WO1996025923A1

WO1996025923A1 - A process for the preparation of an emulsion network for a transdermal drug delivery system

Info

Publication number: WO1996025923A1
Application number: PCT/KR1996/000026
Authority: WO
Inventors: Soonhong Yuk; Sunhang Cho; Haibang Lee
Original assignee: Korea Research Institute Of Chemical Technology
Priority date: 1995-02-24
Filing date: 1996-02-22
Publication date: 1996-08-29
Also published as: KR960030931A; KR0159145B1

Abstract

A process for the preparation of an emulsion network for a transdermal drug delivery system comprising the steps of mixing a polymer (or monomer) aqueous solution with oil using a homogenizer to produce an emulsion solution, adding drugs and additives to the emulsion solution, solidifying the emulsion solution by the process of adding metal ions, cooling, irradiating ultra violet rays based on the polymer used and shaping the solidified emulsion solution applicable to the use thereof.

Description

A PROCESS FOR THE PREPARATION OF AN EMULSION NETWORK FOR A TRANSDERMAL DRUG DELIVERY SYSTEM

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a transdermal drug delivery system, more particularly to a process for the preparation of an emulsion network for a transdermal drug delivery system.

Description of the Related Art

Skin has served as an effective route of administration for drug and much interest has been focused on the development of transdermal drug delivery systems.

In the transdermal drug delivery system, a substantial obstacle is a skin itself. Most drugs can not be administrated through skin except some drugs having a high affinity to skin. For example, transdermal drugs such as nitroglycerin used for curing anginia pectoris or congestive heart failure, scopolamine for motion sickness, nicotine for superior prohibition effect, estradiol or testosterone steroids with enhancers has been proven successful for a transdermal delivery system.

These transdermal drug delivery system can be classified broadly into a membrane moderated transdermal drug delivery system (Transder Scop, Transderm Nitro and Estraderm produced by Ciba-Geigy Co.) , a microsealed transdermal drug delivery system (Nitro-Disc produced by Searle Co.) and a matrix diffusion controlled transdermal drug delivery system (Depnit TTS produced by Pharm Schwarz Co.). In our previous invention (Korean Patent Application No. 93-1880) , we already disclosed a new drug delivery system using an emulsion network. As shown in Fig. 1, the transdermal drug delivery system using an emulsion network is consisted of a flexible polyurethane pad 1, a solidified emulsion network 5 and an adhesive 3 which is also attached to the pad 1. The above transdermal drug delivery system using the emulsion network has advantages of a fixed diffusion amount of drug and a high packing ratio. However, the drug delivery system using the conventional emulsion network has a complicated preparing process and can be applicable to a limited number of drugs because of the stability of the emulsion. For example, clonidine used for hypertension, and indomethacin used for an antiphlogistic anodyne can not be used because these drugs decrease the stability of the emulsion network.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a simple process for the preparation of an emulsion network for a transdermal drug delivery system. It is a further object of the present invention to provide a transdermal drug delivery system using a matrix diffusion controlled emulsion network which has a high loading amount of drug with a constant permeation rate through skin.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and, together with the description, serve to explain the objects, advantages, and principles of the invention. In the drawings:

Fig. 1 is a schematic representation of a transdermal drug delivery system according to the present invention; and Fig. 2 is a schematic representation of an apparatus for measuring the drug release pattern from the transdermal drug delivery system according to the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

To achieve the above objects, the present invention provides a process for the preparation of an emulsion network for a transdermal drug delivery system comprising the steps of mixing an aqueous solution selected from the group consisting of a polymer, a monomer and a mixture thereof, and an oil-phase material to produce an emulsion solution, adding a drug and additives to the emulsion solution and solidifying the emulsion solution.

The present invention also provides a process for the preparation of an emulsion network for a transdermal drug delivery system including an additional step of shaping the solidified emulsion solution applicable to the use thereof.

