Therapeutic Method to Reduce Pain and Inflammation

This invention pertains to a new method for treating pain, inflammation, trauma, allergy, and disease by the topical application of a therapeutic agent having previously unrecognized analgesic, anti-allergenic, and anti-inflammatory properties, or by the topical application of the same agent in combination with a second therapeutic agent, the effectiveness of which is enhanced by the first agent.

As stated in the publication of Texaco Chemical Company entitled "Ethylene Carbonate-Propylene Carbonate," "Propylene Carbonate is a clear, mobile, practically odorless liquid." It is 4-methyl 2-dioxolone, a cyclic organic ester which is a known solvent for a variety of polar and non-polar organic compounds and for many inorganic chemical and biological materials. Its chemical properties include low toxicity. The same publication further indicates that propylene carbonate is an excellent additive for certain clays and gel bases useful in cosmetic and personal care products. Still further, the publication refers to acute toxicity tests which indicate that propylene carbonate is practically non-toxic and is otherwise indicated to be non-offensive in subchronic dermal applications, skin sensitization tests and inhalation tests, though temporarily offensive to a minor degree to the eyes.

The Texaco publication also includes a extensive bibliography, including an applications section entitled "Cosmetics and Personal Care," in which four patent references and three literature references are noted.

No indication whatsoever is found in the above-referenced Texaco publication to suggest, in any way, the possible utility of propylene carbonate as a therapeutic agent for treating pain, inflammation, trauma, allergy, or disease.

A search has been conducted in the U.S. Patent and Trademark Office to identify references relating to or disclosing the use of propylene carbonate for essentially any pharmaceutical purpose. Patents identified in this search were:

The first three of the above-listed patents are listed in the Application-Cosmetics and Personal Care subsection of the bibliography in the above-referenced Texaco Chemical Company publication (page 24). The primary focus of Kudla is on ethylene carbonate rather than propylene carbonate. It will also be noted that the remaining references in that bibliography subsection all deal only with hair-treatment preparations. The patents on Chang, Shastri et al., and Kudla all relate to topical ointment compositions in which, generally, propylene carbonate or ethylene carbonate is combined with co-solvents or with other constituents, such that only a minor proportion of propylene carbonate is included in each composition, generally less than 40% in Chang and 30% in Shastri, for example. The compositions, in which propylene carbonate is incorporated in accordance with the teachings of these patents, each include specific therapeutic agents, such as anti-biotics, steroids, antihistamines, antiseptics, anesthetics, and corticosteroids.

The D'Alelio patent relates to the use of propylene carbonate in removing dental calculus, relying on its non-toxic solvent function for swelling the organic binder phase of the calculus.

Alvarez is directed to novel anti-inflammatory agents. It indicates, however, that such agents may be combined with a "pharmaceutically acceptable solvent," among particularly suitable examples of which is listed propylene carbonate. As in other applications of this type, the carbonate is generally carried in a semi-solid emulsion of oil and water, or water in oil including, for example, white petrolatum.

The Stache patent was cited apparently for its teaching of various carbonate-containing steroids useful in veterinary and human therapy. Notably absent, according to Applicants' reading of this patent, is any suggestion of the use of propylene carbonate in any manner different than that suggested in the other prior art references, cited above.

In addition to the foregoing, Applicants are aware of certain unpublished non-clinical work of others. Applicants' limited knowledge of this work prior to the present invention, indicated that propylene carbonate had been considered only for possible use as a rapid surface skin-penetrating carrier for a topically applied composition, namely suntan lotion, the objective of which was to eliminate the greasy surface feel commonly associated with existing suntan lotion. It is not known whether any such suntan lotion was ever prepared.

Notwithstanding prior knowledge of propylene carbonate and its limited use as a vehicle in topical medicaments, and notwithstanding the unpublished work of others suggesting propylene carbonate as a vehicle for suntan lotion, there remains a continuing need for more effective methods of therapy to relieve pain and inflammation and to treat trauma, allergy, and disease. This need has not been addressed in the art pertaining to propylene carbonate.

It is, therefore, the general object of the present invention to provide such a method by the topical application of a hitherto unrecognized therapeutic agent, either alone or in combination with a second agent, the therapeutic effectiveness of which is enhanced by the first agent.

The present invention comprises a method to reduce pain and inflammation in surface tissue and in deep or sub-dermal tissue, such as bone, muscle, ligaments, or joints, of a human or veterinary patient by topical application, in the patient's skin or mucous membrane proximate the pain or inflammation, of a therapeutically effective amount of a medicament comprising propylene carbonate. The present invention also comprises a method to treat trauma, allergy or disease by the topical application of propylene carbonate, in combination with a second therapeutic agent appropriate to the trauma or allergy or disease, the effectiveness of which is enhanced by the propylene carbonate.

As contrasted with prior art compositions in which limited amounts of propylene carbonate have been used as a vehicle or carrier for other pharmaceutical agents, the present invention involves a therapeutic method in which propylene carbonate is not merely a vehicle but a primary medicament. While the therapeutic composition used in the method of this invention may include other constituents, either as a stabilizer for the propylene carbonate or as a co-reactive medicament, the present invention has been found effective even in the absence of such stabilizers and co-reactive medicaments.

