WO1993019708A1

WO1993019708A1 - Transdermal albuterol absorption dosage unit and process

Info

Publication number: WO1993019708A1
Application number: PCT/US1993/003013
Authority: WO
Inventors: Chia-Shun Lee; Jhili Wu; Chin-Chi Chiang
Original assignee: Tbs Laboratories, Inc.
Priority date: 1992-03-31
Filing date: 1993-03-31
Publication date: 1993-10-14
Also published as: AU3942193A

Abstract

Provided are transdermal albuterol dosage units and methods of administering albuterol transdermally wherein the dosage units provide improved transdermal absorption of albuterol. The dosage untis comprise a backing layer and an adhesive layer in which the albuterol is dispersed along with an enhancing composition comprising one or more carboxylic acids having 6 to 18 carbon atoms and an effective amount of a biocompatible non-ionic surfactant.

Description

TRANSDERMAL ALBUTEROL ABSORPTION DOSAGE UNIT

AND PROCESS

TECHNICAL FIELD

This invention relates to a novel transdermal absorp¬ tion dosage unit adapted for administration of albuterol wherein more efficient and effective administration of albu¬ terol can be obtained. Also provided by this invention is a method of administering albuterol by transdermal absorption using the novel transdermal absorption dosage units provided hereby.

BACKGROUND ART Albuterol is a pharmaceutical that is useful as a bron- chodilator agent and for the relief of bronchospasm in asthma, chronic bronchitis and pulmonary emphysema and for the prevention of bronchial asthma. It has been found desired to have improved and adequate transdermal absorption of albuterol. It would be highly desirable to administer albuterol in an effective and convenient manner as exempli¬ fied by a transdermal route. This way it would be possible to take advantage of the improved results realized by effec¬ tive transdermal absorption of a pharmaceutical compared to its administration by oral means or the like. The transder¬ mal administration of a pharmaceutical provides a long-act¬ ing effect and a relatively constant level of the pharmaceu¬ tical in the system of the subject to which the pharmaceuti¬ cal is administered, thereby preventing unwanted excessively high levels and very low levels. The transdermal adminis¬ tration of a pharmaceutical provides much of the benefits of intravenous administration without the discomforts and the inconveniences of intravenous administration. Transdermal systems are convenient to use and can be withdrawn when desired. They also need to be used less frequently and thus provide increased patient compliance.

It would be highly advantageous to provide an improved transdermal dosage unit for administration of albuterol which would provide effective administration of albuterol by transdermal means. It could be accordingly useful also to have a novel method of administering albuterol by use of such dosage units.

SUMMARY OF INVENTION

Provided by this invention is a transdermal albuterol absorption unit which provides effective administration of albuterol by transdermal absorption. The albuterol trans¬ dermal dosage units of this invention comprise the following elements:

1) a backing layer substantially impervious to the ingre¬ dients of the dosage unit;

2) a biocompatible adhesive layer adhered to said backing layer; 3) an effective amount of albuterol dispersed in said adhesive layer to provide a daily dose of albuterol to .obtain the desired pharmacological effect;

4) an enhancing composition dispersed in said adhesive layer comprising: a) a biocompatible and effective carboxylic acid selected from carboxylic acids having 6 to 18 carbon atoms; and

^• b) an effective and biocompatible non-ionic surfac-

The amount of albuterol to be administered to the human subject can vary, but ordinarily the amount of albuterol found to be effective has been found to be in the range of about 0.5 mg to about 2.0 mg,. ordinarily about 1 to about

1.5 being adequate and satisfactory, and about 1.25 mg being desirable. It is preferable that the albuterol be released from the dosage unit and transdermaily absorbed on a con¬ tinuous basis throughout a 24-hour period in order to pro- vide consistent and effective systemic levels of albuterol.

The amount of carboxylic acid can vary, depending upon the amount of albuterol desired to be administered, the nature of the polymeric adhesive material employed, and the amount and nature of the non-ionic surfactant employed.

