WO1999016434A1

WO1999016434A1 - A transdermal drug delivery system for anti-inflammatory analgesic agent comprising diclofenac diethylammonium salt, and the manufacturing method thereof

Info

Publication number: WO1999016434A1
Application number: PCT/KR1998/000295
Authority: WO
Inventors: Jin Deog Song; Chul Min Park; Young Kwon Choi; Heon Han Lee; Yong Ho Shim; Hye Jeong Yoon
Original assignee: Sam Yang Co., Ltd.
Priority date: 1997-09-26
Filing date: 1998-09-25
Publication date: 1999-04-08
Also published as: BR9815378A; KR100305216B1; AU726448B2; AU9464798A; JP2001517696A; ES2213916T3; CA2304784A1; CN1271280A; HK1030161A1; EP1030660B1; CN1180773C; DE69822327T2; KR19990029556A; DE69822327D1; KR19990026792A; NZ503112A; US6723337B1; BR9815378B1; EP1030660A1; CA2304784C

Abstract

The invention herein relates to a transdermal drug delivery system for anti-inflammatory analgesic agent comprising diclofenac diethylammonium salt, wherein a backing film (1), a matrix layer (2) containing active ingredients, a release liner (3) which is removed before application onto the skin are laminated therein. More particularly, the invention herein relates to a transdermal drug delivery system for anti-inflammatory analgesic agent comprising diclofenac diethylammonium salt, wherein the transdermal penetration and adhesion of the patch to the body are enhanced by means of a matrix layer which comprises a diclofenac diethylammonium salt as active ingredient in addition to acrylic polymer as adhesive constituent, non-ionic surfacant as absorption enhancer, terpene and dissolution assistant, and the volatile and non-volatile constituents of the composition are separately applied therein for significantly reducing the manufacturing time thereof.

Description

A Transdermal Drug Delivery System for Anti-inflammatory Analgesic Agent

Comprising Diclofenac Diethylammonium Salt, and the Manufacturing Method Thereof.

BACKGROUND OF THE INVENTION Field of the Invention

The invention herein relates to a transdermal drug delivery system for anti-

inflammatory analgesic agent comprising diclofenac diethylammonium salt, wherein a

backing film, a matrix containing active ingredients, a release liner which is removed

before application onto the skin are laminated therein. More particularly, the invention herein relates to a transdermal drug delivery system for anti-inflammatory analgesic

agent comprising diclofenac diethylammonium salt, wherein the transdermal penetration

and adhesion of the patch to the body are enhanced by means of a matrix layer which

comprises a diclofenac diethylammonium salt as active ingredient in addition to acrylic

polymer as adhesive constituent, non-ionic surfactant as absorption enhancer, terpene

and dissolution assistant, and the volatile and non-volatile constituents of the

composition are separately applied therein for significantly reducing the manufacturing

time thereof.

Description of the Prior Art

Diclofenac salt, one of non-steroid anti-inflammatory drugs (NSAIDs), shows

therapeutic efficacy by means of inhibiting a biochemical reaction path which is

necessary for the biosynthesis of a pain inducer, prostaglandin. Diclofenac is a drug

which has the effects of pain relief, antifebrile and anti-inflammation and is widely applicable in rheumatic arthritis, osteoarthritis, spastic spondylitis, acute gout, and

inflammation or gout of lesion after operation. However, if diclofenac is orally

administered for a long period of time, a peptic ulcer is induced along with other side

effects such as anemia by hemorrhage. In order to reduce such side effects on stomach,

which is most problematic for an oral dosage form, a research into the method of

formulating the same into a transdermal administration matrix has actively been in

progress. In general, the subject matters of the research done thus far can be classified

into a topical dosage form and a patch (transdermal drug delivery system).

The prior art relating to the topical dosage form is disclosed in USP No.

4,537,776, 5,350,769, 5,422,102, and European Unexamined Patent No. 0,428,352 Al

and International Unexamined Patent No. WO 92/20377. The aforementioned prior art

relates mainly to gel, emulsion and ointment, which are directly applied onto the skin

without a backing film for sealing the active ingredients. As such, the topical dosage is

inconvenient in that the pharmaceutical composition may smear on clothe, result in

variable application dosage, emit odor and necessitate a multiple daily application.

