WO2011028542A2

WO2011028542A2 - Methods of treating pain associated with complex regional pain syndrome

Info

Publication number: WO2011028542A2
Application number: PCT/US2010/046523
Authority: WO
Inventors: Jie Zhang; Andrew Crockett; Larry Rigby
Original assignee: Zars Pharma, Inc.
Priority date: 2009-08-24
Filing date: 2010-08-24
Publication date: 2011-03-10
Also published as: WO2011028542A3

Abstract

The present invention is drawn to methods for treating pain associated with complex regional pain syndrome. Specifically, a method for treating pain associated with complex regional pain syndrome includes the application of an analgesic system to a skin surface of a subject experiencing the pain and maintaining the analgesic system on the skin surface for a period of time of at least 30 minutes. The analgesic system applied to the skin surface can include a heating component and a local anesthetic formulation which includes at least one local anesthetic. The heating component can be capable of heating the skin surface to a temperature of 36°C to 42°C.

Description

METHODS OF TREATING PAIN ASSOCIATED WITH

COMPLEX REGIONAL PAIN SYNDROME

BACKGROUND OF THE INVENTION

Complex Regional Pain Syndrome (CRPS), which includes and sometimes used interchangeably with the term "reflex sympathetic dystrophy

(RSD)", is a chronic neurological syndrome characterized by severe burning pain and extreme sensitivity to touch, among other symptoms. Pain associated with complex regional pain syndrome is suffered by many people and is frequently treated with opioid and non-opioid analgesics. Unfortunately, these treatment options suffer from various drawbacks and undesirable side-effects. These undesirable side-effects are frequently due to their systemic delivery.

Accordingly, an effective topical analgesic system would be advantageous.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a schematic representation of an exemplary analgesic system in the form of a patch which can be used for treating pain associated with Complex regional pain syndrome. DETAILED DESCRIPTION

Before particular embodiments of the present invention are disclosed and described, it is to be understood that this invention is not limited to the particular process and materials disclosed herein as such may vary to some degree. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the present invention will be defined only by the appended claims and equivalents thereof. In describing and claiming the present invention, the following terminology will be used.

The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a local anesthetic" includes reference to one or more of such compositions.

"Skin" is defined to include human skin (intact, diseased, ulcerous, or broken), and mucosal surfaces that are usually at least partially exposed to air such as lips, genital and anal mucosa, and nasal and oral mucosa.

It is also noted that "local anesthetics" in appropriate formulations can be used to provide skin "anesthesia," which by medical definition means preventing a pain before it happens, such as preventing a pain caused by needle stick. The present disclosure, however, is related to methods of using a local anesthetic formulation to provide "analgesia," which by medical definition means to reduce or eliminate an existing pain, e.g., pain associated with complex regional pain syndrome.

The terms "controlled heating" and "controlled heat" are defined as heat application that is capable of heating a skin surface to pre-determined narrow temperature range for a predetermined duration. A controlled heating device that can be used in accordance with systems and methods of the present disclosure can be configured to generate heat promptly when activated. Controlled heating can be achieved through special design of the heating component. For example, controlled heating can be achieved through the use of a properly configured heating element(s) including an exothermic chemical composition.

Considerations in generating controlled heat with an exothermic heating component include proper ratios and exothermic chemical compositions used, as well as physical constraints put on the exothermic chemical compositions, e.g., limiting air flow or oxygen contact, spatial configuration of individual heating elements, conductivity of materials used with the exothermic chemical composition, etc. In one embodiment, the heating component can provide heat at a temperature greater than body temperature, but less than a temperature that would cause irreversible skin damage, e.g., burn the skin. An exemplary temperature range that can be implemented for use is from about 35°C to about 47°C. In one embodiment, another temperature range can be from about 36°C to 42°C. Other desired temperature ranges include from about 38°C to 42°C, or from 36°C to 40°C.

"Complex regional pain syndrome", which is used interchangeably with the term "reflex sympathetic dystrophy" in the current invention, has the same definition as that commonly used in modern medicine, namely a chronic pain condition, the primary symptom of which is continuous, intense pain, typically in the arms, legs, hands or feet, that is out of proportion to the severity of the injury and which gets worse rather than better over time. Accordingly, "pain associated with complex regional pain syndrome" is pain that is present in a subject as a result of complex regional pain syndromw.

As used herein, the term "about" is used to provide flexibility to a numerical range endpoint by providing that a given value may be "a little above" or "a little below" the endpoint. The degree of flexibility of this term can be dictated by the particular variable and would be within the knowledge of those skilled in the art to determine based on experience and the associated description herein.

