WO1988004927A1

WO1988004927A1 - Compositions and formulations containing folic acid, method of treating tissue with folic acid and method for preparing compositions and formulations of folic acid

Info

Publication number: WO1988004927A1
Application number: PCT/US1987/003496
Authority: WO
Inventors: David M. Garrett; Wallace R. Robin
Original assignee: Davirand, Inc.
Priority date: 1986-12-31
Filing date: 1987-12-31
Publication date: 1988-07-14

Abstract

A composition and formulation for relieving pain and enhancing the healing process of wounded tissue including an effective amount of folic acid in a water miscible base carrier. The amount of folic acid effective for purposes of relieving pain and enhancing the healing process of wounded tissue preferably falls within the range of 0.1 to 0.5 % by total weight of the composition, and most preferably is present in 0.2 % by total weight of the composition. A method for relieving pain and enhancing the healing of wounded tissue involves applying a composition of folic acid in a water miscible base carrier to the wounded tissue. A method for preparing compositions and formulations for relieving pain and enhancing the healing of wounded tissue involves first preparing a water miscible base carrier and then incorporating folic acid into the preparation followed by mixing to produce a thixotropic paste-like composition.

Description

COMPOSITIONS AND FORMULATIONS CONTAINING FOLIC ACID, METHOD OF TREATING TISSUE WITH FOLIC ACID AND METHOD FOR PREPARING COMPOSITIONS AND FORMULATIONS OF FOLIC ACID

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to compositions and formulations used to treat wounded tissue. In particular, the present invention is directed to treating damaged or disrupted tissue with folic acid compositions and formulations for the purpose of reducing and eliminating pain associated with the ^■ condition and to enhance the healing of the tissue. The present invention is directed to a composition containing an effective amount of folic acid in an acceptable pharmaceutical carrier preparation for application to wounded tissue. Specifically, the present invention is directed to a composition containing an effective amount of folic acid in an acceptable pharmaceutical water miscible carrier preparation -for topical application to wounded tissue. 2. Discussion of Background and Material Information

The relief of pain and promotion of healing of wounds resulting from injuries and diseases have been an age-old concern. Although those practicing in the fields of medicine and pharmacy have developed over the years numerous compositions and formulations for treating such conditions, a panacea has not been discovered. Thus, the quest to develop new and improved compositions and formulations for alleviating problems associated with such conditions is a continuing and constantly developing area of technology. Although there are a number of topical anesthetics which are recognized for their effects in relieving the sensation of pain, such topical anesthetics are not generally acceptable for use as therapeutic agents for a variety of reasons. In particular, conventional anesthetics, such as amides which include lidocaine, amino benzoate esters which include benzocaine, and nonamide, nonaminobenzoa e esters which include benzyl alcohol, are usually not helpful because they are relatively ineffective if applied to epidermis that has an intact barrier layer and even on inflammed skin. Of these, only agents containing benzocaine have been shown to be positively useful in this regard, with the more effective drugs, e.g., benzocaine, being potential allergenic sensitizers. Thus, notwithstanding that a wide range of local anesthetics are commercially available, most are relatively ineffectual in relieving burn discomfort or preventing epidermal pain except for benzocaine used in concentrations greater than about 10%, and even benzocaine does not appear to have a therapeutic effect.

A number of agents which promote the healing of wounds are known. For example, U.S. Patent 3,232,836, CARLOZZI et al., shows that N-acεtyl glucosamine and related compounds facilitate the healing of body wounds in humans and animals. Typically, however, such agents which are effective in healing wounds do not function as an immediate pain reliever. Although the pain associated with damaged tissue may subside after a period of time upon applying therapeutic agents, this occurs as a resulting of the healing process of the wound rather than being a direct effect of the therapeutic agent. Over the years, the beneficial effects of folic acid on various physical conditions have been recognized. For example, in the J. Am. Med. Assoc., 212:3140315 (Apr. 13) 1970, relatively low dosages of methot exate, a folic acid antagonist, have been found to effectively suppress the signs and symptoms of psoriasis, but was not found to be effective to cure the disease nor induce remissions in most cases. G. D. Weinstein in the article entitled "Three Decades of Folic Acid Antagonists in Dermatology" published in Arch. Dermatll., 1983, 119-6 (525-527), U.S.A., indicates that methotrexate is an effective drug given systemically for the treatment of psoriasis which has been found to be superior to other potential antipsoriatic drugs, such as azaribine and micophenolic acid. F. INOUE et al., of Prince Edward Heights Ministry of Community and Social Services, P.O. Box 440, Picton, Ontario, Canada KOK 2T0, in their article entitled "Folic Acid and Phenytoine Hyperplasia", reported on the relationship between folic acid serum levels and phenytoine induced gingival hyperplasia, and concluded that folic acid supplementation accompanied by good oral hygiene may help to prevent gingival hyperplasia in patients taking long term phenytoine.

