DE3875460T2 - MEDICINE FORMULATION FOR TRANSDERMAL ABSORPTION OF THE ACTIVE SUBSTANCE AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

The invention relates to a multilayer pharmaceutical formulation which, after application to the skin, ensures delayed absorption (suitably for a period of 18 to 24 hours) with a kinetics of the active ingredient contained in it of so-called zero order.

According to another aspect of the invention, a process for producing such multilayer pharmaceutical formulations is provided.

Drug formulations are known in the art, by which the transdermal absorption of the active ingredient portion contained is ensured. The polymeric matrix of a nitroglycerin-containing composition, commercialized by Key Pharmaceuticals Inc. under the trademark Nitro-Dur, contains 2 to 60% glycerin, 2 to 15% polyvinyl alcohol and 2 to 10% of a water-soluble polymer, e.g. PVP (see US Patent No. 4,466,953). This polymeric matrix ensures the appropriate dissolution kinetics of the active ingredient.

Alza Co.'s Transderm compositions are four-layer pharmaceutical formulations containing the active ingredient mixed with a silicone-based ointment; the dissolution of the active ingredient is regulated by a non-porous membrane made of ethylene/vinyl acetate. To ensure the initial dose, the adhesive layer of this composition also contains 8% of the active ingredient.

The compositions manufactured by Searle Co., e.g. Nitrodisc, are prepared in such a way that the active ingredient is suspended in the solution of a water-soluble polymer and the resulting suspension is mixed into a silicone polymer; thereafter, cross-linking is carried out and finally a specific membrane layer is also applied to regulate the solution of the active ingredient (see US Patent No. 3,946,106).

The structure of the Nitroderm TTS compositions from Ciba-Geigy AG is practically identical to that of the Transderm compositions.

In summary, the structure of the formulations known to date is as follows.

1) Matrix system (Fig. 1)

1. diffusion-regulating polymeric matrix (gel, ointment);

2. solid active ingredient;

3. impermeable polymeric layer. [Example: Nitro-Dur (Key Pharm.)]

2) Layer system (Fig.2)

1. Protective film;

2. Ointment (gel) containing active ingredient;

3. solution-regulating membrane;

4. Adhesive layer with the active ingredient.

[Example: Transderm-Nitro (Alza Co.)]

3) Micro-sealed systems (Fig. 3)

1. solution-regulating polymeric membrane;

2. aqueous polymeric drops, containing a suspension of the active ingredient;

3. polymeric matrix (based on silicone);

4. impermeable polymeric layer.

[Example: Nitrodisc (Searle)]

The pharmaceutical formulation according to the invention is a bi-layer or multi-layer system having a structure shown in Fig. 4, wherein

A is a silicone rubber layer from which the dissolution of the active ingredient with zero-order kinetics is ensured;

Bn is a multilayer silicone rubber matrix containing layers (n = 1 to 6) with different proportions of the active ingredient ;

C an aluminium foil or other suitable water-impermeable foil layer; and

D an adhesive layer to fix the formulation on the body surface.

The layers A and Bn of the pharmaceutical formulation according to the invention are prepared in a catalytic (protolytic) polycondensation or polyaddition process using a base material of one- or two-component silicone rubber. The above-mentioned layers A and Bn can be produced in different thicknesses (0.1 to 3 mm): by the catalytic polycondensation of various alkylpolysiloxane-α,ω-diols (preferably methylpolysiloxane-α,ω-diols with a low molecular weight (M = 500 to 100,000) and/or a high molecular weight (M = 100,000 to 20,000,000); or by catalytic addition of polysiloxane polymers containing various alkyl (CnH2n-1), aryl (C₆H₅,C₆H₅CH₂), alkenyl (CH₂=CH-) or -H groups and as an end part a reactive group (OH, H, vinyl or the like) or a mono-functional group [(CH₃)₂SiO, (CH₃)₂CH₂-CHSiO- and the like].