On the other hand, a patch has a constant dosage for application without the

inconvenience of smearing on clothe or multiple applications. A patch can generally

be classified into reservoir and matrix types. As for the reservoir type, the

pharmaceutical composition of gel, emulsion or ointment can be used but cannot be

applied to joints and curved body parts. On the other hand, a matrix type is convenient

in that it can be applied to anywhere on the body depending on the properties of a

backing film and adhesive constituent. Although the matrix can be applied to the skin

for a long period of time without irritation, a difficulty arises in the system architecture

in that an absorption enhancer must be added in order to maintain a continuous _>

transdermal penetration.

With respect to the patch of a matrix type, for enhancing the transdermal

penetration, USP No. 4,738,848 used diclofenac in a free acid form converted from

sodium diclofenac salt via such organic acids as citric acid. In Korean Unexamined

Patent No. 94-23471, the transdermal penetration of the accumulated diclofenac was

increased to 180 .g/cm² • day by using a composition comprising hydroxy ethyl

pyrrolidone or hydroxy ethyl piperidine as absorption enhancer.

Further. Korean Unexamined Patent No. 93-1896 disclosed a sodium

diclofenac salt plaster comprising an absorption enhancer of menthol and propylene

glycol, and a hydrophilic substrate having a water-soluble polymer. In the

aforementioned prior art, the examples of water-soluble polymers generally used in the

plaster as substrate constituents include polyacrylic acid, sodium polyacrylate,

carboxyvinyl polymer, sodium carboxymethyl cellulose, polyvinyl pyrrolidone,

polyvinyl alcohol and gelatin. The solid part of the plaster, comprising the water-

soluble polymer as main substrate, moisturizer, humectant lysosome, inorganic filler,

viscosity controller, cross-linking agent, active ingredient, was manufactured by a

process of mixing of the combinants, stirring and then surface application. However,

if the surface application of all the pharmaceutical compositions is carried out at once

with the plaster containing volatile menthol and propylene glycol, the prolong drying

process at a low temperature range of 40 ~ 50^°C was necessary after application.

Further, in the case of such solid plaster, it was too thick to the point that adhesion

sensation was unduly excessive with poor adhesion, which in turn resulted in easy

detachment. SUMMARY OF THE INVENTION

The invention herein uses diclofenac diethylammonium salt as active

ingredient and acrylic polymer with superior solubility in organic solvents instead of a

water-soluble adhesive constituent. In order to increase absorption, the invention

includes a non-ionic surfactant and terpene at a certain mixing ratio. For increasing the

drug concentration, the invention includes a dissolution assistant in a certain amount so

that the transdermal drug delivery of the active ingredient is more than doubled as

compared to Korean Unexamined Patent No. 94-23741. Therefore, the objective of the

invention herein is to provide a transdermal drug delivery system comprising diclofenac

diethylammonium salt, wherein the transdermal drug delivery of the active ingredient is

more than far more superior than that of the prior art without undue deterioration of

adhesion to the body even for a long-term application.

Further, as for the matrix layer of the present invention, unlike other plasters of the prior art, the adhesive layer (2a') is formed by applying a non-volatile constituent

among the total pharmaceutical composition onto one side of the backing film, after

which is dried for a short period time at a high temperature. Thereafter, a volatile

absorption enhancer layer (2b) is formed by separately applying volatile constituents

comprising a dissolution assistant and a compound such as terpene for imparting cool

sensation upon initial application to the body. Another adhesive layer (2a'^") is formed

onto the release liner (3) by the aforementioned method, after which is laminated onto

the upper portion of the volatile absorption enhancer layer (2b), thereby forming the

matrix layer (2) herein. Consequently, another objective of the present invention lies

in providing a manufacturing method of a transdermal drug delivery system having

diclofenac diethylammonium salt, wherein the manufacturing time is significantly reduced.

Brief Description of the Drawing

Figure 1 is a cross-sectional view of the transdermal drug delivery system.

In Figure 1, (1) as indicated is a backing film. (2) is a matrix layer containing active

ingredients. The matrix layer includes two adhesive layers containing non-volatile

constituents, which are indicated by 2a' and 2a". Within the matrix layer, there is

another layer 2b containing volatile constituents, which is denoted as absorption

enhancer. Lastly, (3) indicates a release liner of the transdermal drug delivery system.

