WO2010048064A2

WO2010048064A2 - Drug delivery system and its use in the treatment of postherpetic neuralgia

Info

Publication number: WO2010048064A2
Application number: PCT/US2009/061114
Authority: WO
Inventors: Igor Kissin
Original assignee: Brigham and Womens Hospital Inc
Current assignee: Brigham and Womens Hospital Inc
Priority date: 2008-10-20
Filing date: 2009-10-18
Publication date: 2010-04-29
Anticipated expiration: 2011-04-20
Also published as: WO2010048064A3

Abstract

The present invention is directed to a drug delivery composition that can be used to topically apply drugs to the skin of patients. It is also directed to a method of treating patients for shingles or postherpetic neuralgia by using the device to occlusively apply topical anesthetic to skin areas without the need for adhesives that attach occlusive dressing to the patient skin. In addition, the invention includes a method for determining the dosing interval for administering topical anesthetic to patients with PHN in procedures involving the complete numbing of skin.

Description

Drug Delivery System and Its Use in the Treatment of Postherpetic Neuralgia

Cross Reference to Related Applications

The present application claims the benefit of United States provisional application 61/136,984, filed on October 20, 2008, the contents of which is hereby incorporated by reference in its entirety.

Field of the Invention

The present invention is directed to compositions that can be used for topically delivering drugs under occlusive conditions, without the need for adhesives that adhere to patients. The compositions will be especially useful in the treatment of shingles and postherpetic neuralgia (PHN) using local anesthetics such as lidocaine. In addition, the invention is directed to a method for determining optimal dosing intervals for topically applying local anesthetics in the treatment of PHN.

Background of the Invention

Shingles is a painful skin rash caused by the reactivation of the Herpes zoster virus in people that have had chickenpox. Virus reactivation often takes place in older people,

HIV patients, and patients receiving chemotherapy. In the US, shingles occurs in about 1 million patients each year and, in most of these cases, the disease subsides in two to four weeks. However, 10-20% of shingles patients develop post-herpetic neuralgia (PHN) that affects the same area where shingles-associated rashes occurred and which can be extremely painful. Although, in most instances, PHN pain gradually decreases and is usually gone in about 1 to 5 years, some patients exhibit debilitating pain that lasts for their entire lives.

The pain associated with PHN may be treated to some extent with standard systemic analgesics, but the only product presently approved by the FDA specifically for this condition is "Lidoderm^®," a patch that is applied directly to the skin and that represents a topical formulation that contains 5% lidocaine. The Lidoderm^® patch is designed to reduce pain without numbing a patient's skin and is typically applied over as much of the painful area as possible for 12 hours each day. The long duration of Lidoderm^® exposure increases the risk of two important side effects associated with this treatment: application site skin reactions and potentially toxic drug concentrations in patients' blood.

Lidocaine treatment for PHN may also be carried out by inducing complete skin anesthesia under occlusive conditions (Kissin, et ah, Neurology 39: 1132-33 (1989); see also Monash, AMA Arch. Derm. 76:752-6 (1957) and US 5,415,866). The induction of this anesthesia (absence of sensitivity to pin prick) was provided by application of 5% lidocaine base under an occlusive dressing for a 60-min period. When anesthesia was induced and the occlusive dressing removed skin anesthesia lasted for 2-3 hours. However, the duration of complete relief of spontaneous superficial pain of PHN was much longer. It lasted for a period of from several hours to several days after a single lidocaine administration. A key factor for successful skin anesthesia is the completeness of the occlusion. Reports of the absence of skin anesthesia with the administration of 5% lidocaine in the form of Lidoderm^® or lidocaine gel (Rowbotham et ah, Ann. Neurol. 57:246-253 (1995), see also, Rowbotham, et al, Pain 65:39-44 (1996); US 5,411,738 and 5,601,838) can probably be explained by insufficient occlusion due to the changes in adhesive attachment caused by body movements.