In addition to the foregoing, preparations of folic acid have also been used systemically as hemotopoietic agents for the treatment of megalobalastic anemias, anemias associated with pregnancy, sprew, and related malabsorption syndroms. Moreover, folic acid has been administered as a vitamin supplement to patients exhibiting a depletion of folate reserves associated with oral contraceptive and anticonvulsant drug therapy and chronic alcoholism.

Recently, Applicants were awarded U.S. Patent No. 4,393,066 for their invention relating to the method for treatment of herpetic lesions through the topical administration to the lesion site and surrounding tissue area of a patient suffering from such lesions of an amount of folic acid effective for treating the lesions. In this patent, Applicants disclose the effectiveness of folic acid on various vesicular lesions which are identified as herpes simplex type I, herpes simplex type II, herpes zoster, and aphthous ulcers and disclose that the methods of their invention could be potentially useful for treating other vesicular lesions including those lesions associ'ated with chicken pox, measles, impetigo, acne, poison ivy, and poison oak. As disclosed, in the normal course of treatment employing the methods of the invention claimed in U.S. Patent 4,393,066, immediate relief of pain on the order of minutes was noted upon the application of the folic acid preparation to the lesion site and surrounding tissue area of a patient suffering herpetic lesions. It was also observed that the analgesic effect provided by the folic acid preparation was not unlike the anesthetic effect provided by preparation such as lidocaine, xylocaine or benzocaine, except that pain relief was observed not to be as immediate with folic acid preparations as would normally be effected by classical anesthetics.

Through Applicant's knowledge, however, folic acid in the manner specified in this application has not heretofore been used for the general treatment of inflammed or wounded tissue.

SUMMARY OF THE INVENTION An object of the present invention is the provision of compositions and formulations containing amounts of folic acid effective to relieve pain and enhance healing of inflammed or wounded tissue in a water miscible base carrier.

Another object of the present invention is to provide compositions and formulations containing folic acid in amounts within the range of .01 to 15% effective in relieving pain and enhancing healing of inflammed or wounded tissue in preferably a water miscible base preparation.

Another further object of the present invention is the provision of compositions and formulations containing 0.2% by total weight of folic acid for relieving pain and enhancing the healing of inflammed or wounded tissue.

A yet still further object of the present invention is the provision of compositions and formulations containing 0.2% folic acid and a carrier composed of 5.0% mineral oil (CAS) (#8012-95-1), 4.5% steric acid (#5-7-11-4), 2T.5% cetyl alcohol (#36653-82-4), 1.5% triethanola ine (TEA) (#102-71- 6), 0.15% methyl paraben (#99-76-3) , 0.05% propyl paraben (#94-13-3) , and water for use in relieving pain and enhancing the healing of inflammed or wounded tissue. It is another object of the present invention to provide a process for relieving pain and enhancing the healing of inflammed or wounded tissue which involves applying compositions and formulations containing an effective amount of folic acid in a water base preparations to the inflammed or wounded tissue. It is yet another object of the present invention to provide a method of using a composition containing 0.2% folic acid and a carrier composed of 5.0% mineral oil (CAS) (#8012-95-1) . 4.5% steric acid (#5-7-11-4), 3.5% cetyl alcohol (#36653-82-4), 1.5% triethanolamine (TEA) (#102-71- 6), 0.15% methyl paraben (#99-76-3), 0.05% propyl paraben (#94-13-3) , and water to relieve pain and enhance the healing of inflammed or wounded tissue.

