WO1990008553A1

WO1990008553A1 - Transdermal drug delivery composition

Info

Publication number: WO1990008553A1
Application number: PCT/US1990/000530
Authority: WO
Inventors: Fu Lu Mou-Ying; Hui Ho-Wah
Original assignee: Abbott Laboratories
Priority date: 1989-01-24
Filing date: 1990-01-13
Publication date: 1990-08-09
Also published as: IE900245L; IL93143A0; GR900100044A; KR910700066A; AU5041190A

Abstract

Pharmaceutical compositions having enhanced membrane permeability that comprise a therapeutically active ingredient, a penetration enhancer, a solubilizing agent and a solvent vehicle. These compositions are useful in oral and transdermal applications.

Description

TRANSDERMAL DRUG DELIVERY COMPOSITION

Technical Field

The present invention relates to pharmaceutical compositions having enhanced permeability through biological membranes.

Background of the Invention

Drugs have been administered by nonspecific, periodic applications as for example by the ingestion of oral dosage forms or injection. The drugs than circulate throughout the body and the concentration of the drug initially may rise to high levels. This initial level may be toxic and cause side effects. As time passes, the concentration diminishes and subsequent doses must be administered to maintain therapeutically effective levels of the drug. In addition, injection of drugs may be painful and inconvenient and may result in poor patient compliance.

Transdermal drug delivery systems have been developed to overcome the disadvantages of oral and injectable routes of administration. Transdermal drug delivery systems provide a number of advantages including the elimination of first-pass effect metabolism, a reduction of side effects, a more predictable and extended duration of activity, enhanced therapeutic efficacy, reduced frequency of dosage and greater patient compliance.

A critical factor in determining whether a drug can be effectively delivered transdermally is the ability of the drug to permeate through the skin which functions as a physical and chemical barrier to most drugs. The diffusive passage across the compact outer layer of the skin, the stratum corneum, is a critical parameter in determining whether a drug can be incorporated in a transdermal drug delivery system.

Similarly, drugs which are administered orally also must be adequately absorbed across transepithelial membranes to achieve effective blood levels.

Summary of the Invention

This invention relates to pharmaceutical compositions having enhanced permeability through biological membranes.

More particularly, this invention relates to pharmaceutical compositions comprising a solvent vehicle, a penetration enhancer, and a therapeutically active ingredient wherein the composition has enhanced permeability through biological membranes.

Another aspect of the invention relates to pharmaceutical compositions as stated above which additionally comprise one or more solubilizing agents,

The compositions of the present invention may be used to enhance the delivery of drugs by oral and transdermal means. Description of the Figures

FIGURE 1 is a graph which plots the permeability of leuprolide acetate formulations versus time;

FIGURE 2 is a graph which plots the permeability of other leuprolide acetate formulations versus time;

FIGURE 3 is a graph which plots the permeability of renin inhibiting formulations versus time;

FIGURE 4 is a graph which plots the permeability of several leuprolide formulations versus time; and

FIGURE 5 is a graph which plots the permeability of insulin formulations versus time.

Detailed Description of the Invention

This invention relates to pharmaceutical compositions having enhanced membrane permeability and comprising a solvent vehicle, a penetration enhancer, a solubilizing agent and a therapeutically active ingredient.

The compositions of this invention may be administered by oral or transdermal means to deliver an effective amount of the therapeutically active ingredient to a host in need of such treatment.

As used herein the term "penetration enhancer" is intended to mean volatile or essential oils or components thereof such as aliphatic esters, aliphatic ketones, aliphatic aldehydes or alicyclic alcohols. Examples of aliphatic esters include geranyl acetate, (-)-carvyl propionate, (-)-carvyl acetate, dl-menthyl acetate and geraniol formate. Acceptable aliphatic ketones include menthone and camphor, while aliphatic aldehydes include trans-cinnamaldehyde and p-anisaldehyde. Alicyclic alcohols such as geraniol, menthol, peppermint oil, cinnamon, pepper or cinnamyl alcohol may also be employed. Geraniol, 3,7-dimethyl-2,6-octadien-l-ol, is an olefinic terpene alcohol found in essential oils such as citronella, lemongrass or rose oil. Menthol, 5-methyl-2-(l-methylethyl) cyclohexanol, is found in peppermint oil or other mint oils.

