Use of allopurinol for the treatment of palmar plantar erythrodysesthesia

[0001] The present invention relates to the field of therapy, especially in oncology. It is associated with the use of allopurinol or its pharmaceutically acceptable salts in the manufacture of a medicament for the treatment or prevention of chemotherapy-induced palmar plantar erythrodysaesthesia (PPE). It is also associated with pharmaceutical compositions containing allopurinol.

BACKGROUND OF THE INVENTION [0002] Cancer belongs to a group of diseases during which cancer-affected cells undergo uncontrolled division. Cancer cells can attack nearby tissues and spread through the blood stream and lymphatic system to other parts of the body. There are several main types of cancer. Malignant tumor is a cancer that begins in the skin or in the tissues that form or cover internal organs. Sarcoma is a cancer that occurs in the bones, cartilage, adipose tissue, muscles, blood vessels, or other connective or supportive tissues. Leukemia is a cancer that appears in a hematopoietic tissue, such as a bone marrow, and causes a large number of abnormal blood cells to enter the bloodstream. Lymphoma and multiple myeloma are cancers that start in the cells of the immune system.

[0003] Several methods of cancer treatment are available, including surgery and irradiation of localized cancer, and administration of drugs that destroy cancer cells (chemotherapy). Chemotherapy plays a key role in the treatment of cancer, it is required for the treatment of advanced cancers with distant metastases and is often helpful in reducing cancer before surgery (neoadjuvant therapy). It is also used postoperatively or after radiation (adjuvant therapy) to destroy any remaining cancer cells or to prevent the cancer coming back.

[0004] The most commonly used, numerous anti-cancer drugs developed on the basis of different modes of action are: alkylating agents that act directly on

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DNA (such as cisplatin, carboplatin, oxaliplatin, busulfan, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine); antimetabolites that interfere with DNA and RNA synthesis (such as 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine (ara-C), fludarabine); anthracyclines that interfere with enzymes involved in DNA replication (such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone); compounds that interfere with microtubule functions (taxanes such as paclitaxel and docetaxel or vinca alkaloids such as vinblastine, vincristine and vinorelbine); topoisomerase inhibitors (such as etoposide, doxorubicin, topotecan and irinotecan); compounds used in hormone therapy (such as tamoxifen, flutamide) and compounds used in recently introduced targeted therapy (such as EGFR inhibitors cetuximab, gefitinib or an imatinib inhibitor of tyrosine kinase protein).

[0005] Chemotherapy in the treatment of cancer may consist of the administration of a single drug or a combination of drugs, cyclically delivered. A cycle consists of treatment with one or more medications followed by a rest period.

[0006] The development of chemotherapy in recent decades has significantly improved the treatment of cancer, resulting in effective treatment of certain cases of cancer and increasing survival or extending the period of development of the disease in other cases. Currently, most chemotherapy drugs are administered intravenously; however, oral administration of drugs during chemotherapy is also widely used.

[0007] Unfortunately, most chemotherapy drugs do not allow distinguishing between cancer cells and healthy cells. Therefore, chemotherapy often affects healthy tissues and organs of the body, which causes complications during treatment or side effects. In addition to the problems caused by this, side effects may prevent you from receiving the dose of chemotherapy prescribed by your doctor, thereby reducing the likelihood of a proper cure for cancer. The most common side effects of chemotherapy are anemia, neutropenia, thrombocytopenia, fatigue, alopecia, nausea and vomiting, mucositis and pain sensation.

[0008] Palmar-plantar erythrodysaesthesia (PPE) was first described by Zuehlke in 1974 as erythema of hand and foot eczema associated with mitotane treatment (Zuehlke, RK Dermatologica, 1974, 148 (2), 90-92). PPE is a characteristic and relatively common toxic reaction induced by certain chemotherapeutic agents. It is manifested by painful swelling and erythematous rash on the hands and feet, often preceded by dysesthesia, usually in the form of a tingling sensation, and often associated with

Edema. The rash may become bullous and then peel off without leaving permanent marks, and the pain gradually increases. Erythema can also occur in periungual areas. Generally limited to the hands and feet, the hands are usually more affected than the feet.