In the present invention, it is preferable that the polymer is selected from the group consisting of sodium alginate, pectin, xanthomonas campestris and a mixture thereof or selected from the group consisting of agar, carboxymethyl cellulose, carboxymethyl cellulose phthalate and a mixture thereof. It is also preferable that the monomer is selected from the group consisting of acrylic derivatives, methacrylic derivatives and a mixture thereof. The acrylic derivative is preferably selected from the group consisting of acrylamide, isopropyl acrylamide and a mixture thereof. The methacrylic derivative is preferably selected from the group consisting of methyl methacrylate, hydroxyethyl methacrylate, methoxyethyl methacrylate, ethoxyethoxyethyl methacrylate, aminoethyl methacrylate, diethyl aminoethyl methacrylate and a mixture thereof.

In the present invention the process of solidifying the emulsion solution can be performed by a mixed process of adding metal ions, cooling and irradiating ultra violet rays. If the polymer is sodium alginate, pectin and xanthomonas campestris, the process of solidifying the emulsion solution can be performed by adding metal ions such as calcium, magnesium and aluminium to produce a crosslinked gel network. If the polymer is agar and the derivatives thereof, the process of solidifying the emulsion solution can be performed by cooling. If the emulsion solution contains monomer, the process of solidifying the emulsion solution can be performed by irradiation of ultra violet rays. In the present invention, the additives are preferably selected from the group consisting of an ionic polymer, an aqueous polymer and a mixture thereof. It is also preferable that the ionic polymer is selected from the group consisting of polyacrylic acid, polyamino acid, polysulfonic acid, polyethylene i ine and a mixture thereof. And the aqueous polymer is preferably selected from the group consisting of hydroxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, glycerine and a mixture thereof. In the present invention, it is preferable that a mixing ratio of the polymer to said additives are 100 : 0 to 20 : 80. The oil-phase material is preferably selected from the group consisting of a corn oil, a peanut oil, a coconut palm oil, a castor oil, a sesame oil, a soybean oil, a perilla oil, a sunflower oil, a walnut oil and a mixture thereof. The present invention also provides a transdermal drug delivery system using an emulsion network comprising a substrate, an emulsion network and an adhesive layer for attachment of the substrate to skin. The process for preparing the transdermal drug delivery system of the present invention is easily performed because the drug is in the polymer network but not in the oil-phase. Therefore, the procedure of mixing the oil and drug is omitted and loading of the drug is performed before the solidification of the emulsion network. The variety of the polymer used in the present invention are not limited at only polysaccharides having metal chelating capability. Agar, an acrylic polymer, a methacrylic polymer and most of aqueous polymer can be applicable in this invention. The present invention has little effect according to a property of a drug used because the emulsion network has an advantage of coexistence of hydrophillic and lipophilic property. The drugs which decrease the stability of the emulsion can be used in the present invention because the drugs do not exist on an oil- phase.

A representative example, preferable working examples and reference example are described below. These examples are exemplary only, and the present invention is not restricted to the scope of the example.

Representative Example

A process for the preparation of an emulsion network for a transdermal drug delivery system of the present invention has the steps of mixing a polymer (or a monomer) aqueous solution with oil using a homogenizer to produce an emulsion solution and adding drugs and additives to the emulsion solution. The emulsion network of the present invention is manufactured by solidifying the emulsion solution by the process of adding metal ions, cooling, or irradiating ultra violet rays based on the polymer used.

Representative Example bv using metal ions

An emulsion solution is prepared by mixing the aqueous solution of sodium alginate and coconut oil as a representative oil using a homogenizer. Drugs and additives in a certain ratio are mixed in the obtained emulsion solution. Subsequently, the solution is cast on a glass panel, dried for a period of time, treated with CaCl₂ and then solidified.

Representative Example bv cooling

An emulsion solution is prepared by mixing agar substituted for sodium alginate to produce a polymer aqueous solution by heating in water at 80 *C and coconut oil as a representative oil using a homogenizer. Drugs and additives in a certain ratio are mixed in the obtained emulsion solution. Subsequently, the solution is coated on a glass panel, cooled for a period of time in the room temperature and then solidified.