It is yet a still further object of the present invention to provide a method of using compositions and formulations containing folic acid in amounts within the range of .01 to 15% by total weight in a water miscible base carrier preparation to relieve pain and enhance the healing of inflammed or wounded tissue.

It is yet another still further object of the present invention to provide a method for treating wounded tissue with a composition containing 0.2% folic acid as an active ingredient and a carrier composed of 5.0% mineral oil (CAS) (#8012-95-1) . 4.5% steric acid (#5-7-11-4), 3.5% cetyl alcohol (#36653-82-4), 1.5% triethanolamine (TEA) (#102-71- 6), 0.15% methyl paraben (#99-76-3), 0.05% propyl paraben (#94-13-3) , and water to relieve pain and enhance the healing of inflammed or wounded tissue.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS The present invention is based on the discovery that folic acid used in effective amounts in a composition or formulation which does not include components which interfere with the pain relieving and healing effects of folic acid, can be used to treat tissue resulting from a wide variety of accidents, illnesses, diseases and conditions, not only herpatic lesions. The structure and formula of pteroylglutamic acid (PteGlu-_j_) is shown in the following general structure :

As shown, major portions of the molecule include a pteridine ring linked by a methylene bridge to para-aminobenzoic acid, which is joined by an amide linkage to glutamic acid. While pteroyl-glutamic acid is the common pharmaceutical form of folic acid, it is neither the principle folate congener in food, nor the active cσenzyme for intracεllular metabolism. In addition to naturally derived sources, several synthetic mechanisms yielding folic acid have been described in the scientific literature and patents, see for example U.S.

Patent Nos. 2,786,056; 2,816,109,* 2,821,527; and 2,821,528.

Notwithstanding the use of the term "folic acid" herein, folic acid is intended to be a collective generic term for each of the various conjugates of folic acid, including substances commonly known as folacin, folanic acid, citrovorum factor, leucovorin, pteroylglutamic acid, either taken singly or in combination, and pharmaceutically acceptable salts thereof.

The particular source of folic acid is not critical for purposes of the present invention. Thus, commercially available forms of folic acid may be used in the practice of the present invention in amounts which prpvide the appropriate concentrations of folic acid in the ultimate composition and formulation to be used for treatment of the wounded tissue. An example of folic acid which may be utilized in the practice of the present invention is folic acid sold under the trademark Folvite by Lederle Laboratories, a division of American Cyanamid Co., Pearl River, New York. Any source of folic acid which conforms to USP standards, however, may be used in the preparation of the composition and formulation of the present invention. Preferably, a pure form of folic acid is incorporated into the carrier preparation. One of the advantages of doing so is that subsequent treatment of commercially available folic acid, for example in the form of tablets which require crushing or pulverizing, prior to admixture with the carrier can be eliminated so that the resultant composition and formulation is more easily formed into an homogenous mixture including the folic acid.

The compositions and formulations for treatment in accordance with the present invention include folic acid incorporated into a water miscible base preparation used as a carrier. The concentration of folic acid in the preparation preferably falls within the range of 0.1 to 0.5% by total weight, and is more preferably present in a concentration of 0.2% by weight.

Various media have previously been considered as pharmaceutical vehicles or carriers for incorporating folic acid, including but not limited to aqueous solutions and suspensions, alcoholic solutions and suspensions, lotions, creams and ointments. It has been found that for treatment in accordance with the present invention as described herein, however, that a water miscible base preparation such as greaseless, stainless vanishing cream formulations should preferably be used as the carrier. In any event, petroleum- based salves and ointments have been found to be less suitable for purposes of preparing the composition and formulation for treatment in accordance with the present invention. Although not wishing to be bound by any particular theory, it is believed that petroleum-base ingredients interfere with the action of folic acid. In this regard, suitable water miscible base preparations include mineral oil, steric acid, cetyl alcohol, triethanolamine, methyl paraben, propyl paraben and water