[0009] Histologically, PPE is a mild spongy condition, intercellular edema of the epidermis, diffuse, necrotic and callous keratinocytes and hydrothermal degeneration in the basal layer. Skin lesions in most cases include dilated blood vessels, papillary edema and scattered, superficial, perivascular lymphohistiocytic infiltrates, occurring to varying degrees in the epidermis.

[0010] PPE is a condition clearly distinguishable from other adverse skin reactions and described in a review of Nagore E. et al., Am J Clin Dermatol. 2000, 1 (4), 225-234, incorporated by reference in its entirety in the description.

[0011] The severity of the PPE case can be classified based on the following WHO scale:

1. Dysesthesia / paraesthesia, tingling in hands and feet.

2. Discomfort when holding objects and while walking, painless swelling or erythema.

3. Painful erythema and swelling of the hands and feet, pericardial erythema and swelling.

4. Peeling, ulceration, blistering, severe pain.

[0012] Another assessment system is based on the criteria of the US National Cancer Institute:

1. Painless skin changes or dermatitis (e.g. erythema, flaking)

2. Painful skin changes that do not interfere with function

3. Painful skin lesions interfering with functions [0013] The agents most commonly indicated as inducing PPE include fluorouracil (5-FU), capecitabine (Xeloda^®), pegylated, liposomal doxorubicin (Caelyx® / Doxil^®), cytarabine (Cytosar-U^®), phloxuridine (FUDR^®), tegafur and idarubicin (Idamycin®).

[0014] Fluorouracil is a fluorinated derivative of pyrimidine that is metabolized intracellularly to its active form, fluorouridine monophosphate, which inhibits DNA synthesis. It is indicated for several types of cancer, including as an adjuvant or palliative therapy for breast, colorectal, stomach and pancreatic cancer. The beneficial effects of fluorouracil-based adjuvant chemotherapy are well described, such as reducing the risk of relapse and prolonging the lives of patients with resected colon cancer, especially in stage III disease. A beneficial effect on survival was demonstrated with the intravenous bolus of fluorouracil (425 mg / m²) plus leucovorins (biomodulator) according to the Mayo Clinic regime (five days, monthly, for six months) or the Roswell regime (weekly dose, six every eight weeks, for eight months) (Sun W. et al. Curr Oncol Rep. 2005 May , 7 (3): 181-5). For metastatic colon cancer, for a 24-hour continuous high-dose 5-FU infusion (2600 mg / m²) and leucovorin, weekly for 6 weeks, followed by a 1- or 2-week rest period (AIO protocol) increased survival compared to the results for the Mayo protocol (Kohne et al. J Clin Oncol, 2003, vol 21, no. 20 , 3721-3728).

[0015] New combinations of fluorouracil, such as with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), resulting in a beneficial survival effect in the treatment of colorectal cancer (Goldberg, Oncologist 2005; 10 Suppl 3: 40-8. Review). Most of these combinations use a fluorouracil infusion.

[0016] Despite the obvious benefits of using fluorouracil in chemotherapy, the incidence of PPE is high with shock dose administration and a high dose delivery regimen by continuous infusion. This is the reason for reducing the dose or stopping treatment. In cases of metastatic colon cancer, prolonged administration

5-FU24H / LV resulted in a high frequency of PPE (34%) compared to the Mayo protocol (13%) (J Clin Oncol, 1998, vol 16, 3537-3541). Fluorouracil infusion was also a cause of PPE during the treatment of breast cancer, see for example Smith IE et al. Ann. Oncol. 2004, 15 (5) 751-758.