As used herein, a plurality of local anesthetics, compounds, and/or heating mechanisms may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.

Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. Additionally, it is noted that all percentages are in weight, unless specified otherwise.

With this background in mind, the present disclosure is drawn to methods for treating pain associated with complex regional pain syndrome, also known as reflex sympathetic dystrophy. Specifically, a method for treating the pain associated with complex regional pain syndrome includes the application of an analgesic system to a skin surface of a subject experiencing the pain and maintaining the analgesic system on the skin surface for a period of time of at least 30 minutes. The application site is typically a skin area proximate the pain. The analgesic system applied to the skin surface can include a heating component and a local anesthetic formulation including at least one local anesthetic. The heating component can be capable of heating the skin surface to a temperature of 36 °C to 42 °C for a sustained period of time within this narrow temperature range.

The methods of the present disclosure can harness the benefits of both increased delivery of the local anesthetic and the therapeutic effect of heating. Furthermore, in some embodiments, the use of heat can actually improve the penetration and benefit of the local anesthetic(s) compared to the use of the same formulation without application of heat. Stated another way, the methods of the present application can provide enhanced transdermal delivery of the local anesthetic through the use of controlled heating, and the added benefit provided by the heat itself. As the skin is heated, the permeability of the skin to the local anesthetics drugs can increase. Additionally, the heating of the skin itself is also believed to reduce the existing pain. Accordingly, the combination of the transdermal delivery of the local anesthetic from the local anesthetic formulation with the heat from the heating component can cause a more efficient, i.e. faster and more effective, reduction in pain than either the drug or the heat alone.

As described above, the analgesic systems used in the methods of the present disclosure can comprise two major components: a controlled heating component and a local anesthetic formulation. The local anesthetic formulation can be incorporated in a patch and can include an amount of the local anesthetic to provide, with the help of the heating component, sufficient transdermal delivery of the local anesthetic for reducing or eliminating existing pain. A sufficient transdermal delivery of the local anesthetic is defined as a rate of delivery that is high enough to reduce the pain intensity (as measured by patient report of pain intensity) in an average patient by at least 20%, and often at least 30% or even 50%. With some patients and some conditions, complete pain relief can be achieved. The heating device can be configured for application over the patch and the human skin site. Additionally, the heating device can be configured to heat a skin site to which it is applied to a temperature that provides a therapeutic effect, such as from about 36 °C to about 42 °C. The heating device can further be capable of maintaining the skin within the above temperature range for a period of time of at least 30 minutes, or in other embodiments, at least 1 hour.

As stated, the analgesic systems of the present disclosure can include a local anesthetic formulation and a heating component. The local anesthetic formulation can be designed to transdermally deliver at least one local anesthetic. The local anesthetic can generally be any local anesthetic known in the art. In one embodiment, the local anesthetic can be selected from the group consisting of tetracaine, lidocaine, prilocaine, ropivacaine, bupivacaine, benzocaine, and combinations thereof. In another embodiment, the local anesthetic formulation can include lidocaine base. In another embodiment, the local anesthetic formulation can include tetracaine base. In yet a further embodiment, the local anesthetic formulation can include a eutectic mixture of lidocaine base and tetracaine base. In another embodiment, the local anesthetic formulation can comprise at least 30 wt% (alone or in combination) of total local anesthetic, e.g., at least 30 wt% of a 1 :1 (by weight) of a eutectic mixture of lidocaine and tetracaine (in combination), or at least 30 wt% of lidocaine or other local anesthetic base (alone). In still other embodiments, lower concentrations of local anesthetics can be used, e.g., at least 15 wt% local anesthetic, at least 20 wt% local anesthetic, or at least 25 wt% local anesthetic

The local anesthetic formulation may also include other ingredients and excipients such as polymers, emulsifiers, chemical permeation enhancers, water or other solvents, and preservatives. In one embodiment, the local anesthetic formulation can include a solidification polymer such as polyvinyl alcohol. In another embodiment, the local anesthetic formulation can include an adhesive polymer which is capable of adhering to skin.

The local anesthetic formulation portion of the analgesic system can have a skin contact region where the local anesthetic formulation contacts the skin surface. The size of the skin contact area can vary depending on the targeted region of the subject's body and the nature of the pain being treated. For example, in certain embodiments, the skin contact region can have an area of 2 cm² to 200 cm², 7 cm² to 150 cm², or 8 cm² to 15 cm². In various other embodiments, other size ranges may be appropriate. For example, the skin contact region can have an area of 3 cm² to 150 cm², 5 cm² to 130 cm², 6 cm² to 100 cm², 7 cm² to 80 cm², 8 cm² to 40 cm², or 8 to about 1 3 cm², etc. In one aspect of the disclosure, a layer of adhesive can be coated onto the analgesic outside the contact area, and/or between the skin and the local anesthetic formulation for affixing the system on the skin.

