AU680731B2

AU680731B2 - New pharmaceutical dosage form for transdermal administration

Info

Publication number: AU680731B2
Application number: AU17675/95A
Authority: AU
Inventors: Philippe Laurent
Original assignee: Laboratoire L Lafon SA
Current assignee: Cephalon France SAS
Priority date: 1994-04-29
Filing date: 1995-04-28
Publication date: 1997-08-07
Anticipated expiration: 2015-04-28
Also published as: KR950028767A; HU221599B; EP0679392A1; PT679392E; HUT75251A; ES2169746T3; HK1008658A1; DE69524470T2; CA2148112A1; NZ272014A; DE69524470D1; TW448050B; ZA953392B; ATE210430T1; FR2719220B1; JP2740465B2; DK0679392T3; HU9501245D0; FR2719220A1; JPH0859456A

Abstract

Compsn. designed to form a film on the skin for transdermal admin. of an active agent, comprises: a) a lipophilic active agent, b) 5-60 wt.% of a silicone-based adhesive polymer compsn. c) 0-25 wt.% of an absorption promoter, and d) 25-95 wt.% of a volatile solvent.

Description

B~L~n~Wls~-~ls u i

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): Laboratoire L. Lafon ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

INVENTION TITLE:

S..

S. New pharmaceutical dosage form for transdermal administration The following statement is a full description of this invention, including the best method of performing it known to me/us:o o o o Irp c-e sa~ la The present invention relates to a new pharmaceutical dosage form for the transdermal administration of an active principle.

The 1980s saw the development of transdermal systems which are applied to a delimited area of the skin and which serve as a carrier or vehicle for one or more active principles, which are generally intended to exert a systemic action after release and passage through the cutaneous barrier.

These systems, generally referred to as "transdermal patches", afford a number of advantages over the traditional dermatological forms such as ointments, salves, gels, solutions and lotions, namely: direct and continuous entry into the general circulation, elimination of the hepatic first-pass effect and/or of degradation in the digestive tract, with a consequent decrease in side effects, extended duration of action, 20 maintenance of a constant level of active principles in the plasma, increase in patient compliance through decrease in the frequency of dosage, decrease in inter-individual variations, 25 control over the dose administered as a result of a matrix or membrane system with a reservoir, production of a constant concentration of active principle during the period of the application.

Despite the degree of innovation provided by these systems, only a very small number of specialities exist today in this form. This is due to the fact that these devices demand: a very sophisticated technology of manufacture, few production sites which belong to a few large groups who have a monopoly of them, this leads to a high cost of manufacture and to a substantial cost and sale price. These systems are, in actual fact, reserved for expensive products.

The present invention is directed towards -2 providing new pharmaceutical dosage forms for the transdermal administration of an active principle which are very simple to use, and do not require massive, complex and costly industrial plants, which are multi-purpose; both from the standpoint of formulation and as regards the procedures for application when used, which are advantageous from an economic standpoint with a lower production cost.

To this end, the subject of the present invention is a composition intended to form a film on the skin for the transdermal administration of an active principle, which comprises: a) a lipophilic active principle b) from 5 to 60 in weight, and advantageously from 5 to 25 by weight, of a silicone-based adhesive polymer composition 0*eS c) from 0 to 25 by weight, of an absorption promoter, and d) from 25 to 95 by weight, and advantageously from 50 to 95 by weight, of a volatile solvent.

The subject of the present invention is also: the use of a composition which comprises: a) an active principle b) from 5 to 60 by weight, and advantageously from 5 to 25 by weight, of a silicone-based adhesive polymer composition 25 c) from 0 to 25 by weight of an absorption promoter, and d) from 25 to 95 by weight, and advantageously from 50 to 95 by weight, of a volatile solvent for the production of a film on a patient's skin for the transdermal administration of the active principle; a process for administering an active principle to a patient transdermally, which comprises the formation of a film on this patient's skin by applying to the skin a composition which comprises: a) an active principle b) from 5 to 60 by weight and advantageously from 5 to 25 by weight of a silicone-based adhesive polymer composition c) from 0 to 25 by weight of an absorption promoter, and d) from 25 to 95 by weight, and advantageously from 50 to 95% by weight, of a volatile solvent.