[0017] Capecitabine (Xeloda®) is a prodrug, orally used fluoropyrimidine carbonate, activated to fluorouracil in tumor tissue by thymidine phosphorylase. It is used in adjuvant therapy in the treatment of colon cancer, as first-line therapy for metastatic colorectal cancer and in the treatment of advanced or metastatic breast cancer. In recently presented results of phase III studies, capecitabine was compared with fluorouracil + leucovorin (Mayo protocol)

EP 2 035 006 B1 in adjuvant therapy of stage III colon cancer (Twelves C. et al., N Engl J Med 2005, 352, 2696-2704). Given the efficacy, capecitabine has been shown to be equivalent to fluorouracil + leucovorin. In first line treatment of metastatic colorectal cancer, capecitabine achieved a higher response level than that obtained using the Mayo Clinic regimen with equivalents for progression-free and overall survival (Van Cutsem E. et al. Br J Cancer 2004, 90: 1190-1197). Considering toxicity, in both cases capecitabine exhibited a lower frequency of grade 3 or 4 severe stomatitis and neutropenia. However, the frequency of hand-foot syndrome (PPE) was significantly higher for capecitabine than for fluorouracil + leucovorin, reaching as high as 49-60% for each scale and 17% for severe cases. This resulted in dose reduction, delayed or discontinued treatment. In metastatic breast cancer, the same situation occurred, capecitabine alone or in combination with docetaxel was more effective than docetaxel, but one of the most common dose limiting side effects was PPE.

[0018] Therefore, although capecitabine provides significant benefits as an oral drug and more beneficial for patients, in particular in combination therapy, palmar plantar erythrodysaesthesia remains one of the main causes considered when using this drug.

[0019] Another drug often associated with PPE is pegylated liposomal doxorubicin, i.e. doxorubicin hydrochloride encapsulated in long circulating liposomes with a methoxypolyethylene glycol binding surface. Pegylation protects liposomes from being detected by the immune system, allowing them to reach tissues or organs with higher endothelial permeability, such as cancer. Liposomal doxorubicin is used to treat advanced ovarian cancer and metastatic breast cancer. The drug-induced PPE is associated with the administration regimen and the incidence is relatively high: 37.4% on each scale, it was reported 16.4% for ovarian cancer for major conditions. Toxicity can be reduced by reducing the dose intensity (e.g. from 50 mg / m² every 4 weeks up to 40 mg / m², Rose PG, The Oncologist, 2005, 10: 205-214).

[0020] Palmar-plantar erythrodysesthesia is therefore a significant side effect of the chemotherapeutic agents mentioned. However, little is known about its causes and there is currently no effective therapy or prophylaxis for PPE.

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Limiting, delaying or withdrawing chemotherapy can be effective in reducing or eliminating PPE, but at the cost of a significant compromise in the fight against cancer.

[0021] Several actions have been proposed, such as: cold compresses or ice packs, especially during chemotherapy; raising hands or feet; moisturizing the skin; softening creams containing lanolin, lactic acid, petroleum jelly (for example Bag Balm^®, ointment based on kerosene and lanolin with hydroxyquinoline sulfate as an antiseptic, or Aquaphor^®), and topical or oral corticosteroids such as dexamethasone.

Pyridoxine (vitamin B6) was used to reduce PPE-induced pain (Fabian et al. Invest. New Drugs 1990, 8: 57-63; Lauman MK et al. ASCO Proceedings, 2001, abbreviation 1565) and provided some symptomatic benefit to patients receiving capecitabine.

Amifostine, a cytoprotective agent, has been used to attempt to prevent PPE in patients treated with liposomal doxorubicin (Lyass O. et al., ASCO Proceedings, 2001, abbreviation 2148).

US 6,060,083 discloses the use of topical DMSO for the treatment of PPE, in particular caused by the administration of pegylated liposomal doxorubicin.

US 6,979,688 describes the topical use of uracil ointments for the treatment of fluorouracil-induced PPE or its precursor.

[0022] None of the proposed methods of treatment allowed effective treatment or prevention of PPE. It is clear that there is still a need for effective PPE treatment to fully utilize the potential of chemotherapeutic agents such as fluorouracil, capecitabine or pegylated liposomal doxorubicin and the various regimes and combinations in which they are used.

[0023] Allopurinol is a structural isomer of hypoxanthine that inhibits xanthine oxidase, an enzyme that converts oxypurins to uric acid. By blocking uric acid production, this factor lowers uric acid serum and urine levels, providing protection against uric acid-induced organ damage in conditions associated with excessive production. It has been used for many years to treat or prevent gout, hyperuricemia and kidney stones, via oral or parenteral systemic administration.

