JPS6168430A - Drug enterosoluble application - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Industrial applications TECHNICAL FIELD The present invention relates to enterally administered 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. Thus, for example, DE 31 31 610 A1 describes enteral preparations of glyceryl trinitrate. However, this application is not suitable for the enteral administration of small, water-bathable solid drugs, since the diffusion rate of the active substance in this type of application is too low.

Means for Solving the Problems In contrast, the application agents according to the invention are also very suitable for the enteral application of water-soluble, slightly 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, prostagranones, prostacyclins, cardioactive glycosides, pharmaceuticals. Active peptides or especially steroid hormones can be used.

Suitable sedative-antirheumatic agents include, for example, phenylbutacin, oxyphenylbutacin, indometacin:
Inaomethacin), naproxen (IJa
proxen), ibuprop x 7 (upr
ofen) etc.

Suitable antibiotics are inter alia penicillin, tetracycline or streptomycin.

Suitable β-receptor blockers include, for example, Pindolol, Mebindolol,
ndolol) or propranolol /I/ (P
rop-ranOlol).

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

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

Suitable pharmaceutically active peptides include, inter alia, HRH (
gonadotropic peptides such as luteinizing hormone-releasing hormone).

Suitable steroid hormones are in particular estrogens such as nistrodan, gestagen, anl-''a-gen or anabolic sex hormones, such as estradiol and its esters, i.e. pareric acid ester, benzoic acid ester or undecylic acid ester, ethinyl estradiol. , norethisterone acetate, LeVOnOrg (38tr81), norethisterone acetate, cibrothyrone acetate (C
-yproteronacetat), Dangest L.
Gestagens such as Deso-gestrel or Ge5todθn, testosterone and its esters (propionate esters,
androdane and meta-androstenolone, nandrolone (Nand-r
olon) 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.

Spring water-soluble pharmaceutical agents 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 water-resistant drug active substances, the gel used for dissolving the active substance may contain especially thickeners, physiological consisting of a high-boiling organic solvent of no concern and possibly water.

The optionally aqueous solvent must be sufficiently lipophilic to dissolve the drug agent, but must also have sufficient hydrophilicity to enable the desired agent delivery. No. Suitable foil stamps, for example nomethylformamide 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, dimethylisonorbide (=3,6-cymethoxyfuro[3,2-t)]furan), diethylene glycol and its ether ("R'6mpp", Dr.

0tto -AlbrlCht Neumiill
er: Rδ', pps ChemieLexi
kon 1 7th edition, 1972, Franckh ac
heverlagshandlung Stuttga
rt 1 Bundesrepubrik Deutsch
mpp
-127502751). The hydrophilicity of the solvent can be increased by adding water. On the other hand, the hydrophilicity of the solvent is influenced by the use of non-polar oils, such as the name ceteol (
esters of long-chain fatty acids known as
pp"539)".

The application agent according to the invention, of course, contains anhydrous solvents only when the thickener necessary for gel formation is swellable, for example in carboxymethylcellulose, as in nomethylinluvit. It's okay. In other cases, an amount of water must be added to the solvent to allow swelling of the thickener.

As a thickener ("R'6mpp"3792);
Well, the swelling agents normally used 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 carboxymethylcellulose or cellulose ethers, or polyesters. Fully synthetic organic thickeners such as acrylic compounds, vinyl polymers or polyethers.

Particularly advantageous thickeners are, for example, Calzepo/L/(C
arbopol(R)) or force/L/N oxymethyl cellulose.

The thickener is metered in such a way that the resulting gel is no longer fluid.

