A new membrane or matrix for regulation of permeability of drugs

 

(57) Abstract:

Describes a method of regulating the permeability of the drug over an extended period of time using elastomer-based siloxane comprising dispersing the above drugs in the above elastomer-based siloxane with the formation of the matrix, or the conclusion of the above drugs as the core of the membrane containing the above-mentioned elastomer-based siloxane, and the above-mentioned elastomer contains 3,3,3-triptoreline group attached to the Si-atoms of parts of the siloxane, with from 1 to about 50% of the substituents attached to the Si atoms in the siloxane units are 3,3,3-triptoreline groups, and elastomer made of or from (i) a mixture consisting of (a) unsubstituted fluorine-based polymer of siloxane and (b) fluorinated polymer-based siloxane, and the above polymer contains 3,3,3-triptoreline group attached to the Si-atoms of parts of the siloxane, or ii) a single polymer-based siloxane containing 3,3,3-triptoreline group attached to the Si-atoms of parts of the siloxane, where the above-mentioned polymer or smester, through which the drug permeates with the desired speed and which is attached to the membrane mechanical properties. 4 C.p. f-crystals, 6 PL.

The scope of the invention

This invention relates to a new membrane or matrix for regulation of permeability of drugs, and the above membrane or matrix is based on the siloxane polymer. The invention relates to a method for producing the above-mentioned elastomer.

The BACKGROUND TO the INVENTION

Used in this publication and other materials describing the background to the invention, in particular cases, describing additional details of practical application, included in this text by reference.

Polysiloxane, such as poly(dimethylsiloxane) (PDMS), are highly suitable for use as a membrane or matrix, regulating the permeability of drugs in different dosage forms, in particular, implants and intrauterine (IU) systems. Polysiloxane are physiologically inert, and it turned out that a wide group of medicines shows the ability to penetrate through polysilk the sources is known, that adding groups of poly(aquisition), i.e. REO-groups, PDMS is a polymer can increase the permeability of drugs. Publication KL Ullman et al., Journal of Controlled Release 10 (1989), 251-260, describes a membrane made of blockcopolymer, which contains REO and PDMS, and the penetration of various steroids through these membranes. In addition, it is known that membrane based on modified PDMS-polymers, in which a certain number of methyl substituents at the Si-atoms substituted triptoreline groups, reduce the penetration of drugs. Publication Ying Sun et al., Journal of Controlled Release, 5 (1987), 69-78, describes the impact of the membranes, made of PDMS, replaced by cryptocaryon PDMS and PDMS/REO/emission spectra obtained for pure (where represents the emission spectra obtained for pure poly(methyl methacrylate)) on the permeability of androgen and gestagennah steroids. The study shows that the permeability for both groups of steroids was lower for membranes made from substituted cryptocaryon PDMS than for membranes made of unmodified PDMS. However, the publication does not disclose any elastomer derived from substituted cryptocaryon PDMS.

The PURPOSE of the INVENTION

The aim of the invention is to develop a method of regulation carstone agent reaches the desired speed and which is attached to the membrane mechanical properties.

The aim of the invention is, in particular, a method of regulating drugs with hormonal activity, using elastomer, the penetration of drugs through which you can control.

A particularly important aim of this invention is to provide elastomer, which retards the penetration of drugs compared with elastomers from normal PDMS.

BRIEF description of the INVENTION

The invention relates to a method of regulating the permeability of the drug over an extended period of time using a membrane or matrix consisting of elastomer-based siloxane comprising dispersing the drug in a specific elastomer-based siloxane with the formation of the membrane or matrix, or the conclusion of the above drugs as the core of the membrane containing the above-mentioned elastomer-based siloxane, and the specified elastomer contains 3,3,3-triptoreline group attached to the Si-atoms of parts of the siloxane, with from 1 to about 50% of the substituents attached to the Si atoms in the siloxane units, are 3,3,3-triptorelin the basis of siloxane and (b) fluorinated polymer-based siloxane, moreover, the above polymer contains 3,3,3-triptoreline group attached to the Si-atoms of parts of the siloxane, or

ii) a single polymer-based siloxane containing 3,3,3-triptoreline group attached to the Si-atoms of parts of the siloxane, with the above-mentioned polymer or mixture of polymers cross linked with the formation of the elastomer.

DETAILED description of the INVENTION

General description elastomer

The term “elastomer-based siloxane” should be understood as covering the elastomers obtained from poly(disubstituted siloxanes), in which the substituents are primarily lower alkyl, preferably alkyl groups of 1-6 carbon atoms, or phenyl group, where the above-mentioned alkyl or phenyl can be substituted or unsubstituted. Widely used and preferred polymer of this type is poly(dimethylsiloxane) or PDMS.

