WO2019234662A1

WO2019234662A1 - Transdermal drug delivery system containing rotigotine

Info

Publication number: WO2019234662A1
Application number: PCT/IB2019/054693
Authority: WO
Inventors: Minhthi Dinh BUI; Ping I Lee; Y. Joseph Mo; Tiffany Kawai
Original assignee: Nal Pharmaceutical Group Limited
Priority date: 2018-06-07
Filing date: 2019-06-05
Publication date: 2019-12-12
Also published as: TW202005648A

Abstract

A transdermal drug delivery system comprises of an adhesive layer consisting of a polyisobutylene pressure sensitive adhesive containing supersaturated rotigotine. The patches appeared to remain stable under accelerated temperature conditions for over one month, which translates to room temperature stability many times that duration, with the incorporation of various effective additives.

Description

TRANSDERMAL DRUG DELIVERY SYSTEM CONTAINING ROTIGOTINE

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority from U.S. Provisional Application Serial No. 62/681,711, filed June 7, 2018, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a transdermal drug delivery system comprising rotigotine as an active ingredient.

BACKGROUND

Transdermal drug delivery systems (TDDS) are an attractive method for the delivery of an active pharmaceutical ingredient (API) into the systemic circulation due to their ability to avoid the first-pass effect, being non-invasive, and frequent dosing while providing a steady state delivery of drug over a long period of time. Transdermal matrix patches are the most common type of TDDS and consist of a backing film, pressure sensitive adhesive containing drug, and release liner. The backing material and release liner should be inert and impermeable to the drug. There are three commonly used pressure sensitive adhesives used for transdermal delivery systems: acrylates, silicone, and butyl rubber such as polyisobutylene (PIB). The PIB pressure sensitive adhesives in particular are advantageous due to its low cost and chemical inertness.

The delivery of drugs from a transdermal patch to the systemic circulation involves drug permeation through the epidermis. However, the outermost layer of the epidermis, the stratum corneum (SC), is an effective barrier to drug diffusion and permeation. To overcome this diffusional barrier, permeation enhancement strategies are often applied to improve the topical bioavailability of the transdermal patches. In addition to chemical means by incorporating permeation enhancers, supersaturating drug-in-adhesive patches are often utilized as a passive permeation enhancement strategy by directly increasing the diffusional driving force. However, these metastable supersaturated systems may lead to crystal formation during storage. Drug crystallization within the patch during storage may compromise the performance of the patch. Therefore, if supersaturation is applied as a permeation enhancement strategy, it is important to stabilize these types of systems. Stabilization of supersaturated transdermal patches is usually done by incorporating suitable additives into the adhesive matrix containing supersaturated drug.

Transdermal delivery of rotigotine, a dopamine D2 receptor antagonist, has been pursued for treating Parkinson’s disease. The transdermal delivery systems described in US 6,884,434, utilize either a silicone adhesive matrix or an acrylate adhesive matrix containing rotigotine in its free base form. This patent also claims the incorporation of hydrophilic polymers (including polyvinylpyrrolidone) to enhance the solubility of rotigotine and various permeation enhancers (including oleic acid). On the other hand, US 8,617,591 focus on transdermal delivery systems based on silicone adhesive matrix containing micro-reservoirs and compared them to acrylate adhesive-based comparative examples. In this case, soluble polymers including

polyvinylpyrrolidone are claimed as“crystallization inhibitors”.

Patent application US20160136107 presents examples of rotigotine transdermal patches consisting of: polyisobutylene (Oppanol B 12/ Oppanol B 10), ethylene vinyl acetate (Elvax 40W), dimethyl isosorbide (Arlasolve DMI), and capric caprylic triglyceride (Crodamol GTCC), where the dimethyl isosorbide serves as the solubility enhancer and capric caprylic triglyceride the plasticizer. These examples are claimed to deliver a therapeutically acceptable amount of the API for a period of about 24 hours but with no description of, or data supporting, the stability of the claimed invention. In another patent application, WO 2012/084969, claims a solvent-free process for making API containing adhesive matrix (including rotigotine) comprising a mixture of biocompatible polymers including silicone, acrylate and polyisobutylene adhesives, as well as common polymers and copolymers including polyurethane and ethylene vinyl acetate copolymers. This application also presents examples using polyisobutylene (DURO-TAK^® 87-608A; Henkel) as the pressure sensitive adhesive matrix containing rotigotine. Other additives that were used in the examples were: crospovidone (Kollidon CL-M), octyldodecanol, alpha tocopherol, sodium metabisulfite, and ascorbylpalmitate. SUMMARY OF THE INVENTION

The present invention relates to a transdermal drug delivery system comprising of an adhesive layer consisting of a polyisobutylene pressure sensitive adhesive containing supersaturated rotigotine. The patches appeared to remain stable under accelerated temperature conditions for over one month, with the incorporation of various effective additives.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows microscopic images demonstrating lack of crystal growth in Example 3 (at 2 different locations) after 5, 13 and 36 days.