Figure 2 is a graph showing the accumulated amounts of the penetrated active

ingredients for examples 1 ~ 9. Figure 3 is a graph showing the accumulated amounts

of the penetrated active ingredients for examples 10 ~ 12. Figure 4 is a graph showing

the accumulated amounts of the penetrated active ingredients for examples 13 ~ 15. Figure 5 is a graph showing the accumulated amounts of the penetrated active

ingredients for examples 16 ~ 18. Figure 6 is a graph showing the accumulated

amounts of the penetrated active ingredients for examples 19 - 22. Figure 7 is a graph

showing the accumulated amounts of the penetrated active ingredients for examples 23

- 26.

Detailed Description of the Invention

A transdermal drug delivery system of the present invention comprises a

backing film (1), a matrix layer (2) having active ingredients, a release liner (3) which is

removed before application onto the skin. In particular, the matrix layer (2) comprises

l~25weight% (wt%) of diclofenac diethylammonium salt as active ingredient. 40~95wt% of acrylic polymer as adhesive constituent, 0.1~20wt% of non-ionic

surfactant, 0.1~10wt% of terpene, and 0.1~10wt% of dissolution assistant.

The invention herein is described in more detail as follows: The invention

uses an acrylic polymer having superior adhesion and durability instead of a water-

soluble polymer as adhesive constituent, which is generally used in the plaster.

Consequently, the amount of the adhesive constituent is reduced, thereby significantly

decreasing the thickness of the patch. The invention is not only applicable on the flat

areas of the body but also on the curved parts for a long period of time with relatively

comfortable feeling on application. Further, a non-ionic surfactant and terpene at a

certain mixing ratio are used as absorption enhancers. In order to increase the

concentration of the drug within the patch, a dissolution assistant is used, thereby

resulting in a synergic effect of the transdermal drug delivery of diclofenac

diethylammonium salt in addition to significantly increasing the administration dosage

of the active ingredient.

In the present invention, it is appropriate to include an active ingredient in the

amount of l~25wt% of diclofenac diethylammonium salt to the total composition

within the matrix layer. If the amount of an active ingredient is less than lwt%, the

transdermal absorption is significantly reduced due to a reduction in the drug

concentration. On the other hand, if the amount is more than 25wt%, the active

ingredient within the patch is extracted out from the matrix layer due to the insufficient

solubility thereof.

In addition, for increasing the concentration of the active ingredient within the

matrix, the invention uses an acrylic polymer as adhesive constituent, which has high

solubility in organic compounds and superior adhesion as compared to the water-soluble polymer. As such, the matrix layer is thin with high concentration of the active

ingredient within the patch. Then, the transdermal absorption is increased thereby,

which in turn results in superior adhesion, for long-term application onto the skin.

Further, due to the thin adhesive layer containing the active ingredient, the drying

process of the adhesive layer in a short period of time is achieved, which in turn has the

effect of significantly reducing the manufacturing time. As for the adhesion

constituent, acrylic polymers such as pressure sensitive adhesive is selected, which is

included in the amount of 40~95wt% to the total composition of the matrix layer. If

the amount of the adhesion constituent is less than 40wt%, the matrix layer is formed

without appropriate epidermal adhesion. If it is more than 95 wt%, the matrix cannot

support the active amounts of the active ingredient, absorption enhancer and dissolution

assistant. The acrylic polymer used as adhesion constituent may include acrylate

polymer, or a co-polymer of acrylate and vinylacetate with or without carboxyl (-

COOH) and hydroxyl (-OH) functional groups.

In addition, a non-ionic surfactant and terpene are used as absorption enhancers.

The absorption enhancer increases the absorption of the active ingredient on the skin, in

a manner directly proportional to the dosage amount, to a certain point of the

concentration. However, the absorption enhancer at or above such point of the

concentration tends to irritate the skin instead of enhancing the absorption. With this

in mind, the absorption enhancer is used within the appropriate range of concentration.

