COMPOSITIONS AND METHODS OF ADMINISTERING A COLCHICINE BASED TOPICAL COMPOSITION FOR THE PREVENTION OF RADIATION FIBROSIS

Abstract

A colchicine-containing composition comprising colchicine as the active ingredient or colchicine in combination with pentoxifylline and tocopherol (Vitamin E) which are formulated for topical use in the prevention and treatment of radiation-induced fibrosis. And methods of making and administering the colchicine-containing compositions. The compositions can be used as topical applications for the prevention and treatment of radiation-induced fibrosis, commonly known as scarring, that can be debilitating, and can occur as a late and permanent complication of radiation therapy

Claims

1. A colchicine-containing composition, the composition comprising: a topical composition that includes colchicine as an active ingredient that is adapted to be applied to the skin for preventing formation of scars due to radiation exposure.

2. The colchicine-containing composition of claim 1, wherein the topical composition solely includes one active ingredient for preventing the formation of scars due to radiation exposure that is the colchicine.

3. The colchicine-containing composition of claim 1, wherein, the topical composition further includes: pentoxifylline and tocopherol.

4. The colchicine-containing composition of claim 3, wherein the topical composition comprises (per 100 ml): approximately 0.1 gram to approximately 1 gram of colchicine, approximately 1 gram to approximately 20 grams of pentoxifylline, and approximately 100 IU to approximately 5000 IU of d-alpha tocopheryl acetate.

5. The colchicine-containing composition of claim 1, wherein the radiation exposure is from radiation therapy in the treatment of at least one of head and neck cancer and breast cancer as well as any other type of cancer where radiation-induced fibrosis may be an issue.

6. The colchicine-containing composition of claim 1, wherein the topical composition is in the form of at least one of: suspension, emulsion, solution, gel, paste, ointment, cream, lotion, spray or aerosol.

7. A colchicine-containing composition comprising: a topical composition that includes colchicine as an active ingredient that is adapted to be applied to the dermal layer of a mammal to treat radiation-induced scars due to radiation exposure.

8. The colchicine-containing composition of claim 7, wherein solely the colchicine is the one active ingredient for treating the formation of scars due to radiation exposure.

9. The colchicine-containing composition of claim 7, wherein the topical composition further includes: pentoxifylline and tocopherol.

10. The colchicine-containing composition of claim 9, wherein the topical composition comprises (per 100 ml): approximately 0.1 gram to approximately 1 gram of colchicine, approximately 1 gram to approximately 20 grams of pentoxifylline, and approximately 100 IU to approximately 5000 IU of d-alpha tocopheryl acetate.

11. The colchicine-containing composition of claim 7, wherein the radiation exposure is from radiation therapy in the treatment of at least one of head and neck cancer and breast cancer as well as any other type of cancer where radiation-induced fibrosis may be an issue.

12. The colchicine-containing composition of claim 7, wherein the composition is in the form of at least one of: suspension, emulsion, solution, gel, paste, ointment, cream, lotion, spray or aerosol.

13. A method of preventing radiation-induced fibrosis in a mammal comprising the steps of: providing a topical administration of a colchicine-containing composition; and applying an effective amount of the colchicine-containing composition to an area to be subjected to radiation twice daily beginning on day one of the radiation therapy.

14. The method according to claim 13, wherein the colchicine-containing composition includes (per 100 ml): approximately 0.1 g to approximately 1 g colchicine

15. The method according to claim 13, wherein the colchicine-containing composition includes: colchicine, pentoxifylline and tocopherol.

16. The method according to claim 15, wherein the colchicine-containing composition comprises (per 100 ml): approximately 0.1gram to approximately 1 gram of colchicine, approximately 1 gram to approximately 20 grams of pentoxifylline, and approximately 100 IU to approximately 5000 IU of d-alpha tocopheryl acetate.

17. The method according to claim 13, wherein the radiation-induced fibrosis is from radiation therapy in the treatment of at least one of head and neck cancer and breast cancer as well as any other type of cancer where radiation-induced fibrosis may be an issue.

18. The method according to claim 13, wherein the colchicine-containing composition is in the form of at least one of: a suspension, emulsion, solution, gel, paste, ointment, cream, lotion, spray or aerosol.

19. The method according to claim 18 wherein the colchicine-containing composition is in the form of a cream.

20. A method of treating radiation-induced fibrosis in a mammal comprising the steps of: providing a topical administration of a colchicine-containing composition; and applying a therapeutic amount of the colchicine-containing composition to an area exhibiting symptoms of radiation fibrosis twice daily for approximately six months to approximately twenty-four months.