According to the invention a certain number of substituents attached to the Si-atoms of parts of the siloxane in the elastomer must be 3,3,3-triptoreline groups. This elastomer can be obtained in various ways. According to one variant of the elastomer alkylsilanes), in which a certain number of alkyl groups in the Si atoms substituted 3,3,3-triptoreline groups. A preferred example of such polymers is poly(3,3,3-triphosphorylation), whose structure is shown below as compound (I

A polymer of this type, in which approximately 50% of methyl substituents at the Si-atoms are replaced by 3,3,3-triptoreline group, is commercially available. The term “approximately 50%” means that the degree of substitution 3,3,3-triptoreline groups is actually slightly below 50%, because the polymer must contain a certain number (about 0.15% of deputies) Poperechnaya groups such as vinyl groups or terminal vinyl groups. Such polymers having a low degree of substitution 3,3,3-triptoreline groups, can be easily synthesized.

Action 3,3,3-triptoreline groups on the slow permeability of drugs through the membrane elastomer depends on the number of these groups. In addition, this action depends on the drug. If the elastomer obtained only from a single polymer, it is necessary to obtain and use polymers with yet another variant, which is especially preferred in cases where you want to create suitable elastomers for several different medicines, you must associate transverse bracing mixture containing (a) unsubstituted fluorine-based polymer of siloxane and (b) fluorinated polymer-based siloxane in which the above polymer contains 3,3,3-triptoreline groups associated with the Si atoms of parts of the siloxane. The first ingredient of the mixture, unsubstituted fluorine polymer can be any poly(disubstituted siloxane), where the substituents are primarily lower alkyl, preferably alkyl groups containing 1-6 carbon atoms, or phenyl group, where the above-mentioned alkyl or phenyl can be substituted or unsubstituted. Preferred unsubstituted fluorine polymer is PDMS. The second ingredient of the mixture, fluoro-substituted polymer can be, for example, poly(dialkylzincs), in which a certain number of alkyl groups in Si-atoms are replaced by 3,3,3-triptoreline group. Preferred examples of such polymers, as mentioned above, is a poly(3,3,3-triphosphorylation. Particularly preferred polymer of this type is the polymer Meucci available polymer, in which approximately 50% of methyl substituents at the Si-atoms substituted 3,3,3-triptoreline groups. Elastomer with a large delay permeability effect can be obtained solely or mainly for the use of the above-mentioned polymer. Elastomers with less retarding effect of the permeability of drugs can be obtained by using mixtures with increasing amounts of unsubstituted fluorine-based polymer of siloxane.

Preferably the elastomer must contain a filler, such as amorphous silica, to give a membrane made of the above elastomer, a sufficient strength.

Description of the method of producing elastomer

According to one variant of the elastomer get through the cross-linking vinyl-functional polysiloxane component and kremnievykh-functional Poperechnaya agent in the presence of a catalyst.

Cross-linking means reaction joining kremnievykh-functional Poperechnaya agent with carbon-carbon double bond wikifunctions polysiloxane component.

The term “vinyl-functional” polysiloxan should be understood as covering polysiloxane, substituted vinyl groups or terminal vinyl groups. The terms “vinyl-functional polysiloxane component” and “polysiloxane component, which must be associated transverse relationship, should be understood to encompass copolymers with polysiloxane with the vinyl substituents or end of the vinyl substituents. For cross-linking number of the components are preferably chosen so that the ratio of the molar quantities of silicon hydrides to the double bonds is at least 1.

As mentioned above, the elastomer for use in this invention can be obtained by cross-linking a single fluorinated polymer-based siloxane or by cross-linking a mixture of unsubstituted fluorine-based polymer of siloxane and substituted by a fluorine-based polymer of siloxane. Thus, the term “vinyl-functional polysiloxane component can mean a mixture consisting of unsubstituted fluorine-based polymer of siloxane and substituted by a fluorine-based polymer of siloxane, and the above floor is vinyl-functional polysiloxane component can mean only one fluorinated polymer-based siloxane, moreover, the above polymer contains 3,3,3-triptoreline group attached to the Si-atoms of parts of the siloxane.

In addition, the so-called part-time may be mixed with the above components. Usually time is of the block copolymers of unsubstituted fluorine polymer and a fluorinated polymer.