Ordinarily, an amount of carboxylic acid employed based on the use of capric acid in the range of about 3 mg to about 15 mg based on a 5 cm² patch is adequate. The amount of a carboxylic acid will vary depending upon the specific car¬ boxylic acid used and other factors. .The amount of non-ionic surfactant used will vary, depending upon the specific non-ionic surfactant employed, the amount of albuterol desired to be administered, and the quantity and the nature of the carboxylic acid employed.

However, assuming that the non-ionic surfactant is Brij 30, it has been found that an effective amount in the range of about 5 mg to about 20 mg will provide the desired result.

Additionally provided by this invention is a method to administer an effective amount of albuterol to a human in need of albuterol treatment by employing the above described and defined transdermal albuterol .transdermal absorption units.

DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

The backing layer can be made of any suitable material which is impermeable to the albuterol and other components dispersed within the adherent adhesive layer. The backing layer serves as a protective cover for the dosage unit and provides also a support function. The backing layer can be formed so that it is essentially the same size layer as the albuterol-containing adhesive layer or it can be of larger dimension so that it can extend beyond the side of the albu- terol-containing layer or overlay the side or sides of the albuterol-containing layer and then can extend outwardly in a manner that the surface of the extended backing layer can be a base for an adhesive for holding the dosage unit in intimate contact with the subjects being treated.

In making the dosage units which provide the desired albuterol absorption, the composition containing the albu- terol can be readily coated onto an albuterol impermeable backing layer, such as a composite sold under the designa- tion Scotch Pak 1109 by 3M Company. Coating equipment can be used to coat the backing layer to a desired thickness. A coater which can be used is a Warner-Mathis laboratory coater, type LTSD with built-in laboratory dryer LDF.

Thickness of the albuterol-adhesive layer can be accurately controlled to desired thickness, such as to 400 microns, using such a designed coater-dryer.

The amount of albuterol added to the adhesive solution used for coating can vary so long as there is provided an effective amount of albuterol for transdermal absorption. Ordinarily, it has beer, found that about an 8 percent amount of albuterol based upon the total weight of the coating mixture of adhesive, albuterol, carboxylic acid, and biocom- patible non-ionic surfactant, provides an effective amount of transdermal absorption of albuterol. The amount of albu- terol can be varied depending upon the rate of absorption desired and the particular adhesive or polymer used in making the dosage unit. The effective amount can be selected from a range of from about 5 to about 15 percent based upon the weight of the coating mixture used to make the dosage unit, a more preferable range being from about 6 to about 12 percent, based on said weight. The amount of the carboxylic acid can also be varied so long as an effec¬ tive amount is utilized to provide, in cooperation with the non-ionic surfactant used, an effective amount of albuterol transdermal absorption.

It has been found that an effective amount of the car- boxylic acid can be incorporated into the adhesive layer.

Capric acid is a presently preferred carboxylic acid, how- ever, other effective and biocompatible carboxylic acids can be selected from those having 6 to 18 carbon atoms, suitably having 8 to 12 carbon atoms.

It has also been found desirable to use in cooperation with the carboxylic acid an effective amount of a biocom- patible non-ionic surfactant. The amount is selected that effectively cooperates with the amount of carboxylic acid present in order to provide an effective transdermal absorp- tion of albuterol. It has been found that surfactants of a non-ionic character which are commercially available can be selected which are effective and which are sold, for example, under the designations Span, Tween and Brij . Suit¬ able non-ionic surfactants are Brij-30 and Span-20. A nu - ber of non-ionic polyoxyethylene non-ionic surfactants can be used. Various other non-ionic surfactants can be used. It has been found, for example, that Span-30 and Span-40 can be used. However, it has been presently found that Span-20 is a preferred non-ionic surfactant. Other surfactants can be used which have the designations and the HLB (hydro- philic/lipophilic balance) as shown as follows:

Generic or Chemical Name Trademark HLB

Polyoxyethylene sorbitan onolaurate Tween 21 13.3

Polyoxyethylene castor oil Atlas G-1794 13.3

Polyoxyethylene sorbitan monooleate

Polyoxyethylene sorbitan monopalmitate

Polyoxyethylene sorbitan monolaurate

Polyoxyethylene lauryl ether

Polyoxyethylene monostearate

It is desirable that the non-ionic surfactant has a HLB value in the range of about 5 to about 30, desirably about 8 to about 20.