As for the non-ionic surfactant, one or more is selected from the group

consisting of glyceryl mono-oleate, glyceryl mono-laurate, sorbitan mono-oleate,

glyceryl tri-oleate, and isopropyl myristate. The non-ionic surfactant is used in the

amount of 0.1~20wt% to the total composition of the matrix layer. A terpene is selected from the group consisting of menthol, D-limonene,

geraniol and nerolidol and included in the total composition of the matrix layer at

0.1~10wt% thereof.

Further, a dissolution assistant is added herein to increase the concentration of

the active ingredient within the matrix layer. As for the dissolution assistant, one or

more is selected from the group consisting of triacetin, isopropyl alcohol, propylene

glycol, dimethylacetamide, propylene carbonate, diethylethanolamine, diethyl amine,

triethylamine, N-methyl morphorine and benzyammonium chloride, which is added in

the amount of 0.1-1 Owt% to the total composition of the matrix layer.

With respect to the combination of the non-ionic surfactant, terpene and

dissolution assistant, the following combinations show superior transdermal penetration:

glyceryl mono-oleate/ menthol/propylene glycol; glycerine mono-

laurate/menthol/propylene glycol; sorbitan mono-oleate/menthol/triacetin, isopropyl alcohol; sorbitan mono-oleate/menthol/propylene glycol; glyceryl mono-

laurate/menthol/triacetin.

Further, a gelling polymer may be added in addition to the aforementioned

constituents of the matrix layer. As for the gelling polymer, hydroxy propyl cellulose,

hydroxy methyl cellulose, carbomer and other commonly used gelling polymers may be

used herein. It is added in the amount of less than 5wt% to the composition

constituent of the matrix layer.

The composition constituent of the matrix layer of the present invention

comprises preferably l~20wt% of diclofenac dimethylammonium salt, 40-95% of acrylic polymer adhesive agent, l~15wt% of sorbitan mono-oleate, 0.1~5%wt% of

menthol, 0.1~5wt% of triacetin, isopropyl alcohol or propylene glycol as dissolution assistants and 0-1 wt% of gelling polymer. The transdermal drug delivery system as

such are shown to have superior transdermal penetration and adhesion.

Further, the conventional plaster containing a water-soluble polymer had poor

adhesion for application onto the curved body parts for a long period of time due to the

thick adhesive layer. Being water-soluble, the conventional plaster showed limitation

with respect to supporting a large amount of active ingredients due to poor solubility of

drug for water. On the other hand, the present invention uses an acrylic polymer

instead of a water-soluble polymer of the prior art for the purpose of dissolving the

active ingredients at high concentration, and consequently a relatively thin adhesive

layer of less than 300 m is incorporated into the matrix layer.

With respect to the manufacture of the transdermal drug delivery system of the

present invention, a backing film is a non-woven fabric or film comprising polymer

substrates selected from the group consisting of polyurethane, polyester, polyethylene

and rayon. As for the release liner, a disposable film impermeable to drugs which is

commonly used in the manufacture of the patch is utilized.

Figure 1 is a cross-sectional view of the transdermal drug delivery system

containing diclofenac diethylammonium salt. The transdermal drug delivery system of

the present invention comprises a backing film (1), a matrix layer containing active

ingredients, and a release liner (3) which is removed before the application onto the skin.

Onto the matrix layer (2) containing active ingredients, the adhesive layers (2a', 2a")

having diclofenac diethyammonium salt and non-volatile constituents are laminated into

two layers. Between the two adhesive layers (2a', 2a"), the absorption enhancer layer

(2b) comprising such volatile constituents as volatile absorption enhancers and

dissolution assistants are inserted therein. In the case of the adhesive layer (2a') adjacent to the backing film (1), it is possible to manufactured the same by use of an adhesive agent only.