Figure 2 shows microscopic images demonstrating the partial crystalline area of 8% rotigotine, 20% oleic acid and 72% DURO-TAK^® 87-6908 (Henkel) composition after 42 days.

Figure 3 shows microscopic images demonstrating the partial crystalline area of 12% rotigotine, 20% oleic acid and 68% DURO-TAK^® 87-6908 (Henkel) composition after 42 days. Figure 4 shows microscopic images demonstrating the partial crystalline area of 5% Plasdone K17, 10% rotigotine, 12% oleic acid and 73% DURO-TAK^® 87-6908 (Henkel) composition after 42 days

Figure 5 shows microscopic images demonstrating the partial crystalline area of 15% rotigotine, 20% oleic acid and 65% DURO-TAK^® 87-6908 (Henkel) composition after 42 days Figure 6 shows microscopic images demonstrating the drug crystal are found in the oleic acid rich micro-reservoirs.

Figure 7 shows various patch formulations. Figure 7A shows patches of 12% rotigotine +20% oleic acid. Figure 7B shows patches of 15% rotigotine+20% oleic acid. Figure 7C shows patches of 5% plasdone Kl7+l0% rotigotine+l2% oleic acid.

DETAILED DESCRIPTION OF THE INVENTION

Transdermal drug delivery systems

Certain aspects of the present invention provide a transdermal drug delivery system comprising an adhesive layer containing rotigotine as an active ingredient, wherein the pressure sensitive adhesive layer such as, but not limited to polyisobutylene pressure sentitive adhesive. Thus, certain embodiments of the invention provide a transdermal drug delivery system containing rotigotine having effective and extent of crystallization inhibition, excellent stability, and reduced skin irritation. In accordance with an aspect of some embodiments of the invention, there is provided a transdermal drug delivery system comprising a drug-in- adhesive matrix containing rotigotine as an active ingredient, wherein the matrix layer contains such as, but not limited to polyisobutylene pressure sensitive adhesive. The transdermal delivery system of this and other embodiments of the invention may further comprise micro-reservoirs. In another embodiment of the invention may further comprise an additive which acts as a crystallization inhibitor and/or permeation enhancer. In a further alternative embodiment of the invention, the transdermal drug delivery system may consist of a backing layer and release liner which are inert and impermeable to the API.

Rotigotine

In the transdermal drug delivery system according to certain embodiments of the invention, the amount of rotigotine free base ranges from 3 to 20% by weight, preferably 5 to 15%, or 5 to 12%, by weight, and more preferably 10 to 12%, by weight based on the total weight of the drug- containing matrix layer.

Pressure sensitive adhesive

The pressure sensitive adhesive is a material that forms intimate contact between transdermal drug delivery system and the surface of the skin. The polymers for pressure sensitive adhesive is selected from group comprising natural rubber, butyl rubber, polyisobutylene, styrene butadiene rubber, styrene isoprene styrene, styrenic block copolymer, acrylic block copolymer, acrylic acid ester, polyalkylacrylates, silicone, polyvinyl ether, methacrylic copolymer, and polyurethane. In the transdermal drug delivery system according to certain embodiments of the invention, the amount of the pressure sensitive adhesive is 60-85% by weight, preferably 65-75%, or 65 to 73% by weight, more preferably 68 to 70% by weight of the adhesive matrix layer.

Micro-reservoirs

Micro-reservoirs of sizes ranging from 5 to50 pm in diameter are present in the pressure sensitive adhesive matrix layer of the transdermal patch containing rotigotine. Micro-reservoirs containing rotigotine is formed during the dispersion of drug solution and drying of miscible organic solvents such as ethyl acetate, chloroform, ethanol, or propanol from the adhesive layer. The resulting numerous microscopic droplets in the adhesive layer are composed of additive -rich (e.g. oleic acid-rich) phases containing supersaturated rotigotine.

Additive

In the transdermal drug delivery system according to another embodiment, the additive is present in an amount ranging from 5 to 30% by weight, preferably 10 to 25% or 15 to 20% by weight, and more preferably 17-20% by weight of the adhesive matrix layer. A non-exhaustive list of the additive that can be used include: polyvinyl pyrrolidone, oleic acid, Labrasol^®, Lauroglycol™ 90, Capryol™ 90, Transcutol® P, Plurol® Oleique CC 497, and isopropyl myristate, or a combination thereof.