Other components can be added as desired, for example, stabilizers, anti-oxidants and other agents which will be suggested to those skilled in the art. For example, a suit¬ able amount of biocompatible anti-oxidant can be incor¬ porated into the adhesive polymer solution containing albu¬ terol, which is used to make the albuterol-containing adhe¬ sive polymer layer.

Examples of materials suitable for making the backing layer are films of high and low density polyethylene, poly¬ propylene, polyurethane, polyvinylchloride, polyesters such as poly(ethylene phthalate) , metal foils, metal foil lami¬ nates of such suitable polymer films, and the like. Prefer¬ ably/ the materials used for the backing layer are laminates of such polymer films with a metal foil such as aluminum foil. In such laminates, a polymer film of the laminate will usually be in cofϊtact with the adhesive layer. The backing layer can be any appropriate thickness which will provide the desired protective and support functions. A suitable thickness will be from about 10 to about 200 microns. Desirably, the thickness will be from about 20 to about 150 microns, and preferably be from about 30 to about 100 microns.

In making the adhesive layer, the adhesive polymer used must be biologically acceptable and compatible with albu¬ terol and other ingredients used. Certain polyacrylic adhe¬ sive polymers (in the form of an alkyl ester, amide, free acid, fatty acid polyaminoacrylate or the like) are suitable and are presently preferred. Illustrative of suitable poly¬ acrylic adhesives for use in making the adhesive layer^" are represented by the following formula:

wherein x represents the number of repeating units suffi¬ cient to provide the desired properties in the adhesive polymer and R is H or lower alkyl including ethyl, butyl and 2-ethylhexyl or fatty acid polyamino group. It is presently preferred to use a polyacrylic adhesive in making the adhe¬ sive layer.

Other suitable hypoallergenic pressure-sensitive con- tact adhesive compositions can also be used. A preferred adhesive layer is pressure-sensitive. However, depending upon pharmaceutical compatibility and other factors, if desired, the adhesive means can extend in the form of a ring attached, for example, to an extended portion of the backing layer so that the adhesive layer is adjacent to the sidewall of the albuterol-containing disc layer. The width of such adjacent adhesive ring must be adequate to hold the dosage unit securely to the subject being treated. Ordinarily, a suitable width of such adhe- sive ring can be about 0.1 to about 1.0 cm, preferably about

0.2 to about 0.8 cm. The adhesive layer then is finally covered with a releasable protective film layer which is made from mate¬ rials which are substantially impermeable to albuterol and other ingredients of the dosage unit. The polymer materials and metal foil laminates used for the backing layer may also be used to make the protective layer, provided the layer is made strippable or releasable such as by applying conven- tional siliconizing or Teflon coating. A suitable releasable material for use with silicone polymer adhesive DC-355 and X7-2970 is Scotch-Pak 1022 material sold by the

3M Company or Bio-Release Material by Dow Corning.

The amount of the components used depends upon the dosage rate desired of albuterol and any other components, and the duration of treatment desired from the applied dosage unit and the amount which can be incorporated into the adhesive layer to retain suitable structural, diffusion and other properties in the final adhesive layer. It has been found, for example, that albuterol can be satisfac¬ torily added to parts of the polymer used in making the polymer layer, such as polyacrylic adhesive polymer. It has been found to be preferable to add and disperse the albu¬ terol, carboxylic acid and non-ionic surfactant used in an amount of a selected adhesive polymer solution. The mixture of the polymer and components is then thoroughly mixed to form a homogeneous solution or microdispersion of the albu¬ terol in the polymer. After the mixing step, it is desirable to remove entrapped air, for example, by per- mitting the composition to stand for a few hours.

