HK1008658B - Pharmaceutical form for transdermal administration - Google Patents

Description

The present invention relates to a novel galenic form for transdermal administration of an active substance.

Transdermal systems were developed in the 1980s which are applied to a defined surface of the skin and which serve as a support or vehicle for one or more active ingredients, generally intended to exert a general action after release and passage through the skin barrier.

Err1:Expecting ',' delimiter: line 1 column 78 (char 77)

Despite the degree of innovation brought about by these systems, very few specialties exist today in this form. The Commission has already made a number of proposals to improve the quality of the products, including the introduction of a new type of production system, which is designed to reduce the cost of production and to reduce the costs of production.

In addition, US 3 836 647 describes a composition for skin protection or treatment, which includes an active substance, a silicone-based adhesive polymer composition and a solvent.

EP 0 560 014 refers to a biodegradable skin protective film comprising an active substance, a composition of a thermoplastic polymer and an organic solvent.

The present invention is intended to provide novel galenic forms for transdermal administration of an active substance The Commission proposes to establish a European standard for the manufacture of electronic cigarettes, which is to be very simple to implement, does not require heavy, complicated and expensive industrial installations, is versatile: both in terms of formulation and in terms of the application methods when used, is economically attractive and has a lower cost of production.

For this purpose, the present invention is intended to form a film on the skin for the transdermal administration of an active substance, which includes: (a) a lipophilic active substance (a) of 5 to 60% by weight, preferably 5 to 25% by weight, of a silicone-based adhesive polymer composition (b) of 5 to 25% by weight of an absorption promoter (c) of 25 to 95% by weight, preferably 50 to 95% by weight, of a volatile solvent.

The purpose of this invention is also to: the use of a composition that includes: (a) a lipophilic active substance (a) of 5 to 60% by weight, and preferably 5 to 25% by weight, of a silicone-based adhesive polymer composition (b) of 5 to 25% by weight of an absorption promoter (c) of 25 to 95% by weight, and preferably 50 to 95% by weight, of a volatile solvent for the manufacture of a medicinal product for transdermal administration of the active substance.

In the present invention, the active substance is mainly a drug or substance with therapeutic properties.

These include lipophilic vitamins such as vitamins D and E and their derivatives, hormones such as calcitonin, steroids such as estradiol and its esters, and prednisone or nicotine.

The percentages of active ingredients in the compositions of the invention obviously depend on the nature of the active ingredient.

According to the invention, a silicon-based polymer composition is a composition containing both silicon-based polymers and silicon-based copolymers.

These silicones, which will be designated according to the nomenclature of the CTFA (Cosmetic, Toiletry and Fragrance Association) dictionary, include polydimethylsiloxane oils or polydimethylsiloxane oils modified by ionic or non-ionic organic groups.

Examples of polydimethylsiloxane oils are dimethycones with formula: where n is an integer less than 5000, and dimethyconols which are dimethylsilicones terminated by hydroxy groups.

An example of modified polydimethylsiloxanes is dimethycone copolyols, which are polymers of dimethylsiloxane with polyoxyethylene and/or polyoxypropylene side chains.

The adhesive polymer composition based on silicone is preferably 9 to 12% by weight of the composition.

The absorption promoters may be selected from propylene glycol, hexylene glycol, propylene glycol dipelargonate, glyceryl monoethyl ether, diethylene glycol, monoglycerides, ethoxylated glyceride monooleate (with 8 to 10 ethylene oxide motifs), azone (1-dodecyl azacycloheptane-2-one), 2-n-nonyl) -1,3-dioxolan, isopropyl myristate, octyl myristate, dodecyl myristate, myrystyl alcohol, lauryl alcohol, acetic acid, lactyl polypyrid, 1-acetyl or polycyclic acids, and their derivatives, such as acetylated glycosides, polypyrid, acyclic acid, and/or its derivatives, such as acyclic acid, polypyrid, and/or its derivatives, and their products, such as acycyl and/or β-acetyl, and their derivatives, and their derivatives.

The volatile solvent can be used in particular polydimethylcyclosiloxanes, i.e. compounds with formula: where n is on average between 3 and 6, and in particular compounds where n = 4 or 5, as well as linear polysiloxanes such as hexamethyl disiloxane or low molecular weight dimethycones.

Other solvents such as ethanol, isopropanol, chloroform, heptane, ethyl acetate can also be used.