I 3 In the present invention, active principle denotes chiefly a medicinal product or substance having therapeutic properties.

These medicinal products are, in particular, lipophilic vitamins such as vitamins D and E and their derivatives, hormones such as calcitonin, steroids such as oestradiol and its esters and prednisone, or nicotine.

The percentages of the active principles in the compositions of the invention clearly depend on the nature of the active principle. Generally, the percentages are from 0.01 to 10 by weight.

According to the invention, silicone-based polymer composition is understood to mean a composition containing silicone-based polymers or siliconebased copolymers.

These silicones, which will be designated according to the nomenclature of the CTFA (Cosmetic, Toiletry Sand Fragrance Association) Dictionary, comprise, in particular, polydimethylsiloxane oils or polydimethyl- 20 siloxane oils modified with ionic or nonionic organic groups.

As ar example of polydimethylsiloxane oils, there may be mentioned dimethicones of formula:

CH

3

HCH

3

CH

3 I I 1 HC-Si-0 -Si-O -Si-CH 3

CH

3

CH

3

CH

3 where n is an integer below 5,000, and dimethiconols, which are dimethyl silicones terminated with hydroxyl groups.

As an example of modified polydimethylsiloxanes, there may be mentioned dimethicone copolyols, which are polymers of dimethylsiloxane containing polyoxyethylene and/or polyoxypropylene side chains.

The silicone-based adhesive polymer composition preferably represents 9 to 12 of the weight of the composition.

4 P1 pc IP IPIBB~ 4- The absorption promoters may be selected in particular, from propylene glycol, hexylene glycol, propylene glycol dipelargonate, glyceryl monoethyl ether, diethylene glycol, monoglycerides, monooleate of ethoxylated glycerides (with 8 to 10 ethylene oxide units), Azone (l-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3dioxolane, isopropylmyristate, octylmyristate, dodecylmyristate, myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate, terpinol, 1-menthol, d-limonene, 6cyclodextrin and its derivatives or surfactants such as polysorbates, sorbitan esters, sucrose esters, fatty acids, bile salts, or alternatively lipophilic and/or hydrophilic and/or amphiphilic products such as polyglycerol esters, N-methylpyrrolidone, polyglycosylated S 15 glycerides and cetyl lactate.

The absorption promoter preferably represents from 5 to 25 of the weight of the composition.

As volatile solvent, it is possible to use, in particular, polydimethylcyclosiloxanes, that is to say 20 compounds of formula: Cl-f 3

H

Si-O i j It is also possible to use other solvents such s

TCH

3 where n is between 3 and 6 on average, and in particular compounds in which n 4 or 5, as well as linear polysiloxanes such as hexamethyldisiloxane or dimethicones of low molecular mass.

It is also possible to use other solvents such as ethanol, isopropanol, chloroform, heptane, ethyl acetate.

The solvent preferably represents from 65 to 85 of the weight of the composition.

The composition according to the invention may be contained in a dispensing apparatus which delivers defined and reproduceable doses of composition. For I I ~~3CI =I 5 example, the dispensing apparatus delivers a drop of composition, and this drop may be spread on the skin using a brush or using a ball which is rolled over the skin.

The present invention finds an especially advantageous use for the transdermal administration of vitamin

D

3 (cholecalciferol).

Recent studies tend to show that all the populations of Western countries, and especially European countries, are lacking in Vitamin D in winter. The phenomenon is of less significance in the United States and in the Scandinavian countries which have a vitamin

D

3 -enriched diet.

In general, hypovitaminosis has been observed in the elderly individuals of all countries, and manifestz itself in an osteomalacia and abnormal phenomena in bone chemistry.

The causes of deficiency are: quantitatively and qualitatively insufficient dietary intake: eggs, butter, liver, fatty fish, etc.

lack of sunshine, since cutaneous synthesis takes place under the effect of UV rays. This source of supply of natural vitamin D is strongly dependent on climatic conditions.