The compositions and formulations containing folic acid in water miscible base preparation of the present invention are manufactured by first preparing the water miscible base preparation prior to incorporating the folic acid into the carrier preparation. In the manufacture of water miscible base preparation, the components are blended together and mixed to form an aqueous solution of the components. During the mixing operation, the blend of components- are typically subjected to temperatures within the range of 70 to 75°C. If folic acid is blended together with the other components of the water miscible base carrier preparation at the above temperature range, the resultant composition and formulation containing folic acid has been found to be noneffective in relieving pain and enhancing healing when the resultant compositions and formulations are topically applied to inflammed or wounded tissue. Although not wishing to be bound by any particular theory, it is believed that the heat used during the manufacture of water miscible base preparations adversely affects, i.e. by inactivating, the folic acid, possibly by breaking down the molecules of folic acid, so as to render the folic acid ineffectual for the goals intended to be achieved by the present invention. Thus, it is extremely important that the folic acid be incorporated into the water miscible base carrier preparation only after the manufacture of the preparation involving the use of heat has been completed, or using a procedure to prepare carrier preparations which do not involve the use of heat.

The following example describes the preparation of the preferred compositions and formulations for use in accordance with the present invention. For example, water miscible base preparations are manufactured by initially forming a mixture of mineral oil (CAS) (#8012-95-1) , steric acid (#5-7-14-4) , cetyl alcohol (#36653-82-4) , triethanolamine (TEA) (#102-71-6) , methyl paraben (#99-76- 3), propyl paraben (#94-13-3), and water, which is stirred in a mechanical mixer at temperatures within the range of 70 to 75° C to produce a solution of the components. After the solution is permitted to cool to about room temperature or to a temperature preferably below about 38° C, a suitable amount of folic acid is added to the solution and stirred at high speed until homogenized to produce a thixotrophic, paste-like composition containing folic acid.

In the preferred embodiment, the previously described procedure is used to prepare a composition or formulation containing 0.2% folic acid, 5.0% mineral oil, 4.5% steric acid, 3.5% cetyl alcohol, 1.5% triethanolamine, 0.15% methyl paraben, 0.05% propyl paraben, with the remainder of the composition being water. Although the previously listed components are preferred for the manufacture of water miscible base carrier preparations for the folic acid treatment composition in accordance with the present invention, it should be understood that the carrier preparations may include other components, conventionally used in the manufacture of pharmaceutical carrier base preparations, so long as the preparations do not include an amount of petroleum-based or other components which would interfere with the efficacy of the folic acid. As used herein, when reference is made to the folic acid treatment composition, or treatment composition, the previously described preferred composition or formulation is being used.

The folic acid treatment composition may be used to treat a wide variety of inflammation manifestations ranging from minor burns, itching, and irritation caused by rashes, insect bites, sunburn and skin poisoning to move severe conditions including burns, heat and urine scalding, abrasions, lacerations, macerations and lesions of all types, and has been found to be particularly effective when treating conditions which are caused by damaged or ruptured cellular tissue. The method of using the folic acid treatment composition preferably involves topical application of the treatment composition to the area of the skin to be treated. Although the treatment composition has been described in detail herein with respect to a particularly preferred water miscible base carrier preparation, other pharmaceutically acceptable carrier preparations, such as those formulated as lip gloss, dropper dispensed preparations, time release preparations, and powdered preparations, as well as carrier preparations used to form lipstick applicators and suppositories, may also be suitably used in accordance with the present invention. In addition, although topical application of the treatment composition is described herein as being preferred, folic acid may be included in mouthwash formulations, douche formulations, as well as formulations incorporated into transdermal applicators for treating tissue in accordance with the present invention.

The following case histories of patients treated with the folic acid treatment composition in accordance with the present invention are provided by way of non-limiting examples of the wide range of conditions, which may be treated in accordance with the present invention.