Thus, in most of the clinical tests described below, the effective therapeutical agent consisted essentially or entirely of propylene carbonate. These tests clearly demonstrate the hitherto unrecognized effectiveness of propylene carbonate as a therapeutic agent. Certain of the tests described below also demonstrate the effectiveness of propylene carbonate as a potentiating agent for a second or co-reactive medicament.

Technical explanations for the surprising results in the clinical tests of the present invention described below are speculative. Accordingly, Applicants do not wish to be bound by any such explanations. However, certain unique characteristics of propylene carbonate seem to be particularly significant.

First, the solvent properties of propylene carbonate are well known. Because of these properties, it has been used or proposed as a vehicle or carrier in a number of topically applied medicinal and cosmetic compositions. These same solvent properties, however, apparently based on the chemical affinity of propylene carbonate for a wide range of other chemical compounds, also make it appropriate as a penetrant. But enhanced penetrating properties due to the propylene carbonate constituent has not been a recognized characteristic of known propylene carbonate-containing medicinal and cosmetic compositions. Applicants now surmise this is because all such compositions include oils, fats, or emulsifiers, in addition to the propylene carbonate. These oils, fats, and emulsifiers are thought to inhibit the penetrating ability and mobility of propylene carbonate. In this respect, the "Comparative Example" discussed below is of interest.

As presently understood then, an important factor in the present invention is the absence, in the topically applied medicament used in this invention, of any penetration inhibiting constituent. This is believed to be important because it apparently enables the propylene carbonate, with its penetrating ability uninhibited, to migrate quickly to the sub-dermal region where its therapeutic value, and/or the therapeutic value of any co-reactive medicament with which it is combined, is expeditiously realized.

A second important characteristic of propylene carbonate, for purposes of the present invention, is thought to be the biological/chemical process by which it degrades through one or more free radical stages to non-toxic final products, namely propylene glycol and carbon dioxide. This may be of significance for two reasons. Primarily, if the final degradation products are innocuous, adverse long range side effects, caused by accumulated by-products, are unlikely. Secondly, the free radical intermediate products, through which propylene carbonate apparently degrades in the body, may function as metabolic accelerators and as nerve cell transmission blockers, resulting respectively in the enhancement of other normal bodily functions dependent on metabolic reactions and in the inhibition of neuro transmission of pain impulses to the brain. The latter may provide symptomatic relief of pain while the former may enhance the normal physiological tendency of a body member to counteract the abnormality, whether it be allergy, inflammation, trauma, or disease.

The accelerated metabolic activity associated with propylene carbonate degradation in the body may also be responsible for the enhanced effectiveness of other co-reactive medications administered in combination with propylene carbonate. For example, the clinical tests described below include several cases in which a solution of propylene carbonate with a co-reactive agent (namely aspirin, iodine, and penicillin, respectively, in separate tests) was used. Positive clinical therapeutic results were obtained in each case. The effectiveness of all three of these medications was apparently enhanced by the presence of propylene carbonate. The apparently improved pharmacologic responses suggest that only a reduced dosage of each medication would be needed in order to produce the desired therapeutic effect. An especially striking example was the case in which a solution of propylene carbonate and penicillin was applied locally to an abcessed tooth and gum (Test 73, below).

In Table I, below, are listed a number of clinical tests in which propylene carbonate was used alone, and in which almost immediate relief from pain, swelling, inflammation, and allergic phenomenon was obtained. Relief from pain usually lasted from 4 to 6 hours which coincides in general with the period of time believed to be required for the degradation of propylene carbonate in the body. In some of the clinical examples, repeated applications of propylene carbonate were necessary in order to obtain relief from pain; in others, prolonged relief was provided after only one application; in still others, continued use of propylene carbonate resulted in prolonged relief as more specifically indicated below. At least, temporary relief from pain, and at best, prolonged remission was obtained by the topical application of propylene carbonate alone. This was especially so in instances where pain and inflammation were associated with joint and muscle trauma, osteoarthritis, bursitis, tendonitis, sprains, hematomas, fractures, torn ligaments and muscles. In those instances where pain returned (although generally lessened) within 4 to 6 hours, repeated application of propylene carbonate seemed to hasten ultimate complete recovery.

In addition, a number of dermatologic conditions have been treated, as reported below in Table II (Tests 60-70 and 74) with propylene carbonate alone and with propylene carbonate in combination with a second therapeutic agent.

Test 73 involved treatment of a specific tooth and gum condition in a manner to demonstrate specifically the potentiating effect of propylene carbonate in combination with penicillin.

In general, the variety of clinical applications in which propylene carbonate has been tested and found to be useful include: as an anti-inflammatory, an anti-allergenic, a carrier of other therapeutic agents, and as a potentiating agent for other therapeutic agents. The types of co-reactive therapeutic agents with which propylene carbonate has been used include analgesics (e.g., aspirin), antibiotics (e.g., penicillin), and anti-septics (e.g., iodine). Other possible co-reactive medicaments include steroids, cortico-steriods, and anti-histamines.