The mixture is then applied as by solvent casting tech- nique, to a suitable substrate, such as a backing laminate or release liner or other suitable substrate as described above with regard to making the adhesive layer. The wet coating polymer formulation desirably is coated to about 100 to 600 microns, preferably about 150 to about 450 microns, in thickness. The resulting adhesive layer is removed from the casting machine and another layer of medicated polymer can be further coated on the first medicated adhesive layer formed by direct casting or lamination. The dosage units are then covered with a transparent low-adhesion release liner (e.g., Scotch-Pak 1022/3M) . The completed dosage layers are then cut into dosage units having various shapes and sizes by using a specially- designed device cutter, such as a 5 cm , 10 cm or 20 cmr sizes in various shapes.

The transdermal absorption of the albuterol from the dosage units of this invention is evaluated by using a skin specimen from human cadaver by following the procedure described by Y.W. Chien, K. Valia and U.B. Doshi in Drug Develop. & Ind. Pharm.. 11(7) 1195-1212 (1985) .

The following examples are in illustration of the invention and are not intended to be limiting.

Example 1

A composition for use in making dosage units of this invention is made by following the procedure described. An amount of 87.72 grams of material Duro-Tak polyacrylic adhe¬ sive solution (Duro-Tak 80-1054) is added to a 6 oz. Quorpak bottle. To that solution there is also added 3.51 grams of albuterol, 6.58 grams of capric acid, 2.19 grams of non- ionic surfactant (Brij 30) . The mixture is mixed for ten hours to obtain a homogeneous formulation.

The formulation is then coated on a backing layer,

Scotch Pak 1109 sold by 3M Corporation. Following are the coating procedures. The oven temperature of a coating machine is set at

60°C and the timer is set at 10 minutes. A coating frame is installed onto the machine. The Scotch Pak 1109 backing material is mounted on the coating frame and the position of the doctor knife is adjusted to provide a thickness of 400 microns onto the backing layer. About 20 grams of the homo¬ geneous formulation is poured onto the backing layer and the doctor knife is pulled toward the operator to coat a thin film of formulation upon the Scotch Pak backing layer. The doctor knife is removed and the control button is activated to advance the coating frame into the drying chamber of the coating machine. The frame holding the backing layer bear- ing the coating is automatically released from the drying chamber and the coated film is removed from the coating frame.

After the coating frame with dried formulation film is removed from the oven, the release liner, said Scotch Pak

1109, is laminated onto the dried formulation film which adheres to the backing layer. This dried adhesive layer provides 8 percent albuterol, 15 percent capric acid and 5 percent non-ionic surfactant, based on the total weight of the adhesive composition. The final laminated layer then also has on the opposite side from the backing layer a release layer adhered to the adhesive albuterol containing layer.

The laminated sheet containing a backing layer, the albuterol adhesive layer and the release layer are formed into 5 cm² or 10 cm transdermal dosage units by using a cutting press.

Example 2

An in-vitro skin permeation procedure described in

Chien et al. referred to herein above is used to evaluate the permeability of albuterol across human cadaver skin. Skin permeation flux measurements are made at 37°C. The albuterol concentration in the receptor medium (5% aqueous- polyethylene glycol-400 solution) is measured at various time intervals. The skin flux or transmission of the albu¬ terol through the cadaver skin is determined and calculated for various time intervals.

The skin permeation rate of albuterol is relatively high, for example, about 10 mcg/cm²/hr from a polyacrylate adhesive layer with 8% albuterol in the formulation.

The following experiments show variation of the albu¬ terol concentration from 6 to 12 percent. Also, they show that the amount and nature of the carboxylic acid and non- ionic surfactant employed can vary and the ratio thereof can be varied. The data are shown in the following Tables I, II, III and IV.