The heating components of the analgesic systems used in the method of the present application can be configured to raise the temperature of a skin surface to which the analgesic system is applied to a therapeutically effective temperature (for providing heat to the site and/or for providing enhanced drug delivery), e.g., about 36 °C to about 42 °C. The heating component can further be configured to maintain the temperature of the skin surface in the above range for a period of time of at least 30 minutes. In one embodiment, the heating component can be configured to maintain the skin surface in the above described temperature range for a period of at least 60 minutes. In still other embodiments, the heating component can be configured to maintain the skin surface in the above described temperature range for a period of at least 2 hours, 4 hours, 6 hours, 8 hours, or 12 hours.

It is noted that regardless of the duration of heating, the analgesic systems used in the methods of the present disclosure can be configured to relieve the pain associated with complex regional pain syndrome. The pain can be relieved for a period of time beyond the period of time in which the heating component heats and/or which the analgesic system is maintained on the skin surface. In one embodiment, the methods of the present disclosure can provide relief of existing pain for a period of time of at least 4 hours. In another embodiment, the relief of pain can be for a period of time of at least 6 hours. In another embodiment, the relief of pain can be for a period of time of at least 12 hours.

In yet another embodiment, the system can be used on a chronic basis (at least once a day for at least 75% of the days in a period of time lasting at least two weeks). In further embodiments, the system can be used more than once a day and for more than 2 weeks. The heating components of the analgesic systems used in the methods of the present disclosure can generate heat through a number of mechanisms or means. In one embodiment, the heating component can generate the heat through chemical-based exothermic reactions. Other heating mechanisms can also be used, such as heating by phase transition of supersaturated solutions (such as phase transition of sodium acetate solutions), radiation (microwave or infrared, for example), electricity-resistor, combinations thereof, and/or other heating sources. In one embodiment, the heating component can be an electric heating device. Such electric heating device can be powered by a variety of sources, for example, battery and/or alternating electric current. Electric devices can be configured to provide a predetermined heating profile so that the heating profile is met automatically after engaging or turning on the electric device, e.g., use of timers, programmed electricity supply, finite batter power, etc.

Alternatively, the heating profile can be met merely by providing heat at an appropriate temperature with an instruction to the user to remove the heating device after a specific period of time.

In one embodiment, the heating component can generate heat by an exothermic oxidative chemical reaction. The chemical-based exothermic oxidation reaction can generate heat through the contact of the oxidative material, e.g. iron, with ambient air. U.S. Patent No. 6,756,053, which is incorporated herein by reference in its entirety, describes examples of exothermic heating components and devices.

The amount of exothermic chemical composition in the heating component can vary from depending on the desired duration of heating and the size of the heating component. It can be beneficial to limit the amount of the exothermic chemical composition in the heating component, as a large amount of exothermic chemical composition can cause the heating component to be excessively large or cumbersome and impractical for use. In one aspect, the heating device can include up to 2 grams of an exothermic chemical composition and can be configured to heat an area of skin greater than about 8 cm².

In addition to the oxidizable component, the exothermic heating

composition can further include activated carbon, salt (such as sodium chloride), and water. In one aspect, a water-retaining substance, such as vermiculite or wood powder, can also be included in the heating component.

In one aspect, the exothermic chemical composition of the heating component can be manufactured in a manner so as to only have access to ambient oxygen through the holes in a cover that is made of air-impermeable material. In this way, the flow rate of oxygen from ambient air into the exothermic chemical composition, which in turn is a factor which can affect the amount and rate of heat generated by the heating component and the temperature of the skin surface on which the analgesic system is applied. Other factors which can influence the temperature and heat generation of the heating component can be the size of the heating component, the amount of the exothermic chemical composition in the heating component, the number and configuration of holes in the heating component's air impermeable cover material, etc.