Summary of the Invention The present invention is based upon the development of a system for topically delivering drugs under occlusive conditions without the use of adhesive attachment of the occlusive dressing to the skin. The invention is also based upon the development of a procedure for optimizing the dosing interval for delivering local anesthetic in the treatment of patients with PHN.

In its first aspect, the invention is directed to a patch for the topical delivery of a biologically active agent. The patch includes at least one (and typically many) drug delivery cells that have a wall made of a solid inert material {e.g., plastic) that completely surrounds and defines an internal space and that terminates at a top rim or surface and a bottom rim. The pharmaceutical composition that will be delivered to a patient is placed within the internal space of each drug delivery cell. This pharmaceutical composition includes a biologically active agent, i.e. a drug, and, optionally, one or more carriers or excipients. It may be in the form of a gel, ointment or cream or may be supplied in the form of a liquid that has saturated, or partially saturated an absorbent material such as cotton or gauze.

One end of each drug delivery cell is attached to a flexible backing layer. For the purposes of the present invention, this attached end is referred to as the "top" of the cell.

The cell's top is a flat planar surface impermeable to air, water and biologically active agent. It may be attached by means of an adhesive or fused to the backing layer. Each cell is surrounded by a rigid wall that terminates in a rim (bottom end) designed to press into the skin of a patient. The cell's wall should also be impermeable to air, water and biologically active agent.

The bottom end of each drug delivery cell, i.e., the end distal to the backing layer, will, when the patch is applied to a patient, be open so that direct contact can be made between the skin of the patient and the pharmaceutical composition. However, during storage, the bottom rim of the cell will be covered with a removable film, sheet or foil to prevent leakage or evaporation of the pharmaceutical composition.

The drug delivery cells can be of many different shapes and sizes. For example, they may be squares or rectangles (preferably with sides 1-3 cm long) or circles (preferably with a diameter 1-3 cm). Typically, they will have walls that are 2-6 mm high and 0.5-2 mm thick. Although plastic will most commonly be used to make the cells, other rigid, pharmaceutically acceptable materials can also be used. Patches will usually contain an array of evenly spaced cells, separated from one another by gaps of about 1-5 mm. This spacing is important to allow cells to adjust to body movements without breaking contact with a patient's skin.

In its most preferred form, the drug delivery patch has multiple drug delivery cells attached to the flexible backing layer and separated from one another by a gap of 1-5 mm. Each cell contains a pharmaceutical composition that has, as biologically active agent, a topical anesthetic (preferably 2-5% of lidocaine base). The cells are covered at the bottom end with a removable, fϊm, sheet or foil to prevent evaporation or leakage from the inner space during storage.. In another aspect, the invention is directed to a method for topically administering an active agent to a patient by occlusively applying any of the drug delivery patches described above to their skin. The term "occlusively applying" means that the cells of the patch are pressed against the patient's skin with sufficient pressure to make the internal space of the cells impermeable to air, water and active agent. In a preferred embodiment, compressive pressure is applied solely by placing the drug delivery patch under an elastic bandage that is wrapped around the patient, e.g., around their torso, leg, arm etc.

The invention also includes methods of treating a patient for shingles or postherpetic neuralgia (PHN) by occlusively applying a drug delivery patch which has a pharmaceutical composition containing a topical anesthetic, preferably 2-5% lidocaine base, as the active agent. This is typically applied for about 60 min, a duration sufficient to cause the complete anesthesia (as evidenced by insensitivity to a pin prick) of the skin area exposed to the pharmaceutical composition. The patch is then reapplied at an interval of between 0.5 and 7 days. The skin treated should be the area where the patient is experiencing pain and will typically coincide with the area where the rash associated with shingles is, or was, located.

Compressive pressure should be applied by placing the drug delivery patch under an elastic bandage that is wrapped around the patient. The use of occlusive dressing without adhesive attachment to the skin is important in that PHN patients are likely to be especially sensitive to pain caused by removal of bandages applied with adhesive.