In addition, the unusual effectiveness (i.e., quick remission) on virus infections and allergic manifestations noted to date suggests that propylene carbonate may have some special effects on histaminic and immunologic systems in the body, thereby, presaging an even wider spectrum of medical applications for this compound.

Among dermatologic and trauma-related conditions which may be treated with propylene carbonate, either alone or in combination with other drugs, are eczemas, burns, lesions, abrasions, incisions, allergies, and infectious disorders such as herpes, scabies, or even psoriatic conditions.

The results of Test 73 indicate that propylene carbonate, in combination with penicillin, is aparently more effective in the treatment of an abscessed tooth and gum (to cause remission of the infectious condition) than either penicillin or propylene carbonate alone. This occurred after the abscess remained resistant to systemic treatment with Tetracycline and SKF Pen VK penicillin. Upon topical application of a solution of propylene carbonate and Pen VK, the abscess showed signs of remission within a week. Upon a second application a week later in conjunction with systemic penicillin treatment, complete remission of the infection resulted.

The results of the other tests reported in Table II may be summarized as follows:

POISON IVY. Upon topical application of propylene carbonate, the poison ivy infected area dried in the same day and was prevented from spreading to other areas. Itching stopped within minutes; the condition healed within a few days without leaving the skin discoloration usually seen as a post-poison ivy condition. This also suggests that propylene carbonate, when applied to other types of lesions of the skin, may accelerate healing and help to minimize scarring.

HERPES SIMPLEX-1 (viral infection). Upon topical application of propylene carbonate to the affected skin area, healing occurred within a few days and did not spread to contiguous areas. Itching stopped immediately and the condition healed within a few days rather than in the usual 7 to 10 days, which occurs without treatment. This suggests the possible efficacy of the use of propylene carbonate in the treatment of the lesions of genital herpes, and the use of propylene carbonate in treating other virus-related conditions.

URTICARIA. Upon the topical application of propylene carbonate to urticaria of the face, the allergic manifestation disappeared within a few hours, apparently acting as an antihistamine.

BURNS. Propylene carbonate was applied topically to first degree burns; pain was immediately relieved, and blistering was prevented. Healing occurred within 2 days.

INFECTED SKIN ULCERATIONS. Upon topical treatment with propylene carbonate the condition healed over a period of 3 days with minimal scarring noted 3 weeks after healing. This condition had been resistant to healing with A & D ointment & Furacin for 2 weeks prior to the use of propylene carbonate.

ACNE VULGARIS (seven cases). By topical application of a solution of 1000 PPM Iodine in propylene carbonate or 2000 PPM Iodine in propylene carbonate, the Acne conditions showed considerable to complete remission. These clinical examples demonstrate the ability of propylene carbonate in combination with a second therapeutic agent, to act as a potentiator as well as a vehicle for that agent.

The only known medicament listed in the Physicians' Desk Reference (Medical Economics Company, Inc., Oradell, NJ: 1982) which includes propylene carbonate is Lidex Ointment, manufactured and sold by Syntex, Inc. of Palo Alto, CA, the apparent assignee of the above-referenced Chang, Shastri, and Alvarez patents. According to the 1982 Physicians' Desk Reference, and the literature distributed with Lidex Ointment, it is composed of "Fluocinonide 0.5 mg/g, in a specially formulated ointment based consisting of Amerchol Cab (mixture of sterols and higher alcohols), white petrolatum, propylene carbonate, and propylene glycol. It provides the occlusive and emollient effects desirable in an ointment. In these formulations, the active ingredient is totally in solution." It is said to be effective in the relief of inflammatory manifestations of corticosteroid-responsive dermatoses.

For purposes of comparison with the present invention, Lidex Ointment was topically administered to test case #31-A 61 year old female with osteoarthritis of the hands (Test #31 in Table I above). No relief from the pain occurred when Lidex Ointment was applied to her left hand. Simultaneously, propylene carbonate was applied to her right hand resulting in immediate relief from pain. Additionally, when 100% propylene carbonate was applied over the Lidex Ointment on the left hand, no relief from the pain was obtained presumably because propylene carbonate could not penetrate the Lidex Ointment.

Thereafter, this same patient was made the subject of a clinical test of the present invention, with good results as indicated in Test #31b of Table I.

This significantly better result, obtained using the present invention, is considered to be a dramatic demonstration of the efficacy of the present invention. Moreover, this result is in sharp contrast to the result obtained using a composition, apparently typical of the prior art, in which propylene carbonate is present only in a minor amount and in combination with other solvents, vehicles, and medicaments.

While this invention has been described with reference to specific embodiments thereof, the appended claims are intended to be construed to extend not only to these embodiments and forms of the invention but to such other forms and embodiments as may be devised by those skilled in the art, without departing from the true spirit and scope of the invention.