Representative Example bv using

An emulsion solution is prepared by mixing acrylamide as a monomer substituted for sodium alginate to produce a monomer aqueous solution and coconut oil as a representative oil using a homogenizer. Drugs and additives in a certain ratio are mixed in the obtained emulsion solution. Subsequently, the solution is cast on a glass panel, irradiated by ultra violet rays for a period of time and then solidified. Working Example 1

An emulsion solution was prepared by mixing 30 wt part of polymer aqueous solution consisted of sodium alginate (4 wt%) and 20 wt part of coconut oil using a homogenizer. 10 wt part of nicotine was mixed in the obtained emulsion solution. Subsequently, the solution was cast on a glass panel, dried for one day at 39 *C, treated with CaCl₂ and then solidified. The emulsion network was shaped to a disk-like form by a punch having 1 cm of radius. A transdermal drug delivery system shown in Fig. 1 was produced by using the shaped emulsion network. A nicotine release experiment was performed using the diffusion apparatus shown in Fig. 2. The results of the experiment is shown in Table 1. To observe the release pattern of nicotine from the transdermal drug delivery system, the apparatus shown in Fig. 2 was prepared. In the diffusion cells 7, a phosphate buffer solution (sodium phosphate monobasic 4.524 g, sodium phosphate dibasic 3.301 g, water 100 g) existed as a receiving media and nicotine diffused into the phosphate buffer solution.

Working Example 2

An emulsion solution was prepared by mixing 30 wt part of monomer aqueous solution consisted of acrylamide (4 wt%) and 20 wt part of coconut oil using a homogenizer. 10 wt part of nicotine, 0.1 wt part of N,N^,-methylenebisacrylic amide as a cross-linker and 0.2 wt part of ammonium persulfate were added in the obtained emulsion solution and the solution was irradiated by ultra violet rays for 15 minutes to produce an emulsion network by polymerization. The emulsion network solidified to a certain thickness was shaped to a disk-like form by a punch having 1 cm of radius. A transdermal drug delivery system shown in Fig. 1 was produced by using the shaped emulsion network. A nicotine release experiment was performed by using the diffusion apparatus shown in Fig. 2 and the results of the experiment is shown in Table l.

Working Example 3

4 g of agar added to 100 g of water was heated to produce 30 wt part of polymer aqueous solution. An emulsion solution was prepared by mixing the polymer aqueous solution and 20 wt part of coconut oil as a representative oil using a homogenizer. 10 wt part of nicotine, were added to the obtained emulsion solution. Subsequently, the solution was cast on a glass panel, cooled at room temperature and then solidified. The emulsion network solidified to a certain thickness was shaped to a disk-like form by a punch having 1 cm of radius. A transdermal drug delivery system shown in Fig. 1 was produced by using the shaped emulsion network. A nicotine release experiment was performed by using the diffusion apparatus shown in Fig. 2 and the results of the experiment is shown in Table 1.

Reference Example

Nicotinell-TTS, which is on the market, produced by Ciba Geigy Co. for smoking cessation was selected for a transdermal drug delivery system. A nicotine release experiment was performed by using the diffusion apparatus shown in Fig. 2. The results of the experiment is shown in Table 1.

Table 1. Diffusion Form of Nicotine in pH 6.8 of a Phosphate Buffer Solution Release Rate

Time

W. Exam. . 1 w . Exam. 2 W. Exam. : 3 Ref Exam.

1 0.47 0.48 0.42 0.30

2 0.89 0.85 0.79 0.65

3 1.25 1.19 1.21 0.85

4 1.55 1.53 1.49 1.12

5 2.01 1.95 1.98 1.25

6 2.54 2.49 2.45 1.42

7 2.92 2.84 2.79 1.56

8 3.44 3.39 3.42 1.63

9, 3.89 3.79 3.75 1.74

10 4.35 4.29 4.31 1.83

11 4.75 4.75 4.69 1.92

12 5.12 5.05 4.98 2.01

24 8.12 8.01 7.99 4.11

As shown in Table 1, the transdermal drug delivery system using the emulsion network obtained by the present invention shows a constant drug release pattern over 12 hours. However, the drug release of Nicotinell- TTS decreases after 3 or 4 hours. According to the results, it is apparent that the transdermal drug delivery system of the present invention has a more constant drug release rate than that of Nicotinell-TTS.

The process for preparing the transdermal drug delivery system of the present invention is easily performed because the drug is in the polymer network but not in the oil-phase like the transdermal drug delivery system using the conventional emulsion network. Therefore, the procedure of mixing the oil and drug can be omitted.