In another aspect, the invention is directed to a method of treating a subset of PHN patients in which complete anesthesia of their skin produces complete pain relief. The method involves: a) topically applying sufficient anesthetic (preferably lidocaine base) to cause complete skin numbing of most (e.g., 60, 70 or 80%) but not necessarily all of the area of pain; b) determining the time at which spontaneous pain reappears; and c) reapplying the anesthetic at an interval that is somewhat less (e.g., by about 1/3-1/4 and preferably about 1/4) than the interval from anesthetic application to the time of pain reappearance. Most preferably, the topical anesthetic in this method is applied using the drug delivery systems described above. Brief Description of the Drawings

Figure 1 : Figure 1 shows a bottom perspective of a drug delivery patch (A) made up of a flexible backing layer (B) and drug delivery cells (C). The backing layer is attached to the top surface of the cells (G) and there is a gap (D) between each. Also shown is the bottom rim of cells (F), absorbent material soaked with drug (or a gel, ointment or cream) (I) located in the inner space of cells, and a removable foil seal or similar covering (J) covering the bottom ends of the drug delivery cells. The foil seal has a portion removed in the figure.

Figure 2: Figure 2 is a side elevation of the drug delivery system (A) of Figure 1, showing the flexible backing layer (B) attached to drug delivery cells (C), with gaps (D) between each and a removable foil covering (J). This is the way that the patch would appear during storage.

Figures 3A and 3B: Figure 3A is an enlarged cross-section taken along line 3-3 in

Figure 1. The top surfaces of the drug delivery cells (G) are shown up against the flexible backing layer (B) to which they are fused or attached by means of adhesive (K). The walls of the cells (H) extend downward and are covered at their bottom rims (F) by a removable foil seal (J). Gaps between cells (D) are shown as well as the pharmaceutical composition (I) within the inner space of the cells. Figure 3B shows the same cross-sectional view of the drug delivery patch as it would appear when in use. The removable covering (J) has been removed and the device is compressing the skin (L) of a patient. The drug composition (I) within the drug delivery cells (C) is in direct contact with the skin.

Figure 4: Figure 4 is a bottom perspective of a drug delivery cell (C) in isolation.

The top surface of the cell (G) is shown, along with the cell wall (H), bottom rim (F) and inner space (E).

Detailed Description of the Invention A. Description of Embodiments Depicted in Figures

Figure 1 is a bottom perspective of a drug delivery patch (A) made up of a flexible backing layer (B) with multiple drug delivery cells (C) attached. Each cell extends out from the plane of the backing layer by about 2-6 mm and has rigid walls (H). The cells are separated by gaps (D) typically of 2-5 mm. These allow the patch to flex in response to the body movements of a patient without losing contact with skin. During storage, cells are covered at the bottom with a removable film, metal foil or sheet (J) which is removed prior to use to allow the bottom rims of the cells (F) to press into the skin of a patient and expose the skin to the medication (I) inside the inner space of the cells. The relationship of the backing layer (B), drug delivery cells (C), gaps (D) and removable covering (J) is shown in a side view in Figure 2.

Figure 3 is a cross-section of a portion of the patch in Figure 1 and shows the top surface (G) of a drug delivery cell (C) fused or attached by adhesive to the backing layer

(B). The cells have rigid walls (H) that terminate in a rim (F) that is covered with a removable foil or sheet (J). Figure 3 A shows the device as it would appear during storage.

Figure 3B shows the device as it would appear in use.

The center of each drug delivery cell has a hollow inner space (E in Figure 4) in which the pharmaceutical composition being delivered (I) is placed. This must be included in the cell in a manner that will hold active agents in place. For example, a drug solution such as a solution of lidocaine may be used to saturate or partially saturate an absorbent material (e.g., gauze, cotton, sponge etc) and this can then be positioned in the inner space. When sufficient pressure is applied pressing the patch against the skin of a patient, the bottom rims (F) push into the skin to form a tight seal that excludes air and moisture.