[0024] Allopurinol treatment of mucositis, frequent chemotherapy- or radiation-induced damage to rapidly dividing mouth cells has also been reported.

EP 2 035 006 B1 of the pharynx and gastrointestinal (GI) system. Allupurinol is used in a form suitable for mouthwash (dispersion in water) (Porta C. et al., Am J clin Oncol. 1994, Vol 17, no. 3, 246-247). An improved mouthwash formulation containing allopurinol, carboxymethyl cellulose and water is described in JP-3106817. Hanawa et al. in Drug Dev Pharm 2004, 30 (2) 151-161 described another mouthwash containing allopurinol, polyethylene oxide and carrageenan.

[0025] Dagher et al., Canadian Journal of Hospital Pharmacy, vol. 40, no. 1987, page 189 disclosed the use of allopurinol for mouthwash and for the use of vaginal 0.1% cream for the treatment of 5-FU-induced mucositis.

[0026] Allopurinol has also been administered systemically to modulate 5-fluorouracil suppression, in particular granulocytopenia (Woolley at al. J. of Clinical Oncology, 1985 vol. 3, no. 1, 103-109). However, preclinical studies have shown antagonism between these two drugs.

[0027] EP278040 describes the use of pteridine or xanthine oxidase inhibitors, including allopurinol, for the treatment of genetically induced, degenerative retinal diseases such as retinal pigment degeneration, in the form of topical eye drops or eye creams. There is no specific disclosure herein for a topically applied composition comprising allopurinol.

[0028] WO94 / 05293 and WO94 / 05291 describe synergistic compositions containing methylsulfonylmethane (MSM) and at least one component selected from oxypurinol or allopurinol and their use in the treatment of conditions, diseases and skin damage such as burns, dermatitis, hyperkeratosis, harmful influence of the sun, skin aging, etc. Oxypurinol or allopurinol have been described as compounds that promote skin healing or MSM repair properties.

[0029] None of the cited documents mentions or suggests that allopurinol could be useful for treating or preventing palmar plantar erythrodysesthesia.

Summary of the invention [0030] Surprisingly, the inventors have found that allopurinol, when applied topically to the patient's hands and feet, is very effective in the treatment and prevention of erythrodysesthesia

Palmar-plantar induced by fluoropyrimidine chemotherapy. As shown in the Examples, topical administration of allopurinol to cancer patients undergoing chemotherapy has completely avoided the appearance of PPE.

[0031] In one aspect, the invention is directed to the use of allopurinol or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of palmar plantar erythrodysaesthesia induced by fluoropyrimidine chemotherapy.

[0032] In a second aspect, the invention is directed to a topical pharmaceutical composition for hands and feet, containing from 1-10% by weight of allopurinol or a pharmaceutically acceptable salt thereof, with the proviso that it does not contain methylsulfonylmethane or cetomacrogol.

[0033] In a third aspect, the invention is directed to a method of treating or preventing palmar plantar erythrodysaesthesia induced by fluoropyrimidine chemotherapy in patients affected or at risk of developing this disease syndrome, comprising topical administration of a therapeutically effective amount of allopurinol or a pharmaceutically acceptable salt thereof .

Detailed description of the invention [0034] Palmar-plantar erythrodysaesthesia (PPE) is also known as peripheral erythema, hand-foot syndrome, palmar-plantar erythema, Burgorf syndrome, and toxic hands and feet erythema. In the context of the present invention, the term palmar plantar erythrodysaesthesia includes all of these synonyms when they relate, as described above, to conditions associated with chemotherapy.

In the context of the present invention, the term allopurinol refers to the various tautomers of the compound because it is a tautomeric mixture of 1H-pyrazolo [3,4-d] pyrimidin-4-ol and 1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one:

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As mentioned above, topical administration of allopurinol or one of its pharmaceutically acceptable salts has proved to be surprisingly useful in the treatment and prevention of PPE.