Layers A and Bn (where n is suitably 1 to 5) are silicone rubber matrices superimposed one on top of the other, containing a varying amount of the active ingredient, e.g. from 0 to 20%, provided that at least one layer contains an active ingredient. Any catalyst which forms a crosslink by condensation (suitably the T-5 product from Wacker, DE) may be used as the polycondensation catalyst in an amount of 0.01 to 15%, suitably 5 to 8%. Various noble metal salts or noble metal complexes may be used as the polyaddition catalyst in an amount of 1 to 100 ppm. This process may be carried out in a wide temperature range of 15 to 140 ºC, suitably between 20 ºC and 40 ºC, depending on the properties of the active ingredient incorporated. This process is suitable for both batch production and a continuous production of the pharmaceutical formulation according to the invention.

According to a preferred embodiment of the invention, a pharmaceutical formulation is prepared which is a multilayer system composed of silicone rubber layers of different thicknesses and with different proportions of active component. This system is provided with a waterproof layer, suitably an aluminum foil layer, over the silicone rubber layers and with an adhesive layer which ensures adhesion to the skin surface. The first layer of the pharmaceutical formulation, which adheres to the skin surface and does not contain any active component and has a thickness of 0.1 to 3 mm (indicated by "A" in Fig. 1), is closely connected to the subsequent layers with different proportions of active component and therefore the zero-order dissolution kinetics of the active component are brought about by the entire laminated system.

In the composition according to the invention, various drugs, e.g. cardiovascular, spasmolytic, anorectogenic, antidiabetic agents, as well as drugs affecting the hormonal system, can be used as active ingredients.

According to the invention, the multilayer system is formed by polymerizing the individual layers one on the surface of the other and one after the other in time.

Depending on the active ingredient of the system, layer A can be prepared in different layer thicknesses, e.g. 0.1 to 3 mm, at different temperatures, e.g. between 15 ºC and 90 ºC, conveniently at 25 ºC to 60 ºC by polycondensation of a mixture prepared from various polydimethylsiloxane-α,ω-diols (hereinafter abbreviated to PDSD), conveniently from Silorol R-1, R-5 and R-30 (trademark) products from Finomvegyszer Svövetkezet Co., Budapest, Hungary, or from mixtures thereof. by using various crosslinking catalysts (hereinafter abbreviated to CLC) (which induce polycondensation) in an amount of 0.1 to 15%, preferably 5 to 10%. A trifunctional methylsilane derivative containing a Si-N and/or a Si-O bond, preferably methyltricyclohexylaminosilane, can be used as a catalyst or main component; a tetraalkoxysilane, preferably tetraethoxysilane, tetramethoxysilane or the like are used as main components; and a catalyst mixture containing a dialkyltin salt of a long-chain fatty acid, preferably dibutyltin laurate, is used as an initiator. In the case of polysiloxane polymers containing alkyl (CnH2n-1), aryl (C₆H₅, C₆H₅CH₂), alkenyl (CH₂=CH-) or -H- groups and having a reactive group (OH, H, vinyl or the like) or a monofunctional group [(CH₃)₃SiO, (CH₃)₂CH₂-CHSiO- or the like] as an end part (hereinafter abbreviated to PSP), the process is carried out in such a way that the layer thickness of layer A resulting from the polyaddition under the action of noble metal salts or noble metal complexes (hereinafter abbreviated to EM type catalyst) used as catalysts and present in a proportion of 1 to 100 ppm, 0.1 to 3 mm and the polyaddition process is carried out at a temperature between 15 ºC and 140 ºC.

The first layer B1 containing an active ingredient is applied to the layer A thus formed. The layer B1 can be conveniently prepared by polymerizing a homogenized mixture of the active ingredient as such or of a solution thereof in a solid or liquid diluent, e.g. lactose, glucose, Aerosil and the like, and the PDSD or PSP base material used in varying amounts, e.g. from 0.5 to 20%, conveniently from 0.5 to 4%, with a CLC or EM type catalyst at various temperatures at 15 to 140 ºC, conveniently at 15 to 50 ºC. When the layer B1 is formed by polycondensation, the proportion of CLC type catalyst can preferably be 0.1 to 15%, conveniently 5 to 10% and the preferred temperature can be 15 to 90 ºC, preferably 20 to 50 ºC.