As used herein the term "solubilizing agent" is intended to mean a material which increases the concentration, prevents recrystallization and maintains the solubility of a therapeutically active ingredient. Solubilizing agents also increase the irascibility of the components of the composition. These materials are generally bioadhesive, hydrophilic or hydrophobic (i.e., water-insoluble) polymers. Examples of bioadhesive polymers include cellulose methyl ether, cellulose 2-hydroxypropyl ether, carbopol (carboxyvinyl polymer), karaya gum, and polymers of acrylic acid crosslinked with divinyl glycol or 2,5-dimethyl-l,5-hexadiene. Hydrophylic polymers suitable for use in the present invention include cellulose derivatives, as for example, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose and hydroxypropyl ethyl- cellulose, as well as polyacrylates, alginates, polysaccharides and polyvinyl pyrolidone. Examples of hydrophobic polymers are crosslinked ethylcellulose and crosslinked polyvinyl pyrollidone.

The solubilizing agents of the present invention can also be surfactants. These surfactants are generally sulfate esters of fatty alcohols, such as sodium lauryl sulfate; sorbitan ethers or esters, such as polysorbate 80, Tween 20 or Tween 80; polyoxyethylene fatty alcohol ethers; or polyoxyethylene fatty acid esters.

As used herein the term "solvent vehicle" is intended to mean water, alcohol, nonvolatile solvents such as propylene glycol and glycerol, and mixtures thereof and other bases for pharmaceutical preparations such as vegetable oils and fats, mineral oil, Neobee oil, paraffins, fatty acid esters and cellusolve. Ethanol and isopropanol are particularly preferred alcohols.

As used herein the term "therapeutically active ingredient" is intended to include all pharmaceutical compounds. However, this invention is particularly directed to the administration of polypeptides as for example thyrotropin releasing hormones, luteinizing hormone releasing hormones, renin inhibitors and other polypeptides. Examples of suitable polypeptides include human growth hormone, bovine growth hormone, leuprolide (5-oxo-L-prolyl-L- histidyl-L-tryptophanyl-L-seryl-L-tyrosyl-D-leucyl-L- leucyl-L-arginyl-L-prolylethylamide acetate) , H-((beta, beta-dimethyl)-beta-Ala)-(4-OCH₃)- Phe-His amide of 2(S)-amino-l-cyclohexyl-3(R) ,4(S)- dihydroxy-6-methyl heptane (a renin inhibitor) and insulin.

The compositions of the present invention can be prepared by conventional techniques and contain a concentration of the therapeutic agent being administered that is sufficient to yield the desired therapeutically effective dose of the therapeutic agent. For example, leuprolide acetate would generally be present in a concentration of 1 to 500 mg/ml, preferably 5 to 100 mg/ml to deliver a therapeutically effective dose. The penetration enhancer would be present in an amount in the range of 0.1 to 60 weight percent, preferably l to 20 weight percent and the solubilizing agent would be present in an amount in the range of 0.1 to 10 weight percent, preferably 1 to 3 weight percent, based on the total weight of the composition. The preferred penetration enhancer is menthol. As stated above, the solvent vehicle may be water, alcohol, a nonvolatile solvent or mixtures thereof. When alcohol:water mixtures are utilized the ratio of alcohol to water is generally in the range of 5:95 to 95:5 and preferably in the range of 70:30 to 30:70. Ethanol:water mixtures are preferred solvents in the compositions of the present invention.

The compositions of the present invention may be administered in a variety of ways. For example, they may be formulated into hydrophilic and oleagenous ointments and emulsions. They may also be coated or deposited onto or impregnated into a suitable substrate such as an adhesive tape or patch for transdermal administration.

The substrate may be a polymeric film, a woven or nonwoven fabric, paper, or the like. Conventional adhesives, plasticizing agents and other -1-

adjuvants can also be used.

