CA2148112C

CA2148112C - New pharmaeutical dosage form for transdermal administration

Info

Publication number: CA2148112C
Application number: CA002148112A
Authority: CA
Inventors: Philippe Laurent
Original assignee: Laboratoire L Lafon SA
Current assignee: Cephalon France SAS
Priority date: 1994-04-29
Filing date: 1995-04-27
Publication date: 2001-01-30
Anticipated expiration: 2015-04-27
Also published as: AU1767595A; CA2148112A1; NZ272014A; AU680731B2; FR2719220B1; HUT75251A; ATE210430T1; PT679392E; KR100233770B1; HU9501245D0; TW448050B; DE69524470T2; EP0679392B1; ZA953392B; FR2719220A1; HK1008658A1; JPH0859456A; ES2169746T3; EP0679392A1; DK0679392T3

Abstract

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.

Description

The present invention relates to a new pharma-ceutical 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 "trans-dermal 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 circu-lation, - 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, - 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, - 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 providing new pharmaceutical dosage forms for the trans-dermal 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) frorn 5 to 60 % in weight, and advantageously rrom 5 to 25 % by weight, of a s~_licone-based adhesive polymer composition c) from 0 to 25 % by weight, of an absorption promoter, and d) f_-~_-om 25 to 95 % by weight, and advantacreously from 5C to 95 % by weight, of a volati7.e solvent.
The subject of the present invention is also:
- the use of a composition which comprises:
a) an active principle b) fro~-n 5 to 00 °/ by y~e,'_ght, and advantageously from 5 to 25 % by weight, of a s~li_cone-based adhesive polymer composition c) from 0 to 25 % by weight of an absorption promoter, and d) from 2.5 to 95 % by weight, and advantageously from 5(? to 95 y by weight, of a volatile solvent .for the production of a film on a patient's sk~_n 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 akin by applying to the skin a composition which comprises:
a) an active principle 3 5 b) from 5 to 60 % by weight and advantageously from 5 to ?.5 % 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 °/ ~,y weight, and advantaaeo~.x:~ly from 50 to 95% by weight, of a volatile solvent.

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 percen tages 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 ~r silicone based copolymers.
These silicones, which will be designated accor-ding to the nomenclature of the CTFA (Cosmetic, Toiletry and Fragrance Association) Dictionary, comprise, in particular, polydimethylsiloxane oils or polydimethyl-siloxane oils modified with ionic or nonionic organic groups.
As an example of polydimethylsiloxane oils, there may be mentioned dimethicones of formula:
i H3 i H3 i Ha H3C_$I 0 ~ 1-~ ~ f-CH3 CH3 CH3 ~ CH3 where n is an integer below 5,000, and dimethiconols,which are dimethyl silicones terminated with hydroxyl groups.
As an example of modified polydimethylailoxanes, 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_ _ 2148112 The absorption promoters may be selected in particular, from propylene glycol, hexylene glycol, propylene glycol dipelargonate, glyceryl monoethyl ether, diethylene glycol, monoglycerides, monooleate of ethoxy-lated glycerides (With 8 to 10 ethylene oxide units), Azone (1-dodecylazacycloheptan-2-one), 2-(n-nonyl)-1,3-dioxolane, isopropylmyristate, octylmyristate, dodecyl-myristate, myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate, terpinol, 1-menthol, d-limonene, ~B-cyclodextrin 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 poly-glycerol esters, N-methylpyrrolidone, polyglycosylated 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 compounds of formula:
i Hs Si-O
.

'L ' n ..___...
where n is between 3 and 6 on average, and in particular compounds in which n - 4 or 5, as well as linear poly-siloxanes 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 reproducible doses of composition. For 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 advan-tageous use for the transdermal administration of vitamin D3 (cholecalciferol).
Recent studies tend to show that all the popu lations 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 D3-enriched diet.
In general, hypovitaminosis has been observed in the elderly individuals of all countries, and manifests 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.
. 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 admini stration by injection (IM) . Now, the oral route is not always well assimilated, and administration by injection is not 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 D3 or a hydroxylated derivative of vitamin D3, and which comprises:
a) vitamin D3 or a hydroxylated derivative of vitamin D3 b) from 5 to 60 ~ by weight, and preferably from 9 to 12 / by ~nei_ght, of a siliccne-based adhesive polymer composition c) from 0 to 25 % by weight of an absorption promoter, and d) from 25 to 95 ~ by weight arid preferably from 65 to 05 ~ by weight, of a volatile soJ_vent.
Examples of compositions according to the inven-tion will be given below.
Examvles 1 to 11: Compositions based on vitamin D3.
The compositions appearing in the table below were prepared by mixing the different constituents until a homogeneous mixture was obtained.