When the polyaddition process is used, the amount of an EM type catalyst may be 1 to 100 ppm and the process may be carried out at a temperature between 15 ºC and 140 ºC, suitably at 20 to 60 ºC.

Depending on the type and properties of the active ingredient, the Bn layers are applied to the polymerized Bn-1 layers by repeating the process described above with an increasingly larger proportion of active ingredient between 15% and 25%, deviating from the proportion of active ingredient in the Bn-1 layer.

On the last layer Bn, PDSD or PSP base material is applied, suitably in a thickness of 0.1 to 1 mm and without an active ingredient and 0.1 to 15%, suitably 5 to 8%, of a CLC type catalyst or 1 to 100 ppm, suitably 20 ppm, of an EM type catalyst, and after the attachment of the waterproof layer, suitably an aluminium foil, the polymerisation is carried out at a temperature between 15 ºC and 140 ºC, suitably 25 to 50 ºC. Finally, the adhesive layer, which causes the formulation to adhere to the skin, is bonded to the waterproof layer.

The formulations according to the invention were investigated in in vitro studies determining the dissolution of the active ingredient per unit time (mg/h), the dissolution rate of the active ingredient (mg,cm2/h) and the percentage of dissolution of the total active ingredient.

The solution was followed in a Keshari-Chien type diffusion cell [cf. Drug Development Industrial Pharmacy 10 (6), pp. 883-913, 1984]. In these measurements, the sample area was 3.14 cm2; the liquid was an isotonic sodium chloride solution with a volume of 10 ml and at a temperature of 37 ºC. The volume of the sample was 1 ml.

The active ingredient content of the sample was determined by measuring the UV absorbance using a VSU 2-P device, Carl Zeiss Jena, DE. Nitroglycerin was determined at 207 nm in a path length of 2 mm against an isotonic sodium chloride solution. Isosorbide dinitrate was determined at 220 nm in a path length of 2 mm against distilled water.

As a result, it can be stated that the formulation according to the invention under the specified conditions shows a uniform release of the active ingredient within 24 hours.

The results of the solution studies are illustrated in diagrams 1 and 2.

The short-term stability of the formulation was also investigated. Since nitroglycerin, used as the active ingredient, is a volatile substance, the nitroglycerin content of the nitroglycerin-lactose trituration should be continuously controlled. The formulations were stored at +5 ºC or +30 ºC packed in aluminum foil and examined at regular intervals. It was found that the formulations according to the invention could be stored at both +5 ºC and +30 ºC without any change. The experimental results obtained with the nitroglycerin-containing formulation according to Example 1 are given in Tables 1 and 2. Table 1 (storage at +30 ºC) Day mean solution mg/cm²/h standard deviation of data mean deviation Table 2 (Storage at +5 ºC) Day Average solution mg/cm²/h Standard deviation of data Mean deviation

Compared with the prior art formulations, the formulation according to the invention shows the following advantages.

- The design of the formulation makes possible the preparation of any transdermally absorbable pharmaceutical composition as well as a steady therapeutic blood level of the active ingredient for a prolonged period of time, conveniently for 18 to 24 hours.

- The silicone rubbers used as a base material are cheap and physiologically inert for the living organism and do not interact with the active ingredient contained.

- The zero-order dissolution kinetics of the active ingredient can be ensured by the appropriate selection of the base material used, its layer thickness and the proportion of active ingredient in the individual layers.

- No porous or microporous membranes, which require a special base material or construction, are required to regulate the dissolution of the active ingredient.

- The adhesion of the individual layers to each other and therefore the Ensuring an acceptable structure can be easily accomplished because the layers are essentially identical from a chemical point of view.