Description

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0073] Before explaining the disclosed embodiments of the present invention in detail it is to be understood that the invention is not limited in its applications to the details of the particular arrangements shown since the invention is capable of other embodiments. Also, the terminology used herein is for the purpose of description and not of limitation.

[0074] In the Summary above and in the Detailed Description of Preferred Embodiments, reference is made to particular features of the invention. It is to be understood that the disclosure of the invention in this specification includes all possible combinations of such particular features. For example, where a particular feature is disclosed in the context of a particular aspect or embodiment of the invention, that feature can also be used, to the extent possible, in combination with and/or in the context of other particular aspects and embodiments of the invention, and in the invention generally.

[0075] In this section, some embodiments of the invention will be described more fully, in which preferred embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will convey the scope of the invention to those skilled in the art. Like numbers refer to like elements throughout, and prime notation is used to indicate similar elements in alternative embodiments.

[0076] It is remarkable that the topical administration of colchicine-containing compositions, including colchicine with a pharmaceutically acceptable carrier and colchicine combined with pentoxifylline and tocopherol (Vitamin E) can prevent radiation-induced scarring resulting from radiation therapy.

[0077] Scarring on the chest wall from radiation also can result in significant problems in range of motion and chest wall infections that could be extremely persistent due to the lack of blood flow secondary to the hardened connective tissue. All of these late radiation-induced scarring problems are basically permanent; the composition of the present invention can be used to alleviate the symptoms. The primary goal of the present invention is to prevent the formation of these scars. Alternatively, if the radiation fibrosis has begun to form, the colchicine-containing compositions of the present invention can lessen the severity of the scarring.

[0078] The individual compounds useful in the composition of the present invention are discussed below.

[0079] Colchicine is a yellow, poisonous alkaloid C.sub.22H.sub.25NO.sub.6 that inhibits mitosis, is extracted from the corms or seeds of the autumn crocus (Colchicum autumnale), and is used especially in the treatment of gout to relieve pain and in the laboratory to arrest cells during cell division (by disrupting the spindle) so their chromosomes can be visualized.

[0080] Colchicine works by disrupting the cytoskeletal functions through inhibition of B-tubulin polymerization into microtubules. This prevents activation, degranulation and migration of neutrophils as well as inhibits migration and proliferation of fibroblasts. It also blocks the production and secretion of collagen. These are the contributing factors to radiation-induced local skin and connective tissue changes. In low doses, without any side effects, colchicine inhibited fibroblast migration by 93%. Colchicine has been successfully used in treatment of liver cirrhosis, a disease caused by scarring.

[0081] Pentoxifylline (PTX) (3,7-dimethyl-1-5-(5-oxohexyl)-xanthine) is widely used systemically for the treatment of peripheral vascular diseases. PTX is used to improve the symptoms of a certain blood flow problem in the legs/arms known as, intermittent claudication due to occlusive artery disease. Pentoxifylline can decrease the muscle aching/pain/cramps during exercise, including walking, that occur with intermittent claudication. Pentoxifylline belongs to a class of drugs known as hemorrheologic agents. It works by helping blood flow more easily through narrowed arteries. This increases the amount of oxygen that can be delivered by the blood when the muscles need more, such as during exercise, thereby increasing walking distance and duration.

[0082] With regard to the present invention, pentoxifylline may be involved in blocking the molecular signaling pathway that is responsible for the development of fibrosis as a response to inflammation and injury. Additionally, pentoxifylline increases the flexibility and permeability of red blood cells which enables them to more easily bring oxygen to the tissues and carry carbon dioxide away. It is because of this mechanism that pentoxifylline is used in the management of peripheral artery disease, leg ulcers, strokes, high-altitude sickness, eye and ear disorders, sickle cell disease, and diabetic neuropathy.

[0083] Tocopherols are a family of Vitamin E compounds. Vitamin E (tocopherol) is a light yellow oil, a fat-soluble vitamin. The tocopherols are found in nature. Alpha-tocopherol is the most common and the most active of the seven currently described forms—alpha, beta, gamma, delta, epsilon, and zeta. Specifically, d-alpha tocopherol is the most potent form, more active than the synthetic dl-alpha tocopherol.