The invention can be illustrated by the following nonlimiting examples:

EXAMPLE 1

In vitro studies were conducted using freshly excised skin obtained from six to eight week old hairless female mice (Charles River Laboratories) The freshly excised skins were mounted on a commercially available 12 cell Franz diffusion apparatus that is available from Vangard International, Inc., Neptune, N.J. Formulations were prepared by standard mixing techniques. 300 ul of each formulation was dosed on a skin area of 4.52 square centimeters. The Franz diffusion apparatus receptor contains 20 ml of 40% polyethylene glycol 400 and 60% of N-2-hydroxyethyl- piperazine-N'-2-ethane sulfonic acid buffer (HEPES) . The water jacket was maintained at 37°C throughout the test period. 150 ul samples are taken from the receptor compartment at intervals of 2, 4, 6, 10, 12, 22 and 24 hours after application of the donor solution and measured by radioimmunoassay or HPLC methods to determine the concentration of drug which permeated the mouse skin. Lag time, permeation rate and permeability were then calculated.

The following formulations were prepared and tested by the above procedure:

Formulation A leuprolide acetate 500 mg/ml

_3 salicylic acid 4x10 M ethanol (190 proof) 50% v/v water 50% v/v Formulation B leuprolide acetate 500 mg/ml salicylic acid 4xl0^~3 M geraniol 10% v/v ethanol 45% v/v water 45% v/v

The results set forth in Table 1 show that the penetration enhancer, geraniol, substantially increased the permeability of leuprolide acetate.

EXAMPLE 2

The following additional formulations containing leuprolide acetate were prepared and tested by the procedure of Example 1:

Formulation 1

leuprolide acetate 5 mg salicylic acid 27 meg geraniol 0.6 ml ethanol/water (7:3) 1.4 ml

The above mixture was then evaporated to yield a final volume of 1.0 ml.

Formulation 3

Klucel® (cellulose 2-hydroxypropyl ether) is available from Hercules, Inc.

The above mixture was then evaporated to yield a final volume of 1.0 ml. Formulation 3 contains Klucel® and is a representative composition of the present invention.

The results set forth in Table 2 demonstrate the improved permeability that can be obtained using the compositions of the present invention. Assuming a patch

2 size of 20 cm , these 3 formulations will deliver the following amounts of leuprolide:

Formulation 1 720 meg/day Formulation 2 1584 meg/day Formulation 3 2016 meg/day

TABLE 2

Lag Permeabil¬

Sample tt Cone. Time Slope Flux ity X1000 mg/ml hr. ug/ml/hr ug/cm /hr cm/hr

Formulation 1

5 4.455 2.8 1.367 4.537 1.019 6 4.455 4.2 0.567 1.943 0.436 7 4.455 5.6 0.530 2.344 0.526 8 4.455 3.2 0.980 4.120 0.925

Average 4.455 4.0 0.861 3.236 0.726

S.D. 1.1 0.342 1.111 0.249

FIGURE 1 illustrates the leuprolide acetate concentration detected in the receptor over time and clearly demonstrates the skin permeation improvements obtained by the compositions of the present invention.

EXAMPLE 3

The following compositions were tested according to the procedure of Example 1. FIGURE 2 illustrates the increased permeability which can be achieved with the compositions of the present invention when they are further evaporated. This demonstrates the ability of the solubilizing agents of the present invention to maintain the solubility of the drug when it is desired to prepare concentrated solutions of the drug that exceed the normal solubility of the drug and thereby increase membrane permeation of the drug.

The formulations are as follows:

Formulation A leuprolide acetate 200 mg geraniol 280 ul

Klucel® 20 mg

70% ethanol/30% water 3.72 ml Formulation A was evaporated to a final volume of 2 ml. The final geraniol concentration was 10% as determined by HPLC.

Formulation B leuprolide acetate 200 mg geraniol 200 ml

Klucel® 20 mg

70% ethanol/30% water 1.8 ml

EXAMPLE 4

The following compositions were tested according to the procedure of Example 1. Each formulation was evaporated to a final volume of 1 ml before testing (n=3 for each) . The in vitro effect of varying solvent ratio on membrane permeability to leuprolide acetate is shown below in Table 3.

EXAMPLE 5

The effects on leuprolide permeability of menthol and ethanol concentration in the inventive compositions were tested using the procedure of Example 1. Each of the following formulations were tested with n=4.

The results, shown in Table 4, illustrate the enhancement of membrane permeability obtainable using the formulations of the present invention.