The invention is explained in more detail by the following non-limiting examples.

example 1

a)

A mixture containing 60% dimethylpolysiloxane-α,w-diol with a viscosity of 50,000 mPa.s and 35% of the same material with a viscosity of 1,000 mPa.s is homogenized with vigorous stirring for 2 minutes, then 5% Wacker T-5 catalyst is added to the polymeric mixture and stirring is continued for an additional 2 minutes. The homogeneous mixture thus obtained is spread in a layer thickness of 0.5 mm in a suitable device and crosslinked at 40 ºC for 3 hours (layer A).

b)

A mixture containing 50% of dimethylpolysiloxane-α,w-diol with a viscosity of 5,000 mPa.s and 25% of the same material with a viscosity of 1,000 mPa.s is homogenized with vigorous stirring for 2 minutes, then 20% of a lactose trituration with 10% nitroglycerine is added in portions, the mixture is slowly stirred for 5 minutes, and then, after adding Wacker T-5 catalyst, the homogenization is continued for a further 5 minutes. The mass obtained is spread in a suitable device on layer A in a layer thickness of 0.5 mm and then crosslinked at 40 ºC for 3 hours (layer B1).

c)

Using the procedure described under b) and applying 35% dimethylpolysiloxane-α,w-diol with a viscosity of 5,000 mPa.s, 20% of the same material with a viscosity of 1,000 mPa.s, 40% of a lactose trituration With 10 % nitroglycerin and 5 % Wacker T-5 catalyst as components on layers A + B1 in a thickness of 1 mm, layer B2 is crosslinked at 40 ºC for 3 hours.

d)

A homogeneous mixture prepared by the process described under b) from 30% dimethylpolysiloxane-α,w-diol with a viscosity of 5,000 mPa.s, 15% of the same material with a viscosity of 1,000 mPa.s, as well as 50% of a lactose trituration with 10% nitroglycerine and 5% Wacker T-5 catalyst is applied to the surface of the laminated layers A + B1 + B2 to a thickness of 1 mm and then crosslinked at 40 ºC for 3 hours to form layer B3.

e)

A layer of 95% dimethylpolysiloxane-α,w-diol with a viscosity of 1,000 mPa.s and 5% Wacker T-5 catalyst is applied to a thickness of 0.1 mm on layer B3 of the laminated matrix of layers A + B1 + B2 + B3 and then covered with a thin aluminum foil and crosslinked at 40 ºC for 3 hours.

f)

A textile adhesive layer, which extends beyond the polymer matrix and ensures the adhesion of the formulation to the skin, is applied to the aluminum foil layer.

Example 2

The layers are built up in the sequence described in Example 1, except:

a)

The thickness of layer A is 1 mm and it contains 50% dimethylpolysiloxane-α,w-diol with a viscosity of 50,000 mPa.s, 45% of the same material with a viscosity of 5,000 mPa.s, as well as 5% Wacker T-5 catalyst. Polymerization is carried out at 60 ºC for 90 minutes.

b)

The thickness of layer B1 is 1 mm and it contains 70% of dimethylpolysiloxane-α,w-diol with a viscosity of 50,000 mPa.s, and 20% of the same material with a viscosity of 5,000 mPa.s, as well as 5% of phenobarbital sodium and 5% of Wacker T-5 catalyst. The polymerization is carried out at 40 ºC for 3 hours.

c)

The thickness of layer B2 is 1 mm and it contains 70% dimethylpolysiloxane-α,w-diol with a viscosity of 50,000 mPa.s, 17% of the same material with a viscosity of 5,000 mPa.s, 8% phenobarbital sodium as well as 5% phenobarbital sodium and 5% Wacker T-5 catalyst. The polymerization is carried out at 40 ºC for 3 hours.

d)

The thickness of layer B3 is 1 mm and it contains 70% dimethylpolysiloxane-α,w-diol with a viscosity of 50,000 mPa.s, 13% of the same material with a viscosity of 5,000 mPa.s, 12% phenobarbital sodium and 5% Wacker T-5 catalyst. The polymerization is carried out at 40 ºC for 3 hours.

Layers C and D are produced as described under e) and f) in Example 1.