Case Histories I. A 45 year-old male suffered from psoriasis in the area on the bridge of his nose up to his lower forehead. The folic acid treatment composition of the present invention was applied for 3 consecutive days. The psoriatic area began to appear more like normal after the first day of application of the folic acid composition and resulted with a termination of itching and cleared the area of dry, flaky epidermal tissue. II. A 27 year-old female suffering with hemorrhoids which she previously had treated with a commercially available hemorrhoidal preparation with no relief, applied the folic acid treatment composition of the present invention to the inflammed hemorrhoidal areas. By the end of an hour from the initial application of the folic acid treatment composition, she no longer experienced pain in the previously affected areas. Later that evening, after bathing, she applied the folic acid treatment preparation of the present invention a second time, and experienced no discomfort during the night nor the following morning. Although she observed that the size of the hemorrhoids had not decreased, she reported that she experienced absolutely no pain. The folic acid treatment composition was again applied the following morning and the patient reported that relief from pain lasted for the entire day so that subsequent applications of the folic acid treatment composition were unnecessary.

III. A male in his late 80s was experiencing pain as a result of bruised gums caused by lower dentures to the extent that he could not wear the dentures. He applied the folic acid treatment composition of the present invention on the sensitive area twice during the course of an evening and a third time before retiring. The following morning, he was able to put in his dentures and ate breakfast without experiencing any pain. IV. A 30 year-old male had developed an ulcer inside his lower lip. The patient applied the folic acid treatment composition several times and reported that the soreness was relieved immediately and that the ulcer had completely healed within 2 days. V. A 27 year-old female having aphthous ulcers, 3 sublingually and 2 on the buccal mucosa, began treating the ulcers with the folic acid treatment composition in accordance with the present invention and reported that the pain stopped immediately upon contact with the folic acid treatment composition, and that by the third day all of the ulcers were healed.

VI. A 30 year-old female orthodontic patient suffering from aphthous-type lesions opposite an orthodontic bracket on the mucous surface of the lower lip reported that the soreness of such lesions was relieved immediately and the lesions healed within 2 days after application of the folic acid treatment composition.

VII. A 15 year-old female suffered from herpetic lesions having a 7-8 mm diameter on the upper lip which were very sore to the touch and raised by blistering. The patient reported that the pain subsided after 5-6 hours from the first application of the folic acid treatment composition, and that the lesions were dry and reduced in size at the end of 48 hours.

The folic acid treatment composition performed well in enhancing the healing of the inflammed or wounded tissue and these examples indicate that the pain relieving effect of the folic acid treatment composition is extremely rapid. Related to this, the relief of pain and discomfort did not appear to fit any commonly recognized pattern for pain relievers. In this regard, the folic acid treatment composition does not appear to cause a blockage of neural transmission of pain, nor does the folic acid treatment composition cause a substitution of one sensation for another, as is the case in many local anesthetics. Although the exact mechanism by which the folic acid treatment composition causes such immediate pain relief is not known, overall, the folic acid treatment composition performs more rapidly and more effectively than expected in the previously described applications of the folic acid treatment composition to various types of inflammed or wounded tissue.

Although the invention has been described with reference to particular means, materials and embodiments, from the foregoing description one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, may make changes and modifications of the invention to adapt to various usages and conditions.

Claims

WHAT IS CLAIMED IS:

1. A pain relieving and healing composition comprising an effective amount of folic acid in a suitable pharmaceutical carrier preparation.

2. The pain relieving and healing composition in accordance with claim 1, wherein said effective amount of folic acid is within the range of .01 to 15%.

3. The pain relieving and healing composition in accordance with claim 2, wherein said effective amount of folic acid is 0.2% by total weight of said composition.

4. The pain relieving and healing composition in accordance with claim 3, wherein said, pharmaceutical carrier preparation is essentially devoid of petroleum-base ingredients.

5. The pain relieving and healing composition in accordance with claim 4, wherein said pharmaceutical carrier preparation is a member selected from the group consisting of water miscible base carrier preparations and alcohol base carrier preparations.

6. The pain relieving and healing composition in accordance with claim 5, wherein said pharmaceutical carrier preparation is a water miscible base carrier preparation.

7. The pain relieving and healing composition in accordance with claim 6, wherein said water miscible base carrier preparation includes at least one member selected from the group consisting of mineral oil, steric acid, cetyl alcohol, triethanolamine, methyl paraben, propyl paraben, and water.