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 silicone elastomers, in particular addition-crosslinked RTv systems are used, but this does not exclude that condensation-crosslinked RTV systems may also be used. Two-component system (Ullmanns Knc
yk-1 opedie der technique
r Chemie% 4th edition, Volume 21 (1982)
, headword-8ilicmne-see pages 511 et seq.) are advantageous. Such a two-component system consists, for example, of 1 to 10% by weight of polymethylhydrogensilochitin with an average molecular weight of 2,300 to 2,000 2.4,6.8-tetramethyl-2°4.6.8-tetra Vinylcyclotetrasilochitin 1-10% by weight platinum catalyst
10-100 ppm and average molecule @3o
'oo~20000 Vinyl-endcapped polydimethylsiloxane O Usually forms two components, the first component containing poly-dimethylhydrogensiloxitin and a portion of vinyl-endcapped polydimethylsiloxane.

The second component is the remainder of vinyl end-capped polydimethylsiloxitin, 2,4,6.8-tetramethyl-2,4
, 6,8-tetravinylcyclotetrasilochitin and a catalyst.

A suitable platinum catalyst is, for example, 2,4,6,8-tetramethyl-2,4,6,8-tetrabi,nyl-cyclotetranoxanyl platinum.

Polydimethylhydrogen siloxane, vinyl end-capped polydimethylsiloxane, and 2,4,6,8-tetramethyl-2,4,6,8-tetravinylsiloxane were mixed in different ratios, and terimethylhydrogen siloxane and vinyl end-capped polydimethylsiloxane were used. By varying the chain length of the polydimethylsiloxane, the crosslinking molecular length of the silicone elastomer 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 is defined as the empirically determined molecular weight between the crosslinking points (=
network chain length) to 1
The crosslinking index (Ne
Kokichi can be confirmed by measuring tzb□genlKnge). Empirical verification of the molecular weight between crosslinking points can be found in 'rre1oar's publication: The Physics of Rubber Elasticity (The Physics of Rubber Elasticity).
Physics □f Rubber K15tici
ty ; C1a-1-endon Prees 0xf
ora), 1975, p. 142.

In general, it is advantageous to choose silicone elastomers with a crosslinking index of 20 to 500, especially steroid P
For hormones, silicone elastomers with a crosslinking index of 50 to 250 are preferred.

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 approximately 5μ·-500μ. and cured at 40-100° C. to give a sheet 0.5-5 mm thick.

The transport of the active substance from the application agent according to the invention (hereinafter referred to as "Qin") through its external interface in the direction of the film is caused by a humidity gradient 01s/Cas (C1s = internal concentration of the system, Caθ = system' external concentration), is written as a function of the interface A, time t, silver concentration 1s and the diffusion coefficient: Ql, = 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 χ 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.

Diffusion coefficient D′ of the active substance in the outer layer, length of the diffusion path 1
and the size A′ of the interface between the internal and external phases determines the agent transport inside the system: qt: f (A
, t, 1. D').

The size X depends on the droplet distribution in the system and can be easily adjusted by processing, e-parameters. Therefore, by varying the ratio A'/A over a wide range, for example from 25 to 500, it is possible to vary the release of active substances in the 1-c series.

Furthermore, the general functional formula: Qt=f(A'/A, t, C,
La, D'/D), it becomes clear that the release liquid can be further improved by changing the diffusion coefficient D' (=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 variability 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, a small disc of the application agent according to the invention is cured onto an aluminium-coated support sheet, the support sheet is provided with an adhesive around the application agent, and the protective sheet is sealed. I can do it.

The following examples are used to illustrate the invention.

EXAMPLES Example I A) Preparation of the active substance-containing gel phase! ! Dissolve Estra, Fall-1 Fuparelianate 30 (1151) in a mixture consisting of 22.55 g of 87% glycerin and 5.641 g of distilled water with 22.55 g of dimethyldiglycol. Power/
L/ Npo/I/ (0arbOpO1) (R) 9
Thicken with stirring at 341.13 fl. For complete gel formation as well as regulation of physiological PH ratio, approximately 1n
- Adjust the pH to 5.0 with aqueous sodium hydroxide solution.

B) Preparation of the silicone elastomer phase: 1, vinyl end-capped dimethylpolysiloxane (average molecular weight 6ooo) 4 in a hermetically sealable reaction vessel with a stirring device.
s, sog, z.