Silicone Poperechnaya agent with hydride functional groups is preferably a hydride-functional polysiloxane, which may be straight chain, branched or cyclic.

The hydride-functional siloxane Poperechnaya agent may also contain triptoreline group.

Fluorinated polymer-based siloxane is preferably PDMS-polymer, approximately 50% of the methyl groups in the specified PDMS were replaced by 3,3,3-triptoreline group.

Filler, such as amorphous silica, preferably added to the vinyl-functional component to cross-linking.

In the case of elastomer, obtained by cross-linking the polymer component in the presence of a peroxide catalyst, such polymeric component can be messagename 3,3,3-triptoreline group, attached to the Si-atoms of parts of the siloxane. In contrast to this, the polymer component may be the only fluorinated polymer-based siloxane, with specified polymer contains 3,3,3-triptoreline group attached to the Si-atoms of parts of the siloxane.

Used for cross-linking catalyst is preferably a catalyst of a noble metal, usually platinum complex in alcohol, xylene, diphenylsiloxane or cyclic vinylsilanes. A particularly suitable catalyst is a complex of Pt(O)-divinyltetramethyldisiloxane.

EXPERIMENTAL PART

Below is a more detailed description of the invention. Got an elastomeric membrane of different types (a-E). Type a is an elastomer made from a mixture consisting of fluorinated polymers based siloxane (degree of substitution 3,3,3-cryptocaryon is 49,5%) and the unsubstituted fluorine-based polymers of siloxane in which the cross-linking was performed using peroxide catalyst. Received three different mixtures with different amounts of fluorinated polymer (example 1). Type In (examples 2 and 3) is an elastomer obtained from edku peroxide catalyst. Type (example 4) is an elastomer made from a mixture containing fluorinated polymers based siloxane (degree of substitution 3,3,3-cryptocaryon is 49,5%), and unsubstituted fluorine-based polymers of siloxane, cross-linking are carried out using a peroxide catalyst. Type D (example 5) is an elastomer obtained from a single fluorinated polymer-based siloxane, cross-linking which was conducted by hydrosilation. Type E (example 6) is an elastomer obtained from a mixture consisting of fluorinated polymers based siloxane (degree of substitution 3,3,3-cryptocaryon 30%), and unsubstituted fluorine-based polymers, siloxanes, cross-linking are carried out by hydrosilation.

EXAMPLE 1

The elastomers of the type And with different amounts of fluorinated polymers

A series of 50 [in the future 25 and 75] parts by weight is filled with silicon dioxide copolymer triphosphorylation and phenilmethylsulfoxide, 50 [and 75 and 25, respectively] parts by weight is filled with silicon dioxide copolymer dimethylsiloxane and phenilmethylsulfoxide and 1.2 parts by weight dibene when 115S for 5 minutes in a thermal press, while receiving the membrane thickness of 0.4 mm, which was subjected to the subsequent vulcanization at 150 for 2 hours.

EXAMPLE 2

Elastomer type IN

100 parts by weight of the filled silicon dioxide copolymer triphosphorylation, dimethylsiloxane and phenilmethylsulfoxide (content, links triphosphorylation is 60 mol.%, i.e., the degree of substitution triptoreline groups is 30%) and 1.2 parts by weight of dibenzoylperoxide-polydimethylsiloxane paste was mixed with 2-roller mill. The mixture was vulcanizable when 115S for 5 minutes in a thermal press, while receiving the membrane thickness of 0.4 mm, which was subjected to the subsequent vulcanization at 150 for 2 hours.

EXAMPLE 3

Elastomer type IN

100 parts by weight of the filled silicon dioxide copolymer triphosphorylation, dimethylsiloxane and phenilmethylsulfoxide (content, links triphosphorylation 99 mol.%, i.e., the degree of substitution triptoreline groups is 49,5%) and 1.2 parts by weight of dibenzoylperoxide-polydimethylsiloxane paste was mixed with 2-roller mill. The mixture was vulcanizable when 115S in dealkalization at 150C for 2 hours.

EXAMPLE 4

Elastomer type WITH

50 parts by weight is filled with silicon dioxide fluoro-substituted polysiloxane obtained in example 2, 50 parts by weight is filled with silicon dioxide copolymer dimethylsiloxane and phenilmethylsulfoxide and 1.2 parts by weight of dibenzoylperoxide-polydimethylsiloxane paste was mixed with a 2-roll mill. The mixture was vulcanizable when 115S for 5 minutes in a thermal press, while receiving the membrane thickness of 0.4 mm, which was subjected to the subsequent vulcanization at 150 for 2 hours.