8. The pain relieving and healing composition in accordance with claim 7, wherein said water miscible base preparation includes mineral oil, steric acid, cetyl alcohol, triethanolamine, methyl paraben, propyl paraben, and water.

9. A pain relieving and healing composition comprising:

0.2% folic acid; 5.0% mineral oil; 4.5% steric acid; 3.5% cetyl alcohol; 1.5% triethanolamine; 0.15% methyl paraben;

0.05% propyl paraben; and water.

10. A process for treating wounded tissue comprising: applying to said wounded tissue a composition comprising an effective amount of folic acid for relieving pain and enhancing healing of said wounded tissue and a suitable pharmaceutical carrier preparation.

11. The process in accordance with claim 10, wherein said effective amount of folic acid is within the range of

.01 to 15% by total weight of said composition.

12. The process in accordance with claim 11, wherein said effective amount of folic acid is 0.2% by total weight of said composition.

13. The process in accordance with claim 12, wherein the pharmaceutical carrier preparation is essentially devoid of petroleum-base ingredients.

14. The process in accordance with claim 13, wherein the pharmaceutical carrier preparation is a member selected from the group consisting of water miscible base carrier preparations and alcohol base carrier preparations.

15. The process in accordance with claim 14, wherein the pharmaceutical carrier preparation is a water miscible base carrier preparation.

16. The process in accordance with claim 15, wherein said water miscible base preparation comprises at least one member selected from the group consisting of mineral oil, steric acid, cetyl alcohol, triethanolamine, methyl paraben, propyl paraben, and water.

17. The process in accordance with claim 16, wherein said water miscible base preparation includes a mixture comprising mineral oil, steric acid, cetyl alcohol, triethanolamine, methyl paraben, propyl paraben, and water.

18. A process for relieving pain and enhancing healing of inflammed or wounded tissue comprising treating said wound with a composition including: 0.2% folic acid; 5.0% mineral oil; 4.5% steric acid; 3.5% cetyl alcohol; 1.5% triethanolamine;

0.15% methyl paraben; 0.05% propyl paraben; and water.

19. A method for manufacturing a composition containing an effective amount of folic acid for relieving pain and enhancing the healing of inflammed or wounded tissue comprising: a) forming a pharmaceutical carrier preparation essentially devoid of petroleum-base ingredients; b) introducing an amount of folic acid into said carrier preparation to form an admixture; and c) mixing said admixture to produce a composition of folic acid homogeneously distributed in said pharmaceutical carrier preparation.

20. A method for manufacturing a composition containing folic acid for relieving pain and enhancing the healing of inflammed or wounded tissue comprising the steps of : a) forming an aqueous solution of mineral oil, steric acid, cetyl alcohol, triethanolamine, methyl paraben, propyl paraben, and water; b) introducing an amount of folic acid into said aqueous solution; and c) mixing said aqueous solution containing folic acid to produce an homogeneous, thixopropic paste-like composition comprising mineral oil, steric acid, cetyl alcohol, triethanolamine, methyl paraben, propyl paraben, water and an amount of folic acid effective for relieving pain and enhancing the healing of inflammed or wounded tissue treated with the composition.

21. The method for manufacturing a composition containing folic acid in accordance with claim 20, wherein the step of providing includes: i) stirring said aqueous solution, while subjecting said aqueous solution to temperatures within the range of 70 to 75° C, and ii) permitting said aqueous mixture to cool to a temperature within the range of ^'30 to 40° F prior to introducing said folic acid into said aqueous solution.

22. The method for manufacturing a composition containing folic acid in accordance with claim 21, wherein said amount of folic acid effective for relieving pain and enhancing healing of inflammed or wounded tissue is 0.2% by total weight of said composition.

23. The method for manufacturing a composition containing folic acid in accordance with claim 22, wherein said resultant composition comprises: 0.2% folic acid; 5.0% mineral oil; 4.5% steric acid; 3.5% cetyl alcohol;

1.5% triethanolamine; 0.15% methyl paraben; 0.05% propyl paraben; and water.