25 malabsorption syndrome: in elderly subjects, there is a decrease in the intestinal absorption of vitamin D as a result of the decrease in liver and kidney functions.

At the present time, the specialities available on the market are essentially presented in pharmaceutical dosage forms for the oral route and a few for administration by injection Now, the oral route is not always well assimilated, and administration by injection is n:.t always accepted by elderly individuals.

The subject of the present invention is hence, more specifically, a composition intended to form a film on the skin for the transdermal administration of vitamin

D

3 or a hydroxylated derivative of vitamin D 3 and which comprises: a) vitamin D 3 or a hydroxylated derivative of vitamin D 3 I- plC I 6b) from 5 to 60 by weight, and preferably from 9 to 12 by weight, of a silicone-based adhesive polymer composition c) from 0 to 25 by weight of an absorption promoter, and d) fron 25 to 95 by weight and preferably from 65 to 85 by weight, pf a volatile solvent.

Examples of compositions according to the invention will be given below.

Examples 1 to 11: Compositions based on vitamin D 3 The compositions appearing in the table below were prepared by mixing the different constituents until a homogeneous mixture was obtained.

~c 311--- 11 ISII -r a a a a S V. 55 5 0aC S. S. S S VS. V V @5 1 2 3 4 5 6 7 8 9 10 11 I I Cholecalciferol 0.0825 0.0825 0.600 1,050 0.750 0.300 0.0825 0.600 0.140 0.280 1.120 Propylene glycol 7.500 7.500 7.500 7.500 7.500 22.500 22.500 22.500 dipelargonateI Cyclomethicone! 30.000 30.000 22.500 22.500 30.000 22.500 76.658 75.818 70.778 dimethiconol (1) Dimethicone/ 22.500 22.500 dimethiconol (2) Alpha-tocopherol 0.413 3.500 1.500 0.700 1.400 5.600 (preservative) BHT/b enz alkoniuni BHT BHT (3) chloride 0.495 3.600 0.002 0.002 0.002 (preservative)

I

13 %Solution of 13 %Solution of dimathiconol in a dimethiconol in a cyclomethicone dimethicone of low viscosity -8 5.5.55

S

S.

S S

S

5* S At the time of use, using an applicator system, a drop is deposited in a composition on the skin and is spread over a specified area.

The transdermal film forms after evapor,,. .on of the silicone solvent.

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

A. 1,2,5-Dihydroxycholecalciferol 2 jzg B. Diethylene glycol monoethyl ether 2.50 C. Glyceryl monooleate 1.25 D. Propylene glycol dipelargonate 1.25 E. Dimethylpolysiloxane 55.00% F. Cyclomethicone QS 100 Al ExAmple 13: Composition based on calcitonin.

15 A. Calcitonin 100 IU B. Azone C. Copolymer of polyacrylamide isoparaff in and polyoxyethylenated lauryl alcohols D. Propylene glycol 20 E. Dimethicone and dimethiconol 20 F. Polydimethylcyclosilor:iane QS 50 microlitres Example 14: Composition based on oestradiol ester.

A. Oestradiol propionic r~nd nicotinic ester 1.3 mg B. Diethylene glycol monoethyl ether 5 C. Glyceryl monooleate 2.5 D. Propylene glycol dipelargonate 2.5 E. Dimethicone and diitethiconol 55 F. Polydimethylcyclosiloxane QS 100 Al Example 15: Composition based on prednisone.

A. Prednisone 2 mg B. Azone 5 C. Beta-cyclodextrin 10 S S.

S.

S. S S S *5 9- Cyclomethicone and dimethiconol Ethanol Polydimethylcyclos iloxane 20 10 OS 100 Al Example-16: Composition based on calcitonin.

A. Calcitonin 100 IU

B.

C.

Azone Copolymer of polyacrylairnide isoparaffin and polyoxyethylenated lauryl al~cohols Propylene glycol Cyclomethicone and dimethiconol Ethanol Polydimethylcyclos iloxane I U :16

D.

E.

F.

G.

40 10 QS 100 /41

C.

C C .0G.

C

0& C C

C

C.

S

C

C C

CC

C

C.