The variety of polymers used in the present invention are not limited to only polysaccharides having metal chelating capability. Agar, an acrylic polymer, a methacrylic polymer and most of aqueous polymer can be utilized in this invention. The transdermal drug delivery system of the present invention can be applicable to the drugs, which are not applicable to the conventional arts, such as clonidine used for hypertension and indomethacin used for an antiphlogistic anodyne agent because of the excellent stability of the emulsion network. The transdermal drug delivery system using the emulsion network of the present invention maintains the advantage of the conventional emulsion network because the hydrophillic and lipophilic property coexist. Irrespective of hydrophillic or lipophilic property of the drugs, the wide range of drugs can be used. The transdermal drug delivery system using the emulsion network of the present invention has a high loading amount because the loading of drugs is performed before the network is solidified.

Claims

WHAT IS CLAIMED IS;

1. A process for preparing an emulsion network for a transdermal drug delivery system comprising the steps of:

(a) mixing an aqueous solution selected from the group consisting of a polymer, a monomer and a mixture thereof, and an oil-phase material to produce an emulsion solution; (b) adding a drug and additives to said emulsion solution; and

(c) solidifying said emulsion solution.

2. The process for preparing the emulsion network for the transdermal drug delivery system according to claim 1, further comprising the step of shaping the solidified emulsion solution, which is solidified in the step (c) , applicable to the use thereof.

3. The process for preparing the emulsion network for the transdermal drug delivery system according to claim 1, wherein said polymer is selected from the group consisting of sodium alginate, pectin, xanthomonas campestris and a mixture thereof.

4. The process for preparing the emulsion network for the transdermal drug delivery system according to claim 1, wherein said polymer is selected from the group consisting of agar, carboxymethyl cellulose, carboxymethyl cellulose phthalate and a mixture thereof.

5. The process for preparing the emulsion network for the transdermal drug delivery system according to claim 1, wherein said monomer is selected from the group consisting of acrylic derivatives, methacrylic derivatives and a mixture thereof.

6. The process for preparing the emulsion network for the transdermal drug delivery system according to claim 5, wherein said acrylic derivative is selected from the group consisting of acrylamide, isopropyl acrylic amide and a mixture thereof.

7. The process for preparing the emulsion network for the transdermal drug delivery system according to claim 5, wherein said methacrylic derivative is selected from the group consisting of methyl methacrylate, hydroxyethyl methacrylate, methoxyethyl methacrylate, methoxyethoxyethyl methacrylate, aminoethyl methacrylate, diethyl aminoethyl methacrylate and a mixture thereof.

8. The process for preparing the emulsion network for the transdermal drug delivery system according to claim

3, wherein said solidifying step is performed by adding metal ions to produce a crosslinked gel network.

9. The process for preparing the emulsion network for the transdermal drug delivery system according to claim 4, wherein said solidifying is performed by cooling.

10. The process for preparing the emulsion network for the transdermal drug delivery system according to claim 5, wherein said solidifying step is performed by irradiation of ultra violet rays.

11. The process for preparing the emulsion network for the transdermal drug delivery system according to claim 1, wherein said additives is selected from the group consisting of an ionic polymer, an aqueous polymer and a mixture thereof.

12. The process for preparing the emulsion network for the transdermal drug delivery system according to claim 12, wherein said ionic polymer is selected from the group consisting of polyacrylic acid, polyamino acid, polysulfonic acid, polyethylene imine and a mixture thereof.

13. The process for preparing the emulsion network for the transdermal drug delivery system according to claim

12, wherein said aqueous polymer is selected from the group consisting of hydroxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, glycerine and a mixture thereof.

14. The process for preparing the emulsion network for the transdermal drug delivery system according to claim 12, wherein a mixing ratio of said polymer to said additives is 100 : 0 to 20 : 80.

15. The process for preparing the emulsion network for the transdermal drug delivery system according to claim 1, wherein said oil-phase material is selected from the group consisting of a corn oil, a peanut oil, a coconut palm oil, a castor oil, a sesame oil, a soybean oil, a perilla oil, a sunflower oil, a walnut oil and a mixture thereof.

16. A transdermal drug delivery system using an emulsion network comprising: a substrate; an emulsion network of claim 1; and an adhesive layer for the attachment of said substrate to skin.