_ 2148112 O m O N

c o n I c ..o .-a N m n I b V c I

rl N n O b O N

O O ~-1 I O ..O

W f1 0D I ~ v O

rl N I

N Y1 I rl O

o N n o ao o N

0 o In I o ...o Va If1 b I n IrlO

N b I O O

o N n 0 0 o I I
N o 0 ~ ~ I I

...b I I

n N I I M

O N

1I7 O Il1 n b~o I o I I ~ w o I I I pp I o I I o o M

0 o I o o I

M ~ I ~ ~ I
I I

o n I N ~ I

N >v a~

' 0 0 o m o I In o I o I I a ~ ~ W n m n I I m I . I I

O n I N I I
>

N

O

O O O O r1 If1 O O I O I

c m In I ,n I o w .. . I . I a o ri n N I ,., I o N a o .~ a ~a o a~ a 0 0 0 0 ..r 0 0 o I I I p M ~ b If1 If1 I t I O JJ

I I I .~ o o r ct I I I a N

a b In o ,., b a N I o I .~ I a a N tn I o I a I . .
~ i o I I I . .

I o I o I a o en O O
a a O O

U1 O U a N I O I I I ' m I O I I 1 C

O I I I I

I O I I I

O 1'0 H H

~i ~rl b b W W

O O

U ~ ~ U O O
~

s~ al o a o o p o o ~ a~o ~ .~ .a> o ..> ar y rl a ~ a a o ~
a a o o .a 0 o a a la la o rl a ena~ a a o > a o >
a le o w o .~., s~w a b w .., ~ a~
a rl a s .a.a I o o ..~o a o >. ~ O a~a~ IEm .qH m ~

M M
a o ~r 0 0 .ao w o 0 o 0 o w a p ~ w w ..~w ~

a w b ab b a' ~ a ' a ~ ..

rl N

tan O

_8-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 evaporation of the silicone solvent.
Example 12: Composition based on 1,2,5-dihydroxycholecal-ciferol.
A. 1,2,5-Dihydroxycholecalciferol 2 ~.g 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 ~.1 Example 13: Composition based on calcitonin.
A. Calcitonin 100 IU
B. Atone 10 %
C. Copolymer of polyacrylamide isoparaffin and polyoxyethylenated lauryl alcohols 5 %
D. Propylene glycol 20 %
E. Dimethicone and dimethiconol 20 %
F. Polydimethylcyclosiloxane QS 50 micro-litres Example 14: Composition based on oestradiol ester.
A. Oestradiol propionic and 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 dimethiconol 55 %
F. Polydimethylcyclosiloxane QS 100 ~,1 Examvle 15: Composition based on prednisone.
A. Prednisone 2 mg B. Atone 5 %
C. Beta-cyclodextrin 10 %

- g _ D. Cyclomethicone and dimethiconol 20 %
E. Ethanol 10 %
F. Polydimethylcyclosiloxane QS 100 ~C1 Example 16: Composition based on calcitonin.
A. Calcitonin 100 IU

B. Azone 10 %

C. Copolymer of polyacrylamidc isoparaffin and polyoxyethylenated lauryl al_cohol~:5 %

D. Propylene glycol 5 %

E. Cyclomethicone and dimethiconol 40 %

F. Ethanol 10 $

G. Polydimethylcyclosiloxane QS 100 ~.l Examples 17 to 22 The following compositions for the transdermal administration of 175-oestradiol were prepared.
8xample 17 18 19 20 21 22 17/$- 0.2508 0.2508 0.2508 0.2508 0.2508 0.2508 Oeatradiol 2 PGDP~1~ 10.008 10.008 10.008 20.008 20.008 20.008 SHPA~Z~ 2.008 S.OOg 2.008 S.OOg Ethanol 20.008 20.008 20.008 20.008 20.008 20.008 Silicone 100.008 100.008100.008100.008100.008100.008 14 01 ~3 ~
Qs ~1~ Propylene glycol dipelargonate ~2~ 2- (n-Nonyl) -1, 3-dioxolane 3~ 13 % solution of dimethiconol in a cyclomethicone.
A study of diffusion through human skin in vitro was performed with these compositions.