The solvent should preferably account for 65 to 85% of the weight of the composition.

The composition of the invention may be contained in a dispensing apparatus which delivers defined and reproducible doses of composition. e.g. the dispensing apparatus delivers a drop of composition and this drop may be spread on the skin by means of a brush or a ball which is rolled over the skin.

The present invention has a particularly interesting application for the transdermal administration of vitamin D3 (cholecalciferol) and its hydroxy derivatives.

Recent studies tend to show that all populations in Western countries and particularly European countries are deficient in vitamin D in winter. The phenomenon is less important in the United States and Scandinavian countries which have a diet rich in vitamin D3.

In general, hypovitaminosis has been observed in elderly people in all countries and is manifested by osteomalacia and abnormal phenomena in bone chemistry.

The causes of deficiency are: . inadequate quantity and quality of food intake: eggs, butter, liver, fatty fish.. lack of sunlight because the skin synthesis is done by UV rays. This natural source of vitamin D supply is highly dependent on climatic conditions.. mal-absorption syndrome: in the elderly there is a decrease in intestinal absorption of vitamin D due to decreased liver and kidney functions.

The specialties currently available on the market are mainly oral galenic forms and a few injectable (IM) forms.

The present invention therefore relates more specifically to a composition intended to form a skin film for transdermal administration of vitamin D3 or a hydroxylated derivative of vitamin D3 and which includes: (a) Vitamin D3 or a hydroxylated derivative of vitamin D3b) 5 to 60% by weight and preferably 9 to 12% by weight of a silicone-based adhesive polymer composition;

The following are examples of compositions according to the invention.

Examples 1 to 11: Vitamin D3 based compositions

The compositions shown in the table below were prepared by mixing the various constituents until a homogeneous mixture was obtained.

At the time of application, a drop of a preparation is applied to the skin using an applicator system and spread on a specific surface.

The transdermal film is formed after the silicone solvent evaporates.

Example 12 : Composition based on 1,2,5-dihydroxycholecalciferol.

A.	1,2,5-dihydroxycholécalciférol	2 µg
B.	Monoéthyléther de diéthylène glycol	2,50 %
C.	Monooléate de glycéryle	1,25%
D.	Dipélargonate de propylène glycol	1,25%
E.	Diméthylpolysiloxane	55,00%
F.	Cyclométhicone	QSP 100 µl

Example 13: Calcitonin based composition.

A.	Calcitonine	100 UI
B.	Azone	10 %
C.	Copolymère de polyacryl amide d'isoparaffine et d'alcools lauryliques polyoxyéthylénés	5 %
D.	Propylèneglycol	20 %
E.	Diméthicone et diméthiconol	20 %
F.	Polydiméthylcyclosiloxane	QSP 50 microlitres

Example 14: Estradiol ester composition

A.	Ester propionique et nicotinique d'estradiol	1,3 mg
B.	Monoéthyléther de diéthylène glycol	5 %
C.	Monooléate de glycéryle	2,5 %
D.	Dipélargonate de propylène glycol	2,5 %
E.	Diméthicone et diméthiconol	55 %
F.	Polydiméthylcyclosiloxane	QSP 100 µl

Example 15: Preparation based on prednisone.

A.	Prednisone	2 mg
B.	Azone	5 %
C.	Bétacyclodextrine	10 %
D.	Cyclométhicone et diméthiconol	20 %
E.	Ethanol	10 %
F.	Polydiméthylcyclosiloxane	QSP 100 µl

Example 16: Calcitonin based composition

A.	Calcitonine	100 UI
B.	Azone	10 %
C.	Copolymère de polyacrylamide d'isoparaffine et d'alcools lauryliques polyoxyéthylénés	5 %
D.	Propylène glycol	5 %
E.	Cyclométhicone et diméthiconol	40 %
F.	Ethanol	10%
G.	Polydiméthylcyclosiloxane	QSP 100 µl

Examples 17 to 22

The following formulations have been prepared for transdermal administration of 17 β-estradiol. - What?

17 β-estradiol	0,250 g	0,250 g	0,250 g	0,250 g	0,250 g	0,250 g
	10,00 g	10,00 g	10,00 g	20,00 g	20,00 g	20,00 g
		2,00 g	5,00 g		2,00 g	5,00 g
Ethanol	20,00 g	20,00 g	20,00 g	20,00 g	20,00 g	20,00 g
	100,00g	100,00g	100,00g	100,00g	100,00g	100,00g

These compounds were used in an in vitro study of diffusion through human skin.