Further, the present invention is characterized by the manufacturing method of

the transdermal drug delivery system in that the volatile and non-volatile constituents

are separately applied thereto for the formation of the matrix layer (1) instead of

simultaneous application of the pharmaceutical compositions. In other words, of all

the pharmaceutical compositions, only the non-volatile constituents are selected and

applied onto one side of the backing film (1) and the release liner (3). Thereafter, the

adhesion layers (2a', 2a") are formed by drying the same at a high temperature range of

80-120^°C for a short period of time of 1-10 minutes. Then, onto the dried adhesive

layer (2a"), a high viscosity solution containing volatile constituents is applied, which is

seeped onto the adhesive layer at a room temperature, thereby forming the volatile

absorption enhancer layer (2b). Then, onto the upper portion of the volatile absorption

enhancer layer (2b), the adhesive layer (2a") is once again laminated therein for the

purpose of manufacturing the transdermal drug delivery system. Based on the

aforementioned process, the drying time for the matrix layer (2) is significantly reduced

while suppressing the volatilizing of the volatile constituents by means of an appropriate

drying process after application. Further, the manufacturing process herein lacks

complicated manufacturing process as compared to the manufacture of a plaster and

also works to enhance the wear and adhesion of the transdermal drug delivery system

upon application onto the body.

The invention herein is explained in more detail by the following examples but

is not limited by such examples. Examples 1 ~ 26

A transdermal drug delivery system was manufactured according to the

following method, and composition of the matrix layer (2) are shown in Tables 1 - 6.

Into a 30ml sample bottle, acrylate adhesive agents (National Starch & Duro-

tak™, 87-2852. 87-2196, 87-4098) were placed. After adding diclofenac

diethylammonium salt (DDA), it was stirred at 300rpm until the pharmaceutical

compositions were completely dissolved in an adhesion solution. Then, a non-ionic

surfactant was added to the adhesion solution, and it was stirred at 300rpm for mixing of

all the constituents in the sample bottle, after which was allowed to stand for 20 minutes.

Thereafter, a lab coater and dryer (Mathis Co. of Switzerland) were used to cast the

mixture onto the release liner film (3M Scotchpak ® 1022) and dried at a high

temperature range of 80-120^°C for 10 minutes. The backing film (1) as in Figure 1

and the adhesive layer (2a') containing pharmaceutical compositions were formed by

laminating the aforementioned mixture onto a backing film (3M® non-woven

polyurethane 9905, 3M® spun-laced non-woven polyester 1538, 3M® rayon non-

woven 1533, 3M® rayon acetate).

On top of the release liner film (3M Scotchpak® 1022, 3M® paper release

liner 1361, 9743), another adhesive layer (2a") was formed by the same method as

used in the aforementioned adhesive layer (2a'). Then, an adhesion solution was

prepared by mixing the solution of terpene and dissolution assistants in addition to a

small amount of gelling polymer as deemed necessary. The volatile absorption

enhancer layer (2b) was formed by directly dispersing an appropriate amount of the

mixture or coating the same onto the dried adhesive layer (2a") via nozzle. By means

of dispersing via coating method, the impregnation of an appropriate amounts of terpene and dissolution assistant into the adhesive constituent was possible. The

impregnated amount of the mixture solution was appropriately controlled by means of

duly manipulating the dispersing time, metering pump speed, and nozzle size.

A transdermal drug delivery system was manufactured by laminating the

adhesive layer (2a") and the backing film (1), which had been prepared as composition

constituents during the formation of the aforementioned adhesive layer (2a^"), onto the

upper portion of the dried volatile absorption enhancer layer (2b).

The drug penetration tests of the respective transdermal drug delivery system

manufactured as aforementioned were carried out in a phosphate culture (0.05M, pH

7.4) with respect to the skin of the 6-week-old hairless mouse after removing

subcutaneous fat by means of the Franz cell automation extraction equipment (Hanson

Research Co. of USA). The collected samples were analyzed by 1100 HPLC

(Hewlett-Packard Co. of USA), and the results therefrom as classified into 6 separate

groups are shown herein.

A transdermal drug delivery system according to the present invention is

characterized by a transdermal penetration agents comprising terpene, surfactant and

dissolution assistant, which show enhancement effects when the aforementioned

constituents are simultaneously utilized. In order to show the amounts of the drug

penetration according to the types of the transdermal penetration agent, amounts and

composition ratios, the appropriate tests were carried out based on the compositions in

the Table 1 - 6. More specifically, the tests were carried out with respect to menthol,

propylene glycol, glycerine, isopropyl alcohol, triacetin, glyceryl mono-oleate, glyceryl

mono-lureate and sorbitan mono-oleate, which particularly showed superior

compatibility and synergistic effects when used simultaneously. The penetration amounts of the accumulated active ingredients of the respective groups are shown in

Figures 2 -7. From the Figures, it was observed that the penetration effect was

significantly enhanced based on a small change in the amount of the transdermal

penetration agent by means of a synergistic effect due to the mutual action thereof. It

was also observed that the penetration amount of the diclofenac diethylammonium salt

was enhanced in a more significant manner as compared to other conventional agents.