[0084] Vitamin E was discovered in 1922 with experiments on rats. When fed a purified diet devoid of vitamin E, the rats became infertile. Wheat germ oil added to their diet restored their fertility. Later, the oil-based substance was isolated and called the “antisterility” vitamin. Tokos and phero are the Greek words for “offspring” and “to bear,” so tocopherol literally means “to bear children.” Though there is no clear deficiency disease in humans, vitamin E is well accepted as an essential vitamin.

[0085] Alpha-tocopherol is basically stable in heat and in acids; other forms are lost in heat, with storage or freezing, or when oxidized by exposure to the air. Vitamin E is absorbed from the intestines, along with fat and bile salts, first into the lymph and then into the blood, which carries it to the liver to be used or stored. Vitamin E is not stored in the body as effectively as the other fat-soluble vitamins, A, D, and K. Vitamin E is partially absorbed through the skin when used as an ointment or oil application.

[0086] Based on the above information and studies, one embodiment of the present invention provides a combination of colchicine and pentoxifylline with the addition of tocopherol as a topical preventive treatment for radiation-induced fibrosis. Colchicine improves very significantly the efficacy of this treatment. By topical administration, the undesired side effects or complications of colchicine are avoided. These three compounds have no interaction making them safe for combined use.

[0087] In another embodiment of the invention, colchicine is used topically while pentoxifylline and tocopherol are administered orally.

EXAMPLE 1

Method for Preventing Radiation Fibrosis

[0088] Prior to beginning radiation therapy treatments, the patient in the mammalian species, should apply the colchicine-containing composition of the present invention to the area marked for radiation twice daily starting with day one of radiation treatment.

[0089] Continue the twice daily application for a total of six months regardless of when radiation treatment ends. Continue the twice daily applications for an additional six months if symptoms arise.

EXAMPLE 2

Method for Treating Radiation Fibrosis

[0090] If radiation fibrosis symptoms are appearing in a patient of the mammalian species, massage therapy should be started and twice daily application of the colchicine-containing composition of the present invention should be applied to the skin that is exhibiting abnormal fibroblast activity. Apply the colchicine-containing composition for a minimum of 6 months, but typically a year or even up to approximately twenty-four months, as long as improvement in the condition is observed.

[0091] Being aware of the risks of radiation fibrosis from the start of radiation therapy is important. Patients should report changes they experience promptly, and they should be monitored throughout treatment for signs of complications and dangerous side effects. The present invention is especially useful for early intervention that can limit side effects, as for example, prior to the first radiation therapy treatment, the topical application of the colchicine-containing product of the present invention can prevent scarring and disfiguring of the area to be subjected to radiation.

[0092] TABLE 1 provides a composition of components for using colchicine as the only active ingredient in a topical application (per 100 ml).

TABLE-US-00001 TABLE 1 Narrow Broad Range Range Preferred Active Ingredient Colchicine approx. 0.1 gram 0.2 gram to approx. 0.2 gram to approx. 1 gram 0.4 gram Inactive Ingredient(s) Sodium 0 to approx. 0.2 gram to approx. 0.2 gram hyaluronate 1 gram 0.4 gram Panthenol 0 to approx. 1 gram to approx. 2 grams 5 grams 3 grams Propolis 0 to approx. 1 gram to approx. 2 grams 10 grams 4 grams Sodium 0 to approx. 0.1 gram to approx. 0.2 gram metabisulfite 1 gram 0.4 gram Bifidobacterium 0 to approx. 1 gram to approx. 2 grams longum lysate 5 grams 3 grams

[0093] The composition referenced in Table 1 can be used with colchicine by itself as the active ingredient and with none or one or more of the inactive ingredients. The surface area depends on the size and location of the cancer. Basically, they have to apply to the whole radiation field (marked by tattoo) as well as outside of the marked field if signs of inflammation (redness, swelling, pain) occur.

[0094] Colchicine can be made alone or in combination with any or all of the inactive ingredients. We would use these with oral PTX and/or tocopherol or by itself if allergy or contraindications to these ingredients should be present.

[0095] TABLE 2 provides a composition of components for using colchicine along with both pentoxifylline and tocopherol as the active ingredients in a topical application (per 100 ml).