Example 3

The layers are built up in the sequence described in Example 1, except:

a)

The thickness of layer A is 1 mm and it contains Wacker-3003/50 type two-component silicone rubber (suitable for polyaddition) as base material, whose components A and B are mixed in a ratio of 50:50. The polymerization is carried out at 70 ºC for 25 minutes.

b)

The thickness of layer B1 is 1 mm and it contains 35% of dimethylpolysiloxane-α,ω-diol with a viscosity of 50,000 mPa.s, 40% of the same material with a viscosity of 5,000 mPa.s, 20% of a lactose trituration with 40% of isosorbide dinitrate as active ingredient, as well as 5% of Wacker T-5 catalyst. The polymerization is carried out at 40 ºC for 3 hours.

c)

The thickness of layer B2 is 0.5 mm and it contains 25% of dimethylpolysiloxane-α,ω-diol with a viscosity of 50,000 mPa.s, 30% of the same material with a viscosity of 5,000 mPa.s, 40% of a lactose trituration with 40% of isosorbide dinitrate as active ingredient, as well as 5% of Wacker T-5 catalyst. The polymerization is carried out at 40 ºC for 3 hours.

d)

The thickness of layer B3 is 0.5 mm and it contains 20% of dimethylpolysiloxane-α,ω-diol with a viscosity of 50,000 mPa.s, 30% of the same material with a viscosity of 5,000 mPa.s, 45% of a lactose trituration with 40% of isosorbide dinitrate as active ingredient, as well as 5% of Wacker T-5 catalyst. The polymerization is carried out at 40 ºC for 3 hours.

Layers C and D are produced as described under e) and f) in Example 1.

Example 4

The layers are built up in the sequence described in Example 1, except:

a)

The thickness of layer A is 0.25 mm and it contains Wacker 3003/50 type two-component silicone rubber as base material, whose components A and B are homogenized in a ratio of 50:50. The polymerization is carried out at 70 ºC for 30 minutes.

b)

Layer B1 contains Wacker 3003/50 type two-component silicone rubber as a base material, whose components A and B are homogenized in a ratio of 35:35%, and then 30% of powdered O-salicylic acid is added. After the homogenization process, it is spread on layer A in a layer thickness of 1.5 mm. Polymerization is carried out at 50 ºC for 1 hour.

c)

The thickness of layer B2 is 1.5 mm and it contains the components A and B of Wacker 3003/50 type silicone rubber as base material in a ratio of 30:30% and 40% powdered O-salicylic acid. The polymerization is carried out at 50 ºC for 1 hour.

Layers C and D are produced as described under e) and f) in Example 1.

The catalyst (preferably a platinum complex compound) for the polyaddition process according to Examples 3 and 4 is contained in one of the components of the silicone rubber which is manufactured industrially by Wacker.

Claims (10)

1. A pharmaceutical composite having zero order absorption kinetics comprising: a multilayer silicone rubber matrix having one or more suitable pharmaceutically active ingredients in one or more of the layers; a water-impermeable layer; and an adhesive layer for attaching the composite to a body surface, characterized in that the rubber layers are formed from polymerized alkylpolysiloxane α,w-diols and/or polysiloxane polymers and that, in use, the rubber matrix directly contacts the skin. 2. Composite according to claim 1, wherein the matrix comprises 2 to 6 silicone rubber layers. 3. A composite according to claim 1 or 2, wherein the layer of the matrix which contacts the skin in use initially contains no active ingredient. 4. Composite according to one of the preceding claims, in which each rubber layer is between 0.1 mm and 3 mm thick. 5. A composite according to any preceding claim, wherein each rubber layer contains between 0 and 25% of active ingredient. 6. A composite according to any one of the preceding claims, in which each layer following the skin contact layer contains an increasingly larger proportion of active ingredient. 7. A composition according to any preceding claim, wherein the active ingredient is accompanied by a pharmacologically acceptable diluent. 8. Composite according to one of the preceding claims, in which the water-impermeable layer consists essentially of aluminum. 9. A method for producing a composite according to one of the preceding claims, in which: a) a non-polymerised silicone rubber is homogenised with a catalyst and as much of the active ingredient and optionally a pharmaceutically acceptable diluent as is required for the particular situation; b) the successive layers are polymerised one on top of the other ; (c) the layer furthest from the layer intended to come into contact with the skin is provided with a waterproof covering; and d) the waterproof layer is covered with a further layer suitable for securing the composite to a body surface. 10. A method according to claim 9, wherein the active ingredient is supplied per se or in combination with a diluent such as glucose, lactose or colloidal silicon dioxide.