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

As shown above, the transdermal drug delivery system according to the present

invention was manufactured by coating the film (2b) containing volatile absorption

enhancers and dissolution assistant between the dried adhesive layers (2a', 2a")

containing diclofenac diethylammonium salt and non-volatile absorption enhancer.

Further, in order to enhance the transdermal penetration of the active ingredient, the

invention uses adhesive constituents with superior adhesion property while including

volatile and non-volatile absorption enhancers and dissolution assistant at a certain

mixing ratio by means of the aforementioned method. Therefore, the invention has the

effects of increasing the transdermal penetration of the active ingredients, enhancing the

wear and adhesion onto the curved body parts, and significantly reducing the

manufacturing time thereof.

Claims

CLAIMSWhat is claimed is:

1. A transdermal drug delivery system for anti-inflammatory analgesic agent comprising diclofenac diethylammonium salt, wherein a backing film, a matrix layer

containing active ingredients and a release liner which is removed before application

onto the skin are laminated therein, and said matrix layer comprises l~25wt% of

diclofenac diethylammonium salt as active ingredient, 40-95 wt% of acrylic polymer

as adhesive constituent, 0.1~20wt% of non-ionic surfactant as absorption enhancer,

0.1 -10wt% of terpene and 0.1-10wt% of dissolution assistant.

2. A transdermal drug delivery system for anti-inflammatory analgesic agent

comprising diclofenac diethylammonium salt according to claim 1, wherein said

acrylic polymer comprises acrylate polymer or a co-polymer of acrylate and

vinylacetate.

3. A transdermal drug delivery system for anti-inflammatory analgesic agent

comprising diclofenac diethylammonium salt according to claim 1 , wherein said non-

ionic surfactant is selected from one or more of the group consisting of glyceryl

mono-oleate, glyceryl mono-laurate, sorbitan mono-oleate, glyceryl tri-oleate, and

isopropyl myristate.

4. A transdermal drug delivery system for anti-inflammatory analgesic agent

comprising diclofenac diethylammonium salt according to claim 1 , wherein said terpene is selected from the group consisting of menthol, d-limonene, geraniol, and

nerolidol.

5. A transdermal drug delivery system for anti-inflammatory analgesic agent

comprising diclofenac diethylammonium salt according to claim 1, wherein said

dissolution assistant is selected from one or more of the group consisting of triacetin,

isopropyl alcohol, propylene glycol, dimethylacetamide, propylenecarbonate,

diethylethanol amine, diethylamine, triethylamine, N-methyl morphorine and

benzyammonium chloride.

6. A transdermal drug delivery system for anti-inflammatory analgesic agent

comprising diclofenac diethylammonium salt according to claim 1, wherein said

matrix layer additionally comprises 5wt% or less of a gelling polymer which is

selected from the group consisting of hydroxypropyl cellulose, hydroxymethyl

cellulose and carbomer.

7. A transdermal drug delivery system for anti-inflammatory analgesic agent

comprising diclofenac diethylammonium salt according to claim 1, wherein said

backing film is a non-woven fabric or film comprising polymer substrates selected

from the group consisting of polyurethane, polyester, polyethylene and rayon.

8. A manufacturing method of a transdermal drug delivery system for anti-

inflammatory analgesic agent comprising diclofenac diethylammonium, which

comprises a process of forming the adhesive layers by means of applying the adhesion solution comprising diclofenac diethylammonium salt and non-ionic

surfactant onto one side of the backing film and the release liner, respectively, after

which is dried at a temperature range of 80-120^┬░C;

a process of forming a volatile absorption enhancer layer by applying a solution

comprising terpene, dissolution assistant and gelling polymer onto one side of said

adhesive layer; and

a process of laminating another adhesive layer on the upper portion of said volatile

absorption enhancer layer.