CC C

C

CC

Examples 17 to 22 The following compositions for the transdermal administration of 17#-oestradiol were prepared.

Examiple 17 18 19 20 21 22 17,6- 0.250g 0.250g 0.250g 0.250g 0.250g 0.250g 20 PGDP~ 1 10.0og 10.0og l0.0og 20.00g 20.00g 20.00q

SEPAM

2 2.00g 5. OOg 2 .OOg Ethanol 20.00g 20.00g 20.00g 20.00g 20.00g 20.00g Silicone 100.0og 100.0Og 100.0og 100.00q 100.00g 100.0og 1401(3)

QS

Propylene glycol dipelargonate (2 2- (n-Nonyl) -1,3-dioxolane (3 13 solution of dimethiconol, in a cyclomethicole.

A study of diffusion through human skin in vitro was performed with these compositions.

10 The method used is the following.

An exact amount of composition, measured volumetrically (10 Il) is applied to a human skin biopsy sliced with a dermatome (constant thickness 350 Am) and placed in a so-called Franz static type diffusion cell.

Contact is maintained for 2, 4, 6, 8, 10 and 24 hours.

The samples of human skin originate from anatomical pieces taken from abdomen and/or breast during an operation for plastic surgery.

The survival fluid is a pH 7.4 phosphate buffer containing albumin (bovine serum albumin 15 At the end of each contact time, the fluid in the dermal compartment is sampled and the active principle it contains 0 is assayed.

At the end of the 24 hours of contact, the skin surface is washed. The active principle remaining at the surface of the skin and carried into the washes is quantified.

The results obtained after 24 hours are given in 20 the following table, in absorbed of the dose applied.

Example 17 2.1 18 2.7 1.1 19 3.8 0.9 20 4.4 1.7 21 4.5 22 9.4 3.1 Examples 23 to 26 The following compositions for the transdermal administration of cholecalciferol were prepared.

II-

11 e• oo L rr oooo .4 3* f *ooO *o a a.

a. a a .a 0 Example 23 24 25 26 Cholecalciferol 0.534 g 0.534 g 0.534 g 0.534 g Alpha- 2,800 g 2.800 g 2.800 g 2.800 g tocopherol

PGDP

1 22.500 g 22.500 g 22.500 g 22.500 g

SEPA

T 2 0.000 g 2.000 g 5.000 g 10.000 g Methy' para- 0.250 g hydroxybenzoate Propyl para- 0.100 g hydroxybenzoate Ethanol 0.650 g Silicone QS 100,000 g 100,000 g 100,000 g 00, 000 g 1) Propylene glycol dipelargonate 2-(n-Nonyl)-1,3-dioxolane 15 13 Solution of dimethiconol in a cyclomethicone.

The procedure was the same as that used with the compositions of Examples 17 to 22, applying 10 mg of composition (53.40 4g of cholecalciferol).

The results are given in the table below: 20 Amounts in pg 2 4 6 8 10 24 of vitamin D 3 hours hours hours hours hours hours absorbed

SD)

Example (pg) 1.0820 1.6223 2.1175 2.5170 2.8520 4.4525 23: 0.3667 0.4696 0.6116 0.7228 0.8417 1.1364 Example (pg) 1.1173 1.52220 1.8880 2.1758 2.4260 3.6465 24: 0.2789 0.3773 0.4594 0.5138 0.5549 0.6630 Example (pg) 1.3078 1.8285 2.3330 2.7273 3.0893 4.8973 0.5660 0.7634 0.9587 1.1191 1.2645 1.8922 Example (jg) 1.1983 1.8933 2.4513 2.8553 3.2080 4,7830 26: 0.5044 0.4308 0.4390 0.4196 0.3928 0.3038 a.

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IA-

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

S S 5 0*

S

5O 5

S.

S

59555 0

S.

S

*5S9 55 5* Ge.

S

55.

S

550555 ~r 4 ,j A *1 ~iY

Claims

1. Composition intended to form a film on the skin for the transdermal administration of an active prin- ciple, which comprises: a) a lipophilic active principle b) from 5 to 60 by weight of a silicone-based adhesive polymer composition c) from 0 to 25 by weight of an absorption promoter, and d) from 25 to 95 by weight of a volatile solvent.