4.6.8-Tetramethyl-2,4,6,8-tetravinyl-tetracyclosiloquitin 0.421 and 350
A doluol solution of 2.99 g of polymethylhydrogensiloxitin with an average molecular weight of ~500 and a platinum catalyst (2,4,6,8-tetramethyl-2°4.6.8-tetravinyl-tetracyclosiloxanylplatinum) ) 15
Mix ppm.

C) Preparation of an enteral application of estradiol-17-parerianate The gel phase prepared according to A) is added to the silicone elastomer phase and the mixture is stirred under vacuum (100 torr) for 20 minutes at 1250 r, p, m. .

Thereafter, the obtained dispersion was mixed with the surface area of IQcrn and 1
．． Cure for 1 hour at 60° C. in a disk-shaped sheet mold with a depth of 5 mm.

Example 2 A) Preparation of active substance-containing gel phase Nidimethyldiglycol 8.5,9. Cetiol (Cet)
iol) (R) HK 8.5 p 1 distilled water 4.0,
Testosterone 500 μl in a mixture consisting of 9.87% glycerin 201, polyglycol (molecular weight 400) 1.0.9 and pH 9.0 μl buffer 3.0 μg.
dissolve. This solution was mixed with Calzebol (Ca-rbop).
ol)(R) 934 o,s 5 g with stirring.

B) Preparation of the silicone elastomer phase.

Vinyl end-capped dimethylpolysiloxane (average molecular weight 6
ooo')sl, 37. p, 2°4.6.8-tetramethyl-2,4,6,8-tetravinyl-tetracyclosiloquitin 0.93y and polydimethylhydrogensiloquitin 0.914F with an average molecular weight of 350-500 and platinum Catalyst (2,4,6,8-tetramethyl-2,4
, 6,8-tetravinyl-tetracyclosiloxanyl platinum in the form of a doluol solution 1) Mix 15 ppm.

C) Manufacture of enteral application of testosterone: Adding the gel phase produced by A) to the silicone elastomer phase,
The mixture was heated under vacuum (1o.

Stir for 20 minutes at 1250 r, 1), m, m.

The resulting dispersion was then mixed with a surface area of 10 crn and a
．． Cure for 1 hour at 60° C. in a disk-shaped sheet mold with a depth of 5 mm.

Example 3 A) Preparation of the active substance-containing gel phase: Anhydrous glycerin 10.68,! i+, cetiol (
R) HE 49.9 F! , 8.93 fj of distilled water, 0.8 g of Estra Fall is dissolved. This solution was mixed with Calzepol (R) 934 1.84.
9. Thicken while stirring. To improve the gel structure and adjust the physiological conditions, p.p.
Adjust to H5.0.

B) Preparation of the silicone elastomer phase: Vinyl end-capped dimethylpolysilochitin (average molecular weight 6000) 82.
40J, 2°4.6.8-tetramethyl-2,4,6,
0.42g of 8-tetravinyl-tetracyclosiloxane
and polydimethylhydrogensilochitin with an average molecular weight of 350-500 2.99.9 and platinum catalyst (2,4
, '6, 8-tetramethyl-2°4.6.8-f travinyl-tetracyclosiloquinanyl platinum (in the form of a doluol solution) 1 sppm is mixed.

C) Manufacture of enteral application of estradiol: The gel phase prepared by A) is added to the silicone elastomer phase and the mixture is heated under vacuum (100 Torr) for 20 minutes at 1250°C.
Stir with r, pJn. Then, the obtained dispersion was
0− surface and 0.9rn! Cure for 1 hour at 60° C. in a disc-shaped sheet mold with a depth of rL.

Example 4 A) Preparation of the active substance-containing gel phase: 5.0 g of distilled water, 5.09 g of anhydrous glycerin and 15.9 g of dimethyldiglycol. Polyglycol (molecular weight 6000) with mild heating (approximately 45° C.) into a mixture consisting of Ofj.5. Dissolve OF.