Table 4

EXAMPLE 6

Formulations of the renin inhibitor H-((beta,beta-dimethyl)-beta-Ala)-(4-0CH₃)-Phe-His amide of 2(S)-amino-l-cyclohexyl-3(R) ,4(S)-dihydroxy- 6-methyl heptane containing the permeation enhancers peppermint oil and geraniol were compared to a control formulation without enhancer. Preparation and testing of the formulations was carried out using the procedure of Example 1, with n=6 for Formulation A and n=3 for Formulations B and C.

The formulations are as follows:

Formulation A

Renin inhibitor 100 mg Ethanol (190 proof) 10 ml

Formulation B

Renin inhibitor 100 mg

Ethanol (190 proof) 10 ml

Peppermint oil 1 ml

Formulation C

Renin inhibitor 100 mg Ethanol (190 proof) 10 ml Geraniol 1 ml

The results shown in Table 5 demonstrate the improved permeability of the inventive renin inhibitor-containing formulations. Table 5

Formulations containing the above renin inhibitor, H-((beta,beta-dimethyl)-beta-Ala)- (4-OCH₃)-Phe-His amide of 2(S)-amino-l-cyclohexyl- 3(R),4(S)-dihydroxy-6-methyl heptane, were prepared and tested according to the procedure of Example 1. The receptor fluid was 40% polyethylene glycol and 60^! HEPES.

The formulations are as follows:

Formulation A

Table 6 and FIGURE 3 demonstrate the further enhancement of permeability of the renin inhibiting compositions of the present invention. Table 6

Leuprolide formulations containing geraniol and menthol as penetration enhancers were compared to a control formulation by the procedure of Example 1. The formulations are:

Formulation A leuprolide acetate 200 mg geraniol 200 ul

Klucel® 20 mg

70% ethanol/30% water 1.8 ml

Formulation B leuprolide acetate 200 mg menthol 400 mg

Klucel® 20 mg

70% ethanol/30% water 2 ml

Control Formulation leuprolide acetate 200 mg 70% ethanol/30% water 2 ml The results of comparative tests are shown in FIGURE 4 and demonstrate the superiority of the leuprolide-containing compositions of the present invention. Compositions with menthol have particularly enhanced permeability.

EXAMPLE 9 The following formulations were tested according to the procedure of Example 1. Table 7 illustrates the effect on permeability of leuprolide of varying the amount of menthol and the composition of the solvent vehicle.

Leuprolide Formulation Acetate Menthol

5 mg 100 mg

B 5 mg 200 mg

100 mg 200 mg

EXAMPLE 10

Insulin-containing compositions of the present invention were compared to conventional insulin-containing compositions by the procedure of Example 1.

The formulations are:

Formulation A 200ul 1—125 labeled Insulin (specific activity lOuCi/O.lug) 400ul Distilled water

Formulation B 400ul 1-125 labeled Insulin (specific activity lOuCi/O.lug Insulin/2ml Sodium acetate buffer solution) 20mg Klucel® 400ul 40% w/v Menthol/Ethanol 400ul Ethanol

The results of comparative tests are shown in FIGURE 5 and demonstrate the superiority of the insulin-containing compositions of the present invention.

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compositions. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A pharmaceutical composition having enhanced membrane permeability comprising a therapeutically active ingredient, a penetration enhancer and a solvent vehicle.

2. The pharmaceutical composition of Claim 1 wherein the therapeutically active ingredient is a polypeptide.

3. The pharmaceutical composition of Claim l wherein the penetration enhancer is an essential oil or a component thereof.

4. A pharmaceutical composition having enhanced membrane permeability comprising a therapeutically active ingredient, a penetration enhancer, a solubilizing agent and a solvent vehicle.

5. The pharmaceutical composition of Claim 4 wherein the therapeutically active ingredient is a polypeptide.

6. The pharmaceutical composition of Claim 5 wherein the polypeptide is leuprolide acetate.

7. The pharmaceutical composition of Claim 4 wherein the solubilizing agent is a polymer selected from bioadhesive, hydrophilic and hydrophobic polymers.

8. The pharmaceutical composition of Claim 7 wherein the polymer is a cellulose derivative.

9. A pharmaceutical composition as in Claim 1 which is impregnated into a substrate or coated onto a substrate.

10. A method of delivering a therapeutically active ingredient across a biological membrane, comprising contacting the membrane with a pharma¬ ceutical composition as in Claim 1.