TABLE I Effect of Carboxylic Acid on Skin Permeation of Albuterol

*Capric Acid **Caprylic Acid ***Myristic Acid TABLE II Effect of Surfactants on Skin Permeation of Albuterol

*Brij-30 (HLB=9.7) **Tween-20 (HLB=16.7) ***Span-20 (HLB=8.6)

HLB: Hydrophilic-Lipophilic Balance Value

TABLE III

Effect of Formulation Ingredients on Skin Permeation of Albuterol

♦Polyacrylate **Bio-PSA Adhesive ***PSA-355 Adhesive TABLE IV Skin Permeation of the Analogs of Albuterol

*Albuterol **Isoproterenol ***Epinephrine

Example 3

The above dosage units are repeated using other car¬ boxylic acid agents and other non-ionic surfactants, as defined. The ratios can be varied depending upon the various factors, including the concentration of albuterol, the amount of albuterol desired to be absorbed, the poly¬ meric adhesive agent employed, the carboxylic acid used, and the non-ionic surfactant used and the various ratios there- of. Other non-ionic surfactants for use in making the dosage units of this invention can be selected from non- ionic surfactants of the following classes: mono and digly- cerides, for example, Atmer 184 (HLB 5.0); sorbitan fatty acid esters, for example, Span 40 (or Arlacel 40) (HLB 6.7) ; polyoxyethylene sorbitan fatty acid esters, for example, Tween 61 (HLB 9.6), Tween 65 (HLB 10.5), Tween 85 (HLB 11.0); polyoxyethylene sorbital esters, for example, Altox

849 (HLB 9.0), Altox 848 (HLB 10.0), G-1086 (HLB 10.2), G-

1096 (HLB 11.4) ; polyoxyethylene sorbital esters, for example, Myrj 45 (HLB 11.1), Renex 20 (HLB 13.8), Myrj 52 (HLB 16.9), Myrj 53 (HLB 17.9); polyoxyethylene alcohols, for example, Brij 52 (HLB 5.3), Brij 76 (HLB 12.4), Brij 78

(HLB 15.3) . Biocompatible derivatives of albuterol can be used which are transdermaily absorbed and which are effec¬ tive in making the dosage units described in the above example. Also, other effective and biocompatible agents indicated to those skilled in the art can be employed, such as bioacceptible antioxidants or other components, so long as the resulting dosage units are effective and have the desired properties.

Claims

What is Claimed is:

1. A transdermal albuterol dosage unit comprising:

_.1) a backing layer substantially impervious to the ingredients of said dosage unit;

2) a biocompatible adhesive layer adhered to said backing layer;

3) an effective amount of albuterol dispersed in said adhesive layer;

4) an enhancing composition dispersed in said adhe¬ sive layer comprising: a) a biocompatible and effective carboxylic acid selected from carboxylic acids having 6 to 18 carbon atoms; and b) an effective and biocompatible non-ionic surfactant selected from non-ionic surfac¬ tants having HLB values ranging from 5-30.

2. A transdermal albuterol dosage unit of Claim 1 wherein the carboxylic acid has 8 to 12 carbon atoms.

3. A transdermal albuterol dosage unit of Claim 2 wherein the carboxylic acid is capric or caprylic acid.

4. A transdermal albuterol dosage unit of Claim 1 wherein the non-ionic surfactant is a sorbitan fatty acid ester surfactant.

5. A transdermal albuterol dosage unit of Claim 1 wherein the non-ionic surfactant is a polyoxyethylene surfac¬ tant.

6. A transdermal albuterol dosage unit of Claim 1 wherein the non-ionic surfactant is a polyoxyethylene ester.

7. A transdermal albuterol dosage unit of Claim 1 wherein the non-ionic surfactant is a polyoxyethylene alcohol.

8. A transdermal albuterol dosage unit of Claim 1 wherein the adhesive layer is made using a polyacrylic adhe¬ sive.

9. A transdermal albuterol dosage unit of Claim 8 wherein the carboxylic acid used has 8 to 12 carbon atoms.

10. A transdermal albuterol dosage unit of Claim 9 wherein the non-ionic surfactant used has an HLB value of about 8 to about 20.

11. A transdermal albuterol dosage unit of Claim 10 wherein the non-ionic surfactant is selected from the group consisting of Span 20, Brij 30, and non-ionic surfac¬ tants having substantially the activity in said dosage unit as Span 20 or Brij 30.

12. A method of administering an effective amount of albuterol to a human in need of albuterol treatment by .employing a dosage unit as described in Claim 1 , 2 , 3 ,

4, 5, 6, 7, 8, 9, 10 or 11.