2. Composition according to Claim 1, in which the lipophilic active principle is selected from hormones, steroids and lipophilic vitamins. too 0

3. Composition according to Claim 1 or 2, in which 15 the active principle is selected from vitamin D 3 and its hydroxylated derivatives. S"

4. Composition according to Claims 1 to 3, in which the adhesive polymer composition comprises polysiloxanes.

Composition according to Claim 4, in which the solvent comprises a polydimethylcycl.osiloxane.

6. Composition intended to form a film on the skin for the transdermal administration of vitamin D 3 or a hydroxylated derivative of vitamin D 3 and- which com- prises: ag 25 a) vitamin D 3 or a hydroxylated derivative of vitamin D 3 b) from 5 to 60 by weight of a silicone-based adhesive polymer composition a• c) from 0 to 25 by weight of an absorption promoter, and d) from 25 to 95 by weight of a volatile solvent.

7. Composition acording to Claim 1 in which the volatile solvent comprises polydimethylsiloxanes or volatile linear polysiloxanes. T -I- I' R\M i (:ql7675-VS 112 121-i19 Sc .15 o 55 I. 4 000 13

8. Process for administering an active principle to a patient transdermally, which comprises the formation of a film on this patient's skin by applying to the skin a composition which comprises: a) a lipophilic active principle b) from 5 to 60 by weight of a silicone-based adhesive polymer composition c) from 0 to 25 by weight of an absorption promoter, and d) from 25 to 95 by weight of a volatile solvent.

9. Composition intended to form a film on the skin for the transdermal administration of vitamin D 3 or a hydroxylated derivative of vitamin D3, and which comprises a) vitamin D 3 or a hydroxylated derivative of vitamin D 3 b) from 9 to 12 by weight of a silicone-based adhesive polymer composition form 0 to 25 by weight of an absorption promoter, and d) from 65 to 85 by weight of a volatile solvent.

10. Composition as claimed in Claim 1, in which the adhesive polymer composition comprises polydimethylsiloxane oils.

11. Composition as claimed in Claim 10, in which the polydimethylsiloxane oils are selected from dimethicones of formula CH 3 CH 3 CH, I 1 1 H 3 C-Si-O Si-O Si-CH 3 I I CH 3 CH 3 CH 3 where n is an integer below 5000, and dimethiconols.

12. Process for administering an active principle to a patient transderrally, which comprises the formation of a film on this patient's skin by applying to the skin a composition which comprises a) a lipophilic active principle b) from 5 to 60 by weight of a silicone-based adhesive polymer composition c) from 0 to 25 by weight of an absorption promoter, and d) from 25 to 95 by weight of volatile solvents comprising polydimethylcyclosiloxanes or volatile linear polysiloxanes. S. o Sr S. I ci P '.O'kR~iC~I675Y I~1215,17 -14-

13. Process as claimed in claim 12, in which the adhesive polymer composition comprises polydimethylsiloxane oils.

14. Process as claimed in claim 13, in which the polydimethylsiloxane oils are selected from dimethicones of formula: CH 3 CH 3 CH 3 I I I H 3 Si-O0 Si-CH 3 CH 3 F Cf- 3 CHt 3 ni where n is an integer below 5000, and dimethiconols. Pharmaceutical compositions or methods of treatment involving them, substantially as hereinbefore described V. with reference to the Examples. 0 :0 DATED this 12th day of May 1997 Laboratoire L. Lafon by DAVIES COLLISON CAVE Patent Attorneys for the Applicant a, 0 New pharmaceutical dosage form for transdermal administration ABSTRACT i The invention relates to a composition intended to form a film on the skin for the transdermal adminis- tration of an active principle, which comprises: a) a lipophilic active principle b) from 5 to 60 by weight of a silicone-based adhesive polymer composition c) from 0 to 25 by weight of an absorption promoter, and d) from 25 to 95 by weight of a volatile solvent. Fig. None °o i IP i -CI l~