TABLE-US-00002 TABLE 2 Narrow Broad Range Range Preferred Active Ingredients Colchicine approx. 0.1 gram to 0.2 gram to approx. 0.2 gram approx. 1 gram 0.4 gram Pentoxifylline approx. 1 gram to 8 grams to approx. 10 grams approx. 20 grams 12 grams d-alpha approx. 100 IU to 250 IU to approx. 350 IU tocopheryl approx. 5000 IU 500 IU acetate Inactive Ingredient(s) Sodium 0 to approx. 0.2 mg to approx. 0.2 gram hyaluronate 1 gram 0.4 mg Panthenol 0 to approx. 1 gram to approx. 2 grams 5 grams 3 grams Propolis 0 to approx. 1 gram to approx. 2 grams 10 grams 4 grams Sodium 0 to approx. 0.1 gram to approx. 0.2 gram metabisulfite 1 gram 0.4 gram Bifidobacterium 0 to approx. 1 gram to approx. 2 grams longum lysate 5 grams 3 grams

[0096] The composition referenced in Table 2 can be used with the combination of colchicine, pentoxifylline and d-alpha tocopheryl acetate as the active ingredients, along with none or one or more of the inactive ingredients. The active ingredients can be made with none or any of the inactive ingredients.

[0097] The surface area depends on the size and location of the cancer. Basically, they have to apply to the whole radiation field (marked by tattoo) as well as outside of the marked field if signs of inflammation (redness, swelling, pain) occur.

[0098] TABLE 3 lists the dosage amounts of each of the active ingredients (per 100 ml).

TABLE-US-00003 TABLE 3 Narrower Preferred Exact Range of dose range of dose amount amount Ingredient (per 100 ml) (per 100 ml) (per 100 ml) (per 100 ml) Colchicine approx. 0.1 approx. 0.1 approx. 0.2 approx. to approx. to approx. to approx. 0.2 gram 1 gram 0.6 gram 0.4 gram Pentoxifylline approx. 1 approx. 5 approx. 8 approx. to approx. to approx. to approx. 10 grams 20 grams 15 grams 12 grams Tocopherol approx. 100 approx. 100 approx. 250 approx. to approx. to approx. to approx. 350 IU 5000 IU 1000 IU 500 IU

[0099] The colchicine dose is based on scientific data (see above −0.2% (0.2 gram per 100 ml) has no side effects and yields same concentration in the dermis 0.5%). Broader doses are in case we need higher concentrations in the future. PTX dose is based on other products that are 10%. Tocopherol dose varies widely in medical and cosmetic products but it gets absorbed well at relatively low concentrations, the dose is based on literature. The dosage can include only colchicine alone with no other active ingredients.

[0100] TABLE 4 lists the dosage amounts of each of the inactive ingredients (per 100 ml).

TABLE-US-00004 TABLE 4 Inactive Ingredient(s) Broad range Narrow range Exact amounts Sodium 0 to approx. 0.2 mg to approx. 0.2 gram hyaluronate 1 gram 0.4 mg Panthenol 0 to approx. 1 gram to approx. 2 grams 5 grams 3 grams Propolis 0 to approx. 1 gram to approx. 2 grams 10 grams 4 grams Sodium 0 to approx. 0.1 gram to approx. metabisulfite 1 gram 0.4 gram 0.2 gram Bifidobacterium 0 to approx. 1 gram to approx. 2 grams longum lysate 5 grams 3 grams

[0101] The inactive ingredients are part of the final cream/gel. It contains everything we mix in when producing the product. We can produce with none, some or all inactives. The benefits of not using inactive ingredients can be used in case someone is allergic to beeswax for example (propolis).

[0102] The ability of panthenol to draw moisture into the skin is considered to have a number of benefits, especially because it can significantly penetrate the skin's surface. It plumps the skin, helps reduce the appearance of fine lines and wrinkles, makes skin feel smoother, firmer, and more supple. It is also thought to encourage the generation of new skin cells.

[0103] A benefit of using propolis can be its antimicrobial effects and its ability to heal sores and burns. (Gregory S R, Piccolo N, Piccolo M T, Piccolo M S, Heggers J P. “Comparison of propolis skin cream to silver sulfadiazine: a naturopathic alternative to antibiotics in treatment of minor burns.” J Altern Complement Med. 2002 February; 8 (1):77-83.)

[0104] A benefit of using Bifidobacterium longum lysate will be described. Reactive skin is characterized by marked sensitivity to physical (heat, cold, wind) or chemical (topically applied products) stimuli and by the impairment of the skin barrier's ability to repair itself. The results of a study demonstrate that this specific bacterial extract has a beneficial effect on reactive skin and can be used for the treatment and/or prevention of symptoms related to reactive skin. (Guéniche A, Bastien P, Ovigne J M, et al. Bifidobacterium longum lysate, a new ingredient for reactive skin. Exp Dermatol. 2010 August; 19(8): e1-8.)