[0035] Accordingly, in one aspect, the invention is directed to the use of allopurinol or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of palmar plantar erythrodysaesthesia induced by fluoropyrimidine chemotherapy.

[0036] In one embodiment, the drug is in the form of a cream. Preferably, the cream is a hydrophilic cream.

[0037] In another embodiment, the medicament is for the treatment of fluorouracil, capecitabine induced PPE alone or in combination with other agents.

[0038] This drug is therefore useful for treating patients suffering from cancer, preferably, colorectal cancer, ovarian cancer, breast cancer, stomach cancer and pancreatic cancer and receiving chemotherapy as adjuvant, neoadjuvant or palliative chemotherapy. Examples of patients and chemotherapy, including PPE, are discussed in the background section of the invention and incorporated herein. The drug for the treatment of PPE is particularly useful for patients receiving or about to receive an infusion of 5-FU, capecitabine, alone or in combination with other agents.

[0039] Non-binding, allopurinol applied topically to the hands and feet is thought to act locally at the epidermis level, inhibiting the metabolism associated with cytotoxic drugs.

[0040] Toxicity to the hands and feet characteristic of PPE may be associated with the specific activity of the local enzymes of this area of ​​the skin, enzymes likely to be involved in the metabolism of cytotoxic drugs. Keratinocytes are composed of 90% epidermal cells. It is noteworthy that hand and foot keratinocytes have a specific phenotype, such as keratin 9 production, hypopigmentation and dense supra-basal layers, which distinguishes them from keratinocytes from other areas of the skin.

[0041] Schwartz et al, in Biochem Pharmacol, 1988, 37,353-355 have shown that human keratinocytes have a higher thymidine phosphorylase (TP) activity that is not present in other animals. This activity is responsible for the preservation of thymidine for DNA synthesis. Other studies have shown strong expression of TP in the epidermal basal layer.

[0042] Thymidine phosphorylase is an enzyme involved in the activation of 5'DFUR (capecitabine metabolite) to 5-FU. It can also be included in the activation of 5-FU. Thymidine phosphorylase (TP) is significantly activated in many solid tumors, such as colorectal, breast and kidney cancers, locally activating fluoropyrimidine prodrugs that "target" tumors. This enzyme is also known as angiogenic platelet-derived endothelial cell growth factor (PD-ECGF), which stimulates endothelial cell migration in vitro and angiogenesis in vivo and plays an important role in cancer progression and metastasis.

[0043] Fischel et al. Anti Cancer Drugs 2004, 15 969-974 proposed the view that capecitabine toxicity to the hands and feet may be due to increased TP activity in the skin, particularly in those areas where epidermal renewal is known to be extremely active. According to the above hypothesis, there may be high levels of cell proliferation and TP activity in the skin area, including angiogenesis and drug metabolism. Therefore, if hand and foot tissue is similar to cancerous tissue, it is likely that chemotherapeutic agents exert increased specific toxic activity against hand and foot keratinocytes in the same manner as they are directed at proliferating tumor tissue.

[0044] According to our hypothesis, when allopurinol is administered topically, it acts directly or indirectly to inhibit the enzyme thymidine phosphorylase. Interestingly, allopurinol has been described in Gallo et al. J Biological Chemistry 1968, vol. 243, 4943-4951, being a selective inhibitor of deoxythymidine phosphorylase, known under another name as the enzyme thymidine phosphorylase. It inhibits TP but not uridine phosphorylase.

[0045] Allopurinol may act by reducing the local production of active, toxic metabolites that may be responsible for the symptoms of PPE. Topical administration allows effective targeting of the affected areas and avoids toxicity and complications that systemic allopurinol could induce in cancer patients, in particular avoiding disruption of chemotherapy.

[0046] In one embodiment, the treatment is to reduce or prevent PPE in patients receiving systemic chemotherapy comprising an agent selected from fluorouracil (5-FU) or capecitabine (Xeloda^®).

[0047] The invention further relates to a topically administered hand and foot treatment composition comprising from 1% -10% by weight of allopurinol or a pharmaceutically acceptable salt thereof together