The method used is as follows.

An exact volume-measured amount of composition (10 μl) is applied to a biopsy of dermatomatous human skin (constant thickness 350 μm) placed in a static diffusion cell called Franz®. Contact is maintained for 2, 4, 6, 8, 10 and 24 hours. Human skin samples are taken from anatomical parts taken from the abdomen and/or breast during plastic surgery.

The survival fluid is a phosphate buffer with a pH of 7.4 containing albumin (bovine albumin serum 15 g/l). At the end of each contact time, the liquid is removed from the dermal compartment and the active substance contained is dosed.

After 24 hours of contact, the skin surface is washed and the active substance that persists on the skin surface and is absorbed into the washing fluids is quantified.

The 24-hour results are given in the following table as % absorbed of the administered dose. - What?

17	2,1 ± 1,0
18	2,7 ± 1,1
19	3,8 ± 0,9
20	4,4 ± 1,7
21	4,5 ± 2,5
22	9,4 ± 3,1

Examples 23 to 26

The following formulations have been prepared for transdermal administration of cholecalciferol. - What?

Cholécalciférol	0,534 g	0,534 g	0,534 g	0,534 g
Alpha tocophérol	2,800 g	2,800 g	2,800 g	2,800 g
	22,500 g	22,500 g	22,500 g	22,500 g
	0,000 g	2,000 g	5,000 g	10,000 g
Parahydroxybenzoate de méthyle	0,250 g
Parahydroxybenzoate de propyle	0,100 g
Ethanol	0,650 g
	100,000 g	100,000 g	100,000 g	100,000 g

As with the formulae in examples 17 to 22, 10 mg of formula (53.40 μg cholecalciferol) was applied.

The results are given in the following table: - What?

Exemple 23 :	(µg)	1,0820	1,6223	2,1175	2,5170	2,8520	4,4525
	(±)	0,3667	0,4696	0,6116	0,7228	0,8417	1,1364
Exemple 24 :	(µg)	1,1173	1,52220	1,8880	2,1758	2,4260	3,6465
	(±)	0,2789	0,3773	0,4594	0,5138	0,5549	0,6630
Exemple 25 :	(µg)	1,3078	1,8285	2,3330	2,7273	3,0893	4,8973
	(±)	0,5660	0,7634	0,9587	1,1191	1,2645	1,8922
Exemple 26 :	(µg)	1,1983	1,8933	2,4513	2,8553	3,2080	4,7830
	(±)	0,5044	0,4308	0,4390	0,4196	0,3928	0,3038

Claims (7)

1. Composition intended to form a film on the skin for the transdermal administration of an active ingredient, comprising:

   a) a lipophilic active ingredient,

   b) from 5 to 60% by weight of a silicone-based adhesive polymer composition,

   c) from 5 to 25% by weight of an absorption promoter, and

   d) from 25 to 95% by weight of a volatile solvent.
2. Composition as claimed in Claim 1, in which the lipophilic active ingredient is chosen from amongst lipophilic vitamins, hormones and steroids.
3. Composition as claimed in Claim 1 or 2, in which the active ingredient is chosen from amongst vitamin D₃ and its hydroxyl derivatives.
4. Composition as claimed in Claims 1 to 3, in which the adhesive polymer composition comprises polysiloxanes.
5. Composition as claimed in Claim 4, in which the solvent is a polydimethylcyclosiloxane.
6. Composition as claimed in Claim 3 intended to form a film on the skin for the transdermal administration of vitamin D₃ or a hydroxyl derivative of vitamin D₃ and comprising:

   a) vitamin D₃ or a hydroxyl derivative of vitamin D₃,

   b) from 9 to 12% by weight of a silicone-based adhesive polymer composition,

   c) from 5 to 25% by weight of an absorption promoter, and

   d) from 65 to 85% by weight of a volatile solvent.
7. Use of a composition comprising:

   a) a lipophilic active ingredient,

   b) from 5 to 60% by weight of a silicone-based adhesive polymer composition,

   c) from 5 to 25% by weight of an absorption promoter, and

   d) from 25 to 95% by weight of a volatile solvent

   for the production of a medicament for the transdermal administration of the active ingredient.