An individual drug delivery cell is depicted in Figure 4. This shows the rigid side wall of the cell (H) , the inner space (E), the bottom rim (F) that will make contact with a patient's skin, and the top surface or rim (G) that will attach to the flexible backing layer.

B. General description of Drug Delivery System

In one aspect, the invention is directed to a drug delivery system that provides occlusive conditions on the skin surface of a patient by creating pressure on the rims of drug delivery cells that protrude into the skin. These cells have a hollow inner area that is completely surrounded by a rigid, solid wall. The inner area is filled with the medication that is to be delivered to a patient and which is formulated or suspended in a manner that holds it in place. For example, the medication may be formulated as a gel or cream or may be suspended in gauze or other sponge-like material.

The top of the drug delivery cells is closed (i.e., ending in a top plate or surface). The cells will typically be fused or attached in any other way to the flexible backing layer. For the purposes of the present invention, the combination of one or more drug delivery cells bound to a flexible backing layer is referred to as a "drug delivery patch." The walls of the drug delivery cells are rigid and should be impermeable to air, water and the medication being delivered. Top surfaces of the cells should also be impermeable.

When in use, the bottom ends of the drug delivery cells are open so that the suspension or drug formulation within its inner area is directly in contact with the skin of a patient when occlusive pressure is applied to the top of the cells. The pressure applied to the cells is referred to as "occlusive" because it creates an air-tight and water-tight seal between the patient's skin and each drug delivery cell. This force may be generated using a bandage that wraps around the patient and pulls the patch tight against the skin (without attachment of the dressing to the skin by adhesive).

In general, drug delivery patches will contain multiple identical cells of relatively small size, each with a protruding narrow rim transmitting pressure against the skin and separated from one another by a gap. The arrangement of small cells separated by gaps and a flexible backing layer permits a hermetic seal to be maintained despite body movements of the patient.

Although adhesive may be used to attach the top surface of drug delivery cells to the flexible backing layer, drug delivery patches should, preferably, not have any adhesive that produces pressure by adhering to the skin of a patient. The use of nonadhesive occlusive pressure eliminates the pain associated with the removal of patches from sensitive skin at the end of treatment and will be especially important in patients that have a condition such as PFIN that makes them especially sensitive to such pain. In addition, it creates more reliable occlusion that can withstand body movement. C. Drug Delivery Cells

The exact dimensions of drug delivery cells is not crucial to the invention. However, cells that are rectangular or square should typically have sides 1-2 cm long and circular cells should typically have a diameter of 1-2 cm. The walls will typically have a width of 0.5 to 2 mm, and a height of 2 to 6 mm (preferably 2 to 4 mm). Cells walls will, in most cases, be made of rigid plastic that is nonporous to air, water and the components of the drug formulation within its inner space. However, the invention is compatible with the use of other solid materials with these characteristics as well.

D. Drug Delivery Patches

Drug delivery patches are made of one or, typically, more drug delivery cells that have been fused or attached by adhesive to an occlusive backing layer at their top surfaces or rims. Appropriate backings have been used in bandages for many years and may be derived from synthetic polymers like polyolefm oils polyester, polyethylene, polyvinyl chloride, and polyurethane. The size and shape of the backing layer and the number of drug delivery cells attached to it can vary widely and will be selected based upon the skin area to which drug is to be applied. Typically, circular patches will have a diameter of 5-20 cm and rectangular or square patches will have sides 5-25 cm long. However, other sizes are compatible with the invention and may be desirable for certain treatments.

The cells should be positioned on the backing layer so as to provide good coverage of the skin area being treated and should include a gap between them to allow for body movement by the patient. The gaps should usually be about 2-10 mm (and preferably 2-5 mm) wide. If desired, the backing layer may be extended beyond the last drug delivery cell on each side to aid in positioning it under occlusive bandages.