After cooling, microcrystalline Li5uriae base 0
．． Mix 19. 30% of the active substance remains insoluble.

Calzeball (R) 934 patch 1. Increase the viscosity while stirring with an OP solution, and adjust the pH to 5.0 using an approximately 100% sodium chloride solution.
Adjust to

B) Shi! Preparation of the J-cone elastomer phase: In a hermetically sealable reaction vessel equipped with a stirrer, vinyl end-capped dimethylpolysiloxane (average molecular weight 6000
) 56.91 g, 2.4,6.8-tetramethyl-
2,4,6,8-tetravinyl-tetracyclosiloxane 0.0911 and polydimethylhydrogensiloxane 1.0417 with an average molecular weight of 350-500 and a platinum catalyst (2,4,6,8-tetramethyl-2, 4,6,
15 ppm of 8-tetravinyl-tetracyclosiloxanyl platinum (in the form of a doluol solution) are mixed.

C) Preparation of an enteral application of Lizulide base; the gel phase prepared according to A) was added to the silicone elastomer phase and the mixture was heated under vacuum (100 Torr) for 20 minutes at 1250 r.
Stir at p, m.

Thereafter, the obtained dispersion was placed in a disc-shaped sheet mold at 60°C.
Let it harden for 1 hour.

Example 5 A) Preparation of the active substance-containing gel phase: Dimethelisosorbide (DMI, At1as-Chs
-mie company product, D-4300Es5en) 49
．． Dissolve 2.76 fi of estradiol in 52 g.

While stirring, add hydroxypropyl-cellulose (K'
1ucel(R)G F ) (Herkules G
mbH product, D 2050 Hamburg)
2.72,! Add 9.

After stirring for 4 hours at room temperature, a gel is obtained.

B) Preparation of the silicone elastomer phase: Vinyl end-capped dimethylpolysiloxane (average molecular weight 6ooo) 47.
14. g, 2°4.6.8-tetramethyl-2,4,6
, 8-tetravinyl-tetracyclosiloxane 0.55
polydimethylhydrogensiloxane with average molecular weight of 350-500 and platinum catalyst (2,
Mix 15 ppm of 4,6,8-tetramethyl-2.4.6.8-tetrahinyl-tetracyclosiloxanyl platinum in the form of a doluol solution.

C) Manufacture of enteral application of estradiol: The gel phase prepared by A) is added to the silicone elastomer phase and the mixture is heated under vacuum (100 Torr) for 20 minutes at 1250°C.
Stir with r, p, m. Then, the obtained dispersion was
Cure for 1 hour at 60° C. in a disc-shaped sheet mold with a surface area of 0 crn and a depth of Q, 5 mm.

Claims (1)

[Claims] 1. 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 agent for pharmaceutically active substances. 2. The drug effect 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 of substances. 3. The enteral preparation of a drug active substance according to claim 2, wherein the drug active substance is a steroid hormone. 4. The administration of pharmaceutically active substances according to any one of claims 1 to 3, wherein the gel is a water-containing liquid containing a thickener and optionally a polyhydric alcohol or polyhydric ether. Enteral application agent. 5. The enteral preparation for pharmaceutically active substances according to any one of claims 1 to 4, wherein the crosslinked silicone elastomer is an addition crosslinked silicone-cold elastomer. 6. Crosslinked silicone elastomer is 20 to 500
The enteral preparation of a drug active substance according to any one of claims 1 to 5, which has a crosslinking index of . 7. Crosslinked silicone elastomer is 50-250
The enteral preparation of a drug active substance according to any one of claims 1 to 6, which has a crosslinking index of . 8. A method for producing an enteral preparation of a drug active substance, which comprises suspending a drug-containing gel in a component necessary for forming a crosslinked silicone elastomer and hardening the resulting suspension. .