soda solution to PH5.0.
Adjust to

(B) Preparation of the silicone elastomer phase: In a hermetically sealable reaction vessel equipped with a stirrer, 56.91 g of vinyl end-capped dimethylpolysiloxane (average molecular weight 6000), 2,4,
0.09 g of 6,8-tetramethyl-2,4,6,8-tetravinyl-tetracyclosiloxane and 1.04 g of polydimethylhydrogensiloxane with an average molecular weight of 350 to 500 and a platinum catalyst (2,
4,6,8-tetramethyl-2,4,6,8-
15 ppm of tetravinyl-tetracyclosiloxanyl platinum (in the form of a triol solution) are mixed.

(C) Preparation of enteral application of Lizulide base: The gel phase prepared by (A) is added to the silicone elastomer phase and the mixture is stirred at 1250 rpm for 20 minutes under vacuum (100 Torr). after that,
The resulting dispersion was heated at 60°C in a disc-shaped sheet mold.
Let it harden for 1 hour.

Example 5 (A) Preparation of active substance-containing gel phase: dimethyl isosorbide (DMI, Atlas-
Dissolve 2.76 g of estradiol in 49.52 g of Chemie D-4300 Essen.

While stirring, 2.72 g of hydroxypropyl cellulose (Klucel ^® GF) (product of Herkules GmbH, D-2050 Hamburg) are added.
After stirring for 4 hours at room temperature, a gel is obtained.

(B) Preparation of the silicone elastomer phase: In a hermetically sealable reaction vessel with a stirrer, 47.14 g of vinyl end-capped dimethylpolysiloxane (average molecular weight 6000), 2,4,6,
0.55 g of 8-tetramethyl-2,4,6,8-tetravinyl-tetracyclohesiloxane and
2.31 g of polydimethylhydrogensiloxane with an average molecular weight of 350-500 and a platinum catalyst (2,4,
15 ppm of 6,8-tetramethyl-2,4,6,8-tetravinyl-tetracyclosiloxanyl platinum (in the form of a toluene solution) are mixed.

(C) Preparation of enteral application of estradiol: The gel phase prepared by (A) is added to the silicone elastomer phase and the mixture is stirred at 1250 rpm for 20 minutes under vacuum (100 Torr). after that,
The dispersion obtained is cured for 1 hour at 60° C. in a disc-shaped sheet mold with a surface area of 10 cm and a depth of 0.5 mm.

Claims (1)

[Scope of Claims] 1. characterized in that at least 50% of the drug active substance is dissolved in a non-flowing and physiologically non-concerning gel that is distributed in fine dispersion in a cross-linked silicone elastomer. enteral application of drug active substances. 2. The drug active substance according to claim 1, wherein the drug active substance is a steroid hormone, an ergot compound, a β-receptor blocker, a prostaglandin, a prostacyclin, a cardioactive glycoside, or a pharmaceutically effective peptide. enteral application. 3 The drug active substance is a steroid hormone,
An enteral preparation of the drug active substance according to claim 2. 4. The gel is an aqueous liquid containing a thickener, optionally a polyhydric alcohol or polyhydric ether;
An enteral preparation of a pharmaceutically active substance according to any one of claims 1 to 3. 5. Any one of claims 1 to 4, wherein the crosslinked silicone elastomer is an addition crosslinked silicone-cold elastomer.
Enteral application agent of the drug active substance described in 2. 6 Cross-linked silicone elastomer is 20~
5. An enteral preparation for pharmaceutically active substances according to any one of claims 1 to 5, which has a crosslinking index of 500. 7 Cross-linked silicone elastomer is 50~
6. An enteral preparation for pharmaceutically active substances according to any one of claims 1 to 6, which has a crosslinking index of 250. 8 suspending the drug-containing gel in the ingredients necessary for the formation of the crosslinked silicone elastomer;
A method for producing an enteral preparation for a drug active substance, which method comprises curing the resulting suspension.