The top surfaces of drug delivery cells should be fused (attached) to the backing layer. Examples of medical grade, pressure-sensitive adhesives that may be used include acrylate ester/vinyl pyrrolidone copolymers, dimethyl silicone polymers, and acrylate polymers.

During storage, the bottom ends of the drug delivery cells should be covered with an inert protective covering, e.g., a cellulose, plastic or metal foil, film or sheet, in order to prevent the evaporation or leakage of the drug formulation in the inner space. Immediately prior to usage, the sheet is removed, leaving the bottom ends of the drug delivery cells, i.e., the ends furthest from the flexible backing layer, open, and thereby allowing direct contact between a patient's skin and the drug formulation in the inner space.

E. Use of Drug Delivery Patches

The drug delivery patches described herein may be used to apply medications topically to patients. Preferably, the patches will be used to treat shingles or postherpetic neuralgia with a topical anesthetic, especially lidocaine. Formulations should typically contain 2-5% of lidocaine base (although other pharmaceutically acceptable forms may also be used) and may include any of the standard inert ingredients found in topical formulations. Excipients that might be used include: polymers; polyethylene glycol; cyclodextrins; saccharides; surfactants; antioxidants; stabilizers; etc. The lidocaine may be formulated as a gel or cream or it may be used to soak an absorbent material such as gauze or cotton which is then placed inside the inner space of the drug delivery cells. The total amount of lidocaine present in a patch should typically be 500 mg. Guidance concerning the preparation of dosage forms may be found in Remington's Pharmaceutical Sciences (1980) A. Oslo ed. and similar works.

Preferably occlusive pressure is applied using elastic bandages compressively wrapped over the drug delivery patch. Many such bandages have been described in the art, see e.g., US 3,613,679, that can be used for this purpose. In order to maintain a hermetic seal, the bandage should apply sufficient pressure so that the rims of the drug delivery cells are incursed into the skin of the patient by at least about 1-3 mm.

F. Customizing Dosing Intervals in Treating Post Herpetic Neuralgia

The present invention also includes a method of treating post herpetic neuralgia based upon the induction of complete skin anesthesia (insensitivity to pin prick over the area of lidocaine application) due to the topical application of anesthetic. In this method, the customized interval between anesthetic applications is based upon the duration of the pain- free period after the first induction of anesthesia. The interval is determined by: a) applying sufficient anesthetic to cause complete skin numbing and b) determining the time at which pain reappears. The dosing interval should be somewhat less (e.g., by 1/3- 1/4) than the interval from the drug application to the reappearance of spontaneous pain. For example, if this interval was 32 hours, a patch delivering a skin numbing dose of anesthetic should be applied about every 24 hours. The interval between the inductions of skin anesthesia can vary from half a day to one week or even more.

This method of customized intermittency minimizes the exposure of skin to local anesthetic and results in a decreased frequency and severity of local skin reactions. It also decreases the amount of lidocaine penetrating into the blood of patients and the possibility of systemic adverse reactions. In addition, it reduces the possibility of development of tolerance to the effect of local anesthetic. However, it should be noted that this method will not work with all PHN patients. In particular, if complete skin anesthesia does not result in complete pain relief, the patient is not a subject for treatment with customized intermittency.

All references cited herein are fully incorporated by reference. Having now fully described the invention, it will be understood by those of skill in the art that the invention may be performed within a wide and equivalent range of conditions, parameters and the like, without affecting the spirit or scope of the invention or any embodiment thereof.

Claims

What is Claimed is:

1. A drug delivery patch for the topical delivery of a biologically active agent, comprising; a) at least one drug delivery cell, comprising: i) an outer wall made of a solid inert material that completely surrounds and defines an internal space in said cell and which terminates at a top surface and a bottom rim; ii) a pharmaceutical composition located within said internal space and comprising a biologically active agent; and b) a flexible backing layer which is attached to the top surface of said drug delivery cell.

2. The drug delivery patch of claim 1, wherein said drug delivery cell is fused to said flexible backing layer or attached to it using an adhesive that is impermeable to air, water or said biologically active agent.