EXAMPLE 5

Elastomer type D

100 parts by weight of the filled silicon dioxide copolymer triphosphorylation and phenilmethylsulfoxide (degree of substitution triptoreline groups 49,5%), 0.04 parts by weight of the complex Pt(O)-divinyltetramethyldisiloxane, 0.05 parts by weight of 1-ethinyl-1-cyclohexanol and 1.0 part by weight kremniikarbidnoi Poperechnaya agent were mixed in Decameron mixer. The mixture was vulcanizable when 115S for 5 minutes in a thermal press, while receiving membrane thickness 0,4 mm

Example 6

Elastomer type E

50 parts by weight filled with silica forzamilan and phenilmethylsulfoxide, 0.04 parts by weight of the complex Pt(O)-divinyltetramethyldisiloxane, 0.05 parts by weight of 1-ethinyl-1-cyclohexanol and 1.0 part by weight of silicone Poperechnaya agent with hydride groups were mixed in a two-chamber mixer. The mixture was vulcanizable when 115S for 5 minutes in a thermal press, while receiving membrane thickness 0,4 mm

The study of membrane permeability

Investigated the permeability of various drugs through the above-described elastomeric membrane types a, b and C.

In experiments to test the permeability used the apparatus described in Yie W. Chien, Transdermal Controlled Systemic Medications, Marcel Dekker inc. New York and Basel, 1987, page 173.

Streams of medicines (permeability) through the membrane was measured using a two-chamber with diffuser S (“wall to wall” diffuser, Crown Glass Company). The apparatus consists of two concentric cells (donor and receptor chambers), which divided the studied elastomeric membrane. The donor and receptor chambers were locked up in a shirt and thermostatically by external circulating bath, each cell was equipped with a magnetic stirrer. The solution of a drug and solvent (without drug) was added to doerry and was replaced by the same volume of solvent. The amount of drug that permeated through the membrane was measured using HPLC. In all experiments, the thickness of the membrane (0.4 mm) and surface area of the membrane were constants.

In the following tables 1-6 show the results of the relative permeability of various drugs through various elastomeric membrane. A control membrane made of elastomer, based on the copolymer dimethylsiloxane and phenilmethylsulfoxide that contains silicon dioxide as a filler. In the following table, the term “degree of substitution by cryptocaryon, %” has the same meaning as mentioned previously, and this percentage means the substituents at the Si-atoms of parts of the siloxane in the elastomer, i.e., 3,3,3-triptoreline deputies.

The above-described elastomer used only as either membrane or matrix to control the permeability of the drug.

The above-described elastomer is, for example, is highly suitable for regulating the permeability of drugs with hormonal action, implants and in vnutrennie medicines, non-hormonal activity, such as androgens, antiprogestin, progestins and estrogens.

It should be borne in mind that the methods of the present invention may be incorporated in the form of different variants, but only some of them are revealed in this text. The person skilled in the art it is obvious that there are other options and they are covered by the present invention. Thus, the described options are illustrative and should not be construed as limiting the invention.

1. The method of regulating the permeability of the drug over an extended period of time using elastomer-based siloxane comprising dispersing the above drugs in the above elastomer-based siloxane with the formation of the matrix, or the conclusion of the above drugs as the core of the membrane containing the above-mentioned elastomer-based siloxane, and the above-mentioned elastomer contains 3,3,3-triptoreline group attached to the Si-atoms of parts of the siloxane, with from 1 to about 50% of the substituents attached to the Si atoms in the siloxane units are 3,3,3-triptoreline GRU is a and b) fluorinated polymer-based siloxane, moreover, the above polymer contains 3,3,3-triptoreline group attached to the Si-atoms of parts of the siloxane, or ii) a single polymer-based siloxane containing 3,3,3-triptoreline group attached to the Si-atoms of parts of the siloxane, where the above-mentioned polymer or mixture of polymers cross linked with the formation of the elastomer.

2. The method according to p. 1, characterized in that the polymer mixture is a mixture of a) poly(dimethylsiloxane) and b) poly(dimethylsiloxane), in which at least 30% of a metal of groups attached to the Si-atoms of parts of the siloxane substituted 3,3,3-triptoreline groups.

3. The method according to p. 2, characterized in that approximately 50% metal groups in the polymer (b) substituted 3,3,3-triptoreline groups.

4. The method according to p. 1, wherein the elastomer contains a filler.

5. The method according to p. 4, characterized in that the filler is amorphous silica.

 

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