[0105] A benefit of using sodium hyaluronate will now be described. Topically applied sodium hyaluronate can facilitate the absorption of biomacromolecules, i.e. pharmaceuticals, and function like a nanocarrier. (Wickens J M, Alsaab H O, Kesharwani P, et al. Recent advances in hyaluronic acid-decorated nanocarriers for targeted cancer therapy. Drug Discov Today. 2016 Dec. 23. pii: S1359-6446 (16)30491-3.) It also enhances penetration into the epidermis. (Witting M, Boreham A, Brodwolf R, et al. “Interactions of Hyaluronic Acid with the Skin and Implications for the Dermal Delivery of Biomacromolecules”. Mol. Pharmaceutics. 12 (5): 1391-1401. Apr. 14, 2015)

[0106] A benefit of using sodium metabisulfite is that it can be used as a disinfectant, antioxidant and preservative agent.

[0107] A method of preparing an example of the novel composition will now be described. A Humco Salt Stable Lo base is an improved, stable and durable Pluronic Lecithin Organogel, which is a great delivery system for penetrating the skin and delivering one or many APIs (active pharmaceutical ingredients) through the many layers of skin. The final product can be a cream like dispersion. An example of the composition in USP (United States Pharmacopial convention book of drug information) can include: [0108] Colchicine USP 0.2% (0.2 gram per 100 ml) [0109] Pentoxyfilline USP 10% (10 grams per 100 ml) [0110] Vitamin E D-Alpha Tocophero 100 IU/30 ml (or 350 IU per 100 ml) [0111] Humco Salt Stable LS Advanced Base Qs to final volume

[0112] All compounding this compound can be performed in an air containment hood. Combining and mixing the APIs and base. The APIs will directly be mixed into the base without a wetting agent, such as propylene glycol, mineral oil, alcohol.

[0113] Each API can be weighed out in separate weigh boats which wets the entire surface of the active drug. The weight receipt can be printed out and attached to a batch record.

[0114] The calculated Humco base can be weighed plus an additional 10% in the weigh boat. Any excess over the QS (quantity sufficient) can be discarded.

[0115] Tare balance with mixing bowl (container vessel) in a tared container, and add 25% of base to bottom of container and coat bottom and sides with a rubber spatula.

[0116] Next, add all three APIs into the mixing bowl with base. Gently mix together into the base with a rubber spatula. Next, mix until most large lumps of APIs have been decreased or dissolved.

[0117] Next add approximately 50% of base and mix together with a rubber spatula.

[0118] QS with the base to the calculated weight on balance.

[0119] Hand mixing by mixing with a rubber spatula for 2 minutes by hand.

[0120] Initial mixing can include set up mixing vessel into a high speed mixer, and mix at speed 1000 rpms with a mixing time of ten minutes.

[0121] For milling set up 3 roller Mill (machine to mix and reduce particle size of compound). Compound will be passed through the mill for approximately three times until particle size is less than 50 microns. The Hegman gauge (measuring tool to measure particle size in a compound) will be used to test compound for correct particle size.

[0122] Pass One set back roller at setting 15 and front roller at setting 10.

[0123] Pass Two set back roller at setting 12 and front roller at setting 8.

[0124] Pass Three set back roller at setting 10 and front roller at setting 6.

[0125] Final mixing is to set vessel onto high speed mixer, and mix at speed of 2000 rpms (revolutions per minute), with a mixing time of ten minutes.

Pharmacist Quality Control

[0126] pH range between 4.5 to 7

[0127] Particle size less than 50 microns.

[0128] Spread test on ointment slab, and smooth with no streaks or particles.

[0129] Odor to be determined after Research and Development and validation.

[0130] Specific gravity to be determined after Research and Development and validation.

[0131] Warning and Precautions can include keeping the composition out of reach of children, and is to be used for external use only, as directed. Composition should be kept away from light, and needs to be stored at room temperature.

[0132] The term “approximately” can be +1-10% of the amount referenced. Additionally, preferred amounts and ranges can include the amounts and ranges referenced without the prefix of being approximately.

[0133] While the invention has been described, disclosed, illustrated and shown in various terms of certain embodiments or modifications which it has presumed in practice, the scope of the invention is not intended to be, nor should it be deemed to be, limited thereby and such other modifications or embodiments as may be suggested by the teachings herein are particularly reserved especially as they fall within the breadth and scope of the claims here appended.