By way of example, FIG. 1 is a schematic profile of one embodiment of an analgesic system which could be used in accordance with the methods of the present application. The analgesic system includes a heating component 34 and a local anesthetic formulation 30. The heating component includes an air- impermeable top cover film 20 having a plurality of holes 36 therein. When exposed to ambient air, the holes allow for the passage of the ambient air through the air-impermeable top cover film to the exothermic chemical composition 22. The layer of exothermic chemical composition is disposed between the air-impermeable top cover film and an adhesive film layer 24. The adhesive film layer extends beyond the circumference of the exothermic chemical composition layer and the local anesthetic formulation layer and can function, at least in part, to adhere to the analgesic system to a skin surface. A heat sealable film layer 26 is below to the adhesive film layer and acts to impede the transfer of substances, particularly moisture, between the local anesthetic formulation layer and the exothermic chemical composition layer. Below the heat sealable film layer, a sodium-borate coated non-woven film layer 28 acts aids in gelling the local anesthetic formulation during manufacturing. The entire analgesic system is adhered in an air and moisture impermeable packing tray 32 which holds the local anesthetic formulation during storage. EXAMPLES

The following examples illustrate the embodiments of the disclosure that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present disclosure. Numerous modifications and alternative compositions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope of the present disclosure. The appended claims are intended to cover such modifications and arrangements. Thus, while the present disclosure has been described above with particularity, the following examples provide

further detail in connection with what are presently deemed to be the most

practical and preferred embodiments of the disclosure.

Example 1 - System for treating pain associated with complex regional pain syndrome

The analgesic system described herein has two components: a drug

component (drug formulation composition in a patch) and a heating component.

Table 1 lists exemplary ingredients in the drug formulation. Table 2 lists

exemplary ingredients of the heat generating medium. The drug formulation of the system has a skin contact area of about 10 cm².

Table 1

Weight

Amount per

Ingredient percentage Function patch

(%)

Lidocaine base 20.00 70.00 mg Active ingredient

Tetracaine base 20.00 70.00 mg Active ingredient

Polyvinyl alchol (PVA) 7.20 25.20 mg Polymeric matrix

Sorbitan monopalmitate (Span 40) 3.00 10.50 mg Emulsifying agent

Purified Water 49.68 173.88 mg Solvent

Methyl parahydroxybenzoate 0.10 0.35 mg Preservative Propylparagydroxybenzoate 0.02 0.07 mg Preservative

Sodium-borate coated 10.84 cm² Gelling of drug nonwoven film formulation

Table 2

The physical configurations of the drug component and the heating component, and their integration, are schematically shown in FIG.1 . The heat generating medium is enclosed in a closed space as shown in FIG. 1 , and has access to the external environment only through the 6 holes on the air- impermeable cover. The diameter of each of the holes is about 1/16 of an inch. This heat generating medium can provide controlled heat at from 36 to 42 °C for a sustained period of time.

Example 2 - System for treating pain associated with complex regional pain syndrome

Four small analgesic systems described in Example 1 are prepared, except that the size of the patches are varied to have a skin contact area of 2 cm², 3 cm², 6 cm², and 8 cm², respectively. Thus, the weight percentages are the same for both the drug formulation (Table 1 ) and the heat generating medium (Table 2), but since the patches are smaller in size, the total amount of each ingredient is proportionally reduced. The number of holes or the size of the holes is also modified so that the total hole area (number of holes times the surface area of each hole) is adjusted proportionally in order to achieve a similar heating profile for the patch size, e.g., 1 -6 holes of similar or slightly different size.

Example 3 - System for treating pain associated with complex regional pain syndrome

Four large analgesic systems described in Example 1 are prepared, except that the size of the patches are varied to have a skin contact area of 40 cm², 60 cm², 120 cm², 180 cm², respectively. Thus, the weight percentages are the same for both the drug formulation (Table 1 ) and the heat generating medium (Table 2), but since the patches are much larger in size, the total amount of each ingredient is proportionally increased. The number of holes or the size of the holes is also adjusted proportionally in order to achieve a similar heating profile for the patch size. The number of holes or the size of the holes is also modified so that the total hole area (number of holes times the surface area of each hole) is adjusted proportionally in order to achieve a similar heating profile for the patch size, e.g., 12-100 holes of similar or slightly different size.

Example 4 - System for treating pain associated with complex regional pain syndrome

An analgesic systems described in Example 1 is prepared, except that 40 wt% lidocaine base is used rather than 40 wt% of eutectic mixture of lidocaine and tetracaine base. Also, the patch size is modified to be 120 cm². Thus, the weight percentages are the same for both the drug formulation (Table 1 ) and the heat generating medium (Table 2), but since the patch is larger in size, the total amount of each ingredient is proportionally increased. The number of holes or the size of the holes is also modified so that the total hole area (number of holes times the surface area of each hole) is adjusted proportionally in order to achieve a similar heating profile for the patch size, e.g., 40-80 holes of similar or slightly different size.