3. The drug delivery patch of claim 1, wherein the rim of said drug delivery cell distal to said flexible backing layer (the bottom rim) is covered with a removable covering to prevent the leakage or evaporation of said biologically active agent during storage and which is removed prior to use.

4. The drug delivery patch of claim 1, further comprising an absorbent material located in said internal space and saturated or partially saturated with said pharmaceutical composition.

5. The drug delivery patch of claim 4, wherein said biologically active agent is a topical anesthetic, topical nonsteroidal anti-inflammatory drug (indomethacin, diclofenac, ketoprofen, etc.) or any other topical agent.

6. The drug delivery patch of claim 5, wherein said topical anesthetic is lidocaine base.

7. The drug delivery patch of claim 1, wherein said pharmaceutical composition is in the form of a solution, gel, ointment or cream.

8. The drug delivery patch of claim 7, wherein said biologically active agent is a topical anesthetic.

9. The drug delivery patch of claim 8, wherein said topical anesthetic is lidocaine base.

10. The drug delivery patch of claim 1, wherein said flexible backing layer does not have any adhesive, apart from that used to attach said drug delivery cell.

11. The drug delivery patch of claim 1 , wherein said drug delivery patch comprises multiple drug delivery cells attached to said flexible backing layer and separated from one another by a gap of 1-10 mm.

12. The drug delivery patch of claim 11, wherein said drug delivery cells: a) are rectangular or square with a side length of 1-2 cm or are circular with a diameter of 1-2 cm; b) are 1-6 mm in height; c) have walls that are 0.5 to 2 mm thick; and d) are made of plastic.

13. The drug delivery patch of claim 1 , wherein a) said drug delivery patch comprises multiple drug delivery cells attached to said flexible backing layer and separated from one another by a gap of 1-10 mm; b) each drug delivery cell is fused to said flexible backing layer or attached to it using an adhesive and has a bottom rim that is covered with a removable film, foil or sheet to prevent the leakage or evaporation of said biologically active agent during storage and which is removed prior to use; c) said pharmaceutical composition comprises topical anesthetic as said biologically active agent.

14. The drug delivery patch of claim 13, said pharmaceutical composition comprises 2- 5% lidocaine base as said biologically active agent.

15. The drug delivery patch of claim 14, wherein said flexible backing layer does not have any adhesive, apart from that used to attach said drug delivery cell.

16. A method for topically administering a biologically active agent to a patient, comprising applying the drug delivery patch of any one of claim 1-15 to the skin of said patient such that said skin is compressed sufficiently by the rim of said cell to make the internal space of said cell impermeable to air, water and said biologically active agent.

17. The method of claim 16, wherein compressive pressure is applied solely by placing said drug delivery patch under an elastic bandage that is wrapped around said patient.

18. A method of treating a patient for shingles or postherpetic neuralgia (PHN) comprising: a) applying the drug delivery patch of any one of claims 13-15 to the skin of said patient such that said skin is compressed sufficiently by the rim of said cell to make the internal space of said cell impermeable to air, water and said biologically active agent and wherein said composition is applied for a duration sufficient to cause the complete anesthesia of the skin area exposed to said pharmaceutical composition; b) removing said drug delivery patch after complete anesthesia is attained; c) reapplying said drug delivery patch at intervals of 0.5-7 days.

19. The method of claim 18, wherein compressive pressure is applied solely by placing said drug delivery patch under an elastic bandage that is wrapped around said patient.

20. A method of treating PHN in patients in which complete anesthesia produces complete pain relief, comprising; a) topically applying sufficient anesthetic to cause complete skin numbing of the area treated; c) determining the time at which spontaneous pain reappears; d) reapplying said anesthetic at an interval that is shorter by 1/3-1/4 than the interval from the drug application to the time of pain reappearance.

21. The method of claim 20. wherein said anesthetic is lidocaine and is applied using the drug delivery patch of any one of claims 1-15.