Release layer and Backing layer

The transdermal drug delivery system of certain embodiments of the invention may be prepared by forming the drug-containing matrix layer on a release layer and then forming a backing layer thereon. For the release layer, conventional release liners or their laminates used in the field of a transdermal drug delivery system may be used. For example, there may be used a film, a paper, or a laminates thereof, which is made of polyethylene, polyester, polyvinyl chloride, polyvinylidene chloride, etc. coated with silicone resin or fluoride resin. And also, drug non absorbable and flexible materials conventionally used in the field of a transdermal drug delivery system may be used as the backing layer (also referred to as "backing membrane"). For example, there may be used polyolefin, polyether, a multi-layer ethylene vinyl acetate film, polyester, polyurethane, etc. The transdermal drug delivery system of certain embodiments of the invention may be prepared, for example by dissolving donepezil or its pharmaceutically acceptable salt and an acrylate -rubber hybrid adhesive, optionally along with an absorption enhancer and/or a crystallization-inhibiting agent, in an appropriate solvent (e.g., ethyl acetate, etc.), casting the resulting solution on a release liner coated with silicone followed by drying the mixture, and then laminating a backing layer.

Method of preparation

In one embodiment of the present invention, the pressure sensitive adhesive was weighed directly in a glass vial. In a separate vial, rotigotine and an additive were dissolved in a minimal amount of ethyl acetate and stirred mechanically until rotigotine was completely dissolved. The rotigotine and the additive mixture was directly added to the weighed adhesive. The mixture was stirred using a stir plate for about 1 hour to ensure a homogeneous mixture. The mixture is then casted onto the release liner and left at room temperature for 15 minutes and an additional 15 minutes in the oven at an increased temperature to remove any trace of solvent. After drying, the backing film was rolled onto adhesive matrix.

It should be understood that the components of the transdermal drug delivery system described above may be prepared using varying combinations of the components described above, and that the particular embodiments described above are non-limiting examples of these combinations. For instance, transdermal drug delivery systems prepared according to the invention may include or exclude: an absorption enhancer, a hydrogenated rosin glycerol ester or a plasticizer. The inclusion or absence of these components is determined on an individual basis, selected by the artisan in order to prepare a transdermal system with a desirable release profile.

It should be understood that singular forms such as“a,”“an,” and“the” are used throughout this application for convenience, however, except where context or an explicit statement indicates otherwise, the singular forms are intended to include the plural. Further, it should be understood that every journal article, patent, patent application, publication, and the like that is mentioned herein is hereby incorporated by reference in its entirety and for all purposes. All numerical ranges should be understood to include each and every numerical point within the numerical range, and should be interpreted as reciting each and every numerical point individually. The endpoints of all ranges directed to the same component or property are inclusive, and intended to be independently combinable. EXAMPLES

The following examples are merely exemplary in nature and is not intended to limit application and uses. The following examples further illustrate the present invention without, however, limiting the scope of the invention thereto. Various changes and modifications can be made by those skilled in the art on the basis of the description of the invention, and such changes and modifications are also included in the present invention.

EXAMPLE 1

The pressure sensitive adhesive was weighed directly in a glass vial. In a separate vial, rotigotine, oleic acid, and isopropyl myristate were dissolved in a minimal amount of ethyl acetate and stirred mechanically until rotigotine was completely dissolved. The rotigotine, oleic acid, and isopropyl myristate mixture was directly added to the weighed adhesive. The mixture was stirred using a stir plate for about 1 hour to ensure a homogeneous mixture. The amount of the components is shown in Table 1. The mixture was then casted onto the release liner and left at room temperature for 15 minutes and an additional 15 minutes in the oven at an increased temperature to remove any trace of solvent. After drying, the backing film was rolled onto adhesive matrix.

Table 1.

EXAMPLE 2

The same steps described in Example 1 were carried out, except only oleic acid was used as the additive in this example. The amount of the components is shown in Table 2.

Table 2

EXAMPLE 3 The same steps described in Example 1 were carried out, except only oleic acid was used as the additive in this example. The amount of the components is shown in Table 3.

Table 3

EXAMPLE 4

The same steps described in Example 1 were carried out, except only lauroglycol 90 was used as the additive in this example. The amount of the component is shown in Table 4.

Table 4

EXAMPLE 5

The same steps described in Example 1 were carried out, except only isopropyl myristate was used as the additive in this example. The amount of the component is shown in Table 5.

Table 5.

EXAMPLE 6

The formulations presented in above examples were kept under accelerated temperature conditions (50°C). The samples from Example 2 and 3 both showed a slight yellow/brown discoloration over time, and less than 1.5 % of crystallinity was detected. The results are shown in Table 6.

Table 6

* Less than 1.5% of drug load crystallized as quantified by DSC. Example 7

The formulation of 8% Rotigotine, 20% oleic acid and 72 % DURO-TAK^® 87-6908 (Henkel) was subjected to a long-term stability study following the ICH Guidelines for stability testing using accelerated conditions (40°C ± 2/75% RH ± 5). The partial crystalline area was measured to be 562.953 pm² at day 42. This crystalline area was less than the crystalline area of Example 2 or Example 3, which suggests that these samples are stable. Microscopic images are shown in Figure 2. Example 8

The formulation of 12% Rotigotine, 20% oleic acid and 68% DURO-TAK^® 87-6908 (Henkel) was subjected to a long-term stability study under accelerated conditions (40°C ± 2/75% RH ± 5). The total crystalline area was measured to be 429.81 pm² at day 42. This crystalline area was less than the crystalline area of Example 2, which suggests that these samples are stable. Microscopic images are shown in Figure 3.

Example 9

The formulation of 5% Plasdone K17, 10% Rotigotine, 12% oleic acid and 73% DURO-

TAK^® 87-6908 (Henkel) was subjected to a long-term stability study under accelerated conditions (40°C ± 2/75% RH ± 5). The total crystalline area was measured to be 255.787 pm² at day 42. This crystalline area was less than the crystalline area of Example 2 or Example 3, which suggests that these samples are stable. Microscopic images are shown in Figure 4.

Example 10

The formulation of 15% Rotigotine, 20% oleic acid and 65% DURO-TAK^® 87-6908 (Henkel) was subjected to a long-term stability study under accelerated conditions (40°C ±

2/75% RH ± 5). The total crystalline area was measured to be 2082.943 pm² at day 42. This crystalline area was less than the crystalline area of Example 2 or Example 3, which suggests that these samples are stable. Microscopic images are shown in Figure 5.

Example 11 Rotigotine containing adhesive compositions were cast on 9741 release liner (polypropylene film) and laminated with 9733 backing (polyester film laminate) to simulate patches for stability testing. Following compositions were stored in a stability chamber under

40°C and 75%±5 RH:

· 12% Rotigotine + 20% oleic acid

• 15% Rotigotine + 20% oleic acid

• 5% Plasdone K17 + 10% Rotigotine + 12% oleic acid.

All cast patches appear to be stable for over 2 months.

Claims

CLAIMS We claim:

1. A transdermal drug delivery system comprising:

a drug containing matrix layer comprising:

rotigotine;

a pressure sensitive adhesive;

an additive; and

a micro-reservoirs.

2. The transdermal drug delivery system of claim 1 , wherein amount of rotigotine is present in an amount of 3-20%, 5-15%, 5-12% or 10-12% by weight based on a total weight of the drug- containing matrix layer.

3. The transdermal drug delivery system of claim 1, wherein the pressure sensitive adhesive is polyisobutylene based pressure sensitive adhesive.

4. The transdermal drug delivery system of claim 1 , wherein the pressure sensitive adhesive is present in an amount of 60-85%, 65-75%, 65-73% or 68-70% by weight based on a total weight of the drug-containing matrix layer.

5. The transdermal drug delivery system of claim 1, wherein the additive is one or more selected from the group consisting of polyvinyl pyrrolidone, oleic acid, Labrasol^®,

Lauroglycol™ 90, Capryol™ 90, Transcutol® P, Plurol® Oleique CC 497, and isopropyl myristate, or a combination thereof.

6. The transdermal drug delivery system of claim 1 , wherein the additive is present in an amount of 5-30%, 15-20%, 10-25% or 17-20% by weight based on a total weight of the drug- containing matrix layer.

7. The transdermal drug livery system of claim 1, wherein the size of the micro- reservoirs varying from 5-50 mih in diameter.

8. The transdermal drug livery system of claim 1, further comprising a backing layer and release liner.

9. A transdermal drug delivery system comprising a backing layer, a drug-containing matrix layer, and a release layer,

wherein the drug containing matrix layer comprising:

rotigotine;

a pressure sensitive adhesive;

an additive; and

a micro-reservoirs,

wherein the backing layer and release liner are inert and impermeable to the active pharmaceutical ingredient.