Example 5 - System for treating pain associated with complex regional pain syndrome

An analgesic systems described in Example 1 is prepared, except that 40 wt% ropivacaine base is used rather than 40 wt% of eutectic mixture of lidocaine and tetracaine base. Also, the patch size is modified to be 120 cm². Thus, the weight percentages are the same for both the drug formulation (Table 1 ) and the heat generating medium (Table 2), but since the patch is larger in size, the total amount of each ingredient is proportionally increased. The number of holes or the size of the holes is modified so that the total hole area (number of holes times the surface area of each hole) is adjusted proportionally in order to achieve a similar heating profile for the patch size, e.g., 40-80 holes of similar or slightly different size. Example 6 - System for treating pain associated with complex regional pain syndrome

An analgesic systems described in Example 1 is prepared, except that the heat generating medium is from an electric heating device, and the patch size is modified to 120 cm². Thus, the weight percentage is the same for the drug formulation (Table 1 ), but since the patch is larger in size, the total amount of each ingredient is proportionally increased.

Example 7 - Treating pain associated with complex regional pain syndrome

A patient is suffering from severe pain associated with complex regional pain syndrome in his neck. An analgesic system similar to that described in Example 1 is applied to the neck twice daily (every 12 hours) for two hours each time, which reduces the pain and enables her to discontinue the oral pain medications.

Example 8 - Treating pain associated with complex regional pain syndrome

A patient experiencing pain associated with complex regional pain syndrome in his arm is treated with an analgesic system similar to that in

Example 1 . The analgesic system is applied to the skin site under which the pain exists and removed after one hour. Pain relief is obtained within 30 minutes following the commencement of the application and lasted 10-12 hours.

Example 9 - Treating pain associated with complex regional pain syndrome

Same as that described in Example 7, except that the analgesic system is similar to that described in Example 2 with a skin contact area of 6 cm².

Example 10 - Treating pain associated with complex regional pain syndrome

Same as that described in Example 8, except that the analgesic system similar to that described in Example 3 with a skin contact area of 40 cm²

It is noted in the above examples that various skin contact area sizes, drug choices, methods of treating specific conditions, etc., are provided for exemplary purposes only. The ranges and choices described in the specification more accurately reflect the appropriate ranges of choices for treating subjects. Thus, while the invention has been described with reference to certain embodiments, those skilled in the art will appreciate that various modifications, changes, omissions, and substitutions can be made without departing from the spirit of the invention. It is therefore intended that the invention be limited only by the scope of the appended claims.

Claims

What Is Claimed Is: 1 . A method for treating pain associated with complex regional pain syndrome , comprising:

a) applying an analgesic system to a skin surface of a subject

experiencing pain associated with complex regional pain syndrome , said analgesic system comprising:

i) a heating component capable of heating the skin surface to a temperature of 36 °C to 42 °C, and

ii) a local anesthetic formulation including at least one local anesthetic; and

b) maintaining the analgesic system on the skin surface for a period of time of at least 30 minutes.

2. The method of claim 1 , wherein the heating component begins heating at about the same time as the analgesic system is applied to the skin surface.

3. The method of claim 1 , wherein the local anesthetic is selected from the group of tetracaine, lidocaine, prilocaine, ropivacaine, bupivacaine, benzocaine, and combinations thereof.

4. The method of claim 1 , wherein the local anesthetic formulation includes at least one of lidocaine base or tetracaine base.

5. The method of claim 1 , wherein the local anesthetic is a eutectic mixture of lidocaine base and tetracaine base.

6. The method of claim 5, wherein the weight percentage of the eutectic mixture is at least 30 wt% of the local anesthetic formulation.

7. The method of claim 1 , wherein the analgesic system is maintained on the skin surface for a period of time of at least 60 minutes.

8. The method of claim 1 , wherein the analgesic system is maintained on the skin surface for a period of time of about two hours.

9. The method of claim 1 , wherein the local anesthetic formulation has a skin contact area of 2 cm² to 200 cm².

10. The method of claim 1 , wherein the local anesthetic formulation has a skin contact area of 7 cm² to 1 50 cm².

1 1 . The method of claim 1 , wherein the local anesthetic formulation has a skin contact region, said skin contact region having an area of 8 cm² to 15 cm².

12. The method of claim 1 , wherein the local anesthetic formulation is applied to the skin surface directly over a site of the pain associated with complex regional pain syndrome.