' The method used is the following.
An exact amount of composition, measured volu-metrically (10 ~,1) is applied to a human skin biopsy sliced with a dermatome (constant thickness 350 Ecm) 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 oper-ation for plastic surgery.
The survival fluid is a pH 7.4 phosphate buffer containing albumin (bovine serum albumin 15 g/1). At the end of each contact time, the fluid in the dermal com-partment is sampled and the active principle it contains 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 the following table, in % absorbed of the dose applied.
Example 17 2.1 t 1.0 18 2.7 t 1.1 19 3.8 t 0.9 20 4.4 t 1.7 21 4.5 t 2.5 22 9.4 t 3.1 Examples 23 to 26 The following compositions for the transdermal administration of cholecalciferol were prepared.

8xample 23 24 25 26 Cholecalciferol0.534 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 22.500 g 22.500 22.500 g g g SSPA~~Z~ 0.000 g 2.000 g 5.000 g 10.000 g Methyl para- 0.250 g hydroxybenzoate Propyl para- 0.100 g hydroxybenzoate Ethanol 0.650 g Silicone ~3~ 100,000 100,000 100,000 100,000 QS g g g g Propylene glycol dipelargonate ~ 2-(n-Nonyl)-1,3-dioxolane ~3~ 13 % Solution of dimathiconol 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 ~.g of cholecalciferol).
The results are given in the table below:
2 Amounts in 2 4 6 8 10 24 0 ~g of vitamin hours hours hours hours hours hours absorbed (* SD) Example (fig)1.0820 1.6223 2.1175 2.5170 2.8520 4.4525 2 23: (*) 0.3667 0.4696 0.6116 0.7228 0.8417 1.1364 Example (fig)1.1173 1.522201.8880 2.1758 2.4260 3.6465 24: (*) 0.2789 0.3773 0.4594 0.5138 0.5549 0.6630 Example (~Cg)1.3078 1.8285 2.3330 2.7273 3.0893 4.8973 25: (*) 0.5660 0.7634 0.9587 1.1191 1.2645 1.8922 3 Example (fig)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

Claims

1. 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% 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 selected from polydimethylcyclosiloxanes and polysiloxanes of low molecular weight.

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

3. Composition according to Claim 1 or 2, in which the active principle is selected from vitamin D3 and its hydroxylated derivatives.

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

5. Composition as claimed in Claim 4, in which the adhesive polymer composition comprises polydimethylsiloxane oils.

6. Composition as claimed in Claim 5, in which the polydimethylsiloxane oils are selected from dimethicones of formula:

where n is an integer below 5000, and dimethiconols.

7. Composition according to Claims 4 to 6, in which the solvent is a polydimethylcyclosiloxane.

8. Composition intended to form a film on the skin for the transdermal administration of vitamin D3 or a hydroxylated derivative of vitamin D3, and which comprises:

a) vitamin D3 or a hydroxylated derivative of vitamin D3 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 selected from potydimethylcyclosiloxanes and polysiloxanes of low molecular weight.

9. Use of 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 selected from polydimethylcyclosiloxanes and polysiloxanes of low molecular weight, for the production of a film on a patient's skin for the transdermal administration of the active principle.

10. Composition intended to form a film on the skin for the transdermal administration of vitamin D3 or a hydroxylated derivative of vitamin D3, and which comprises:

a) vitamin D3 or a hydroxylated derivative of vitamin D3 b) from 9 to 12% by weight of a silicone-based adhesive polymer composition c) form 0 to 25% by weight of an absorption promoter, and d) from 65 to 85% by weight of a volatile solvent selected from polydimethylcyclosiloxanes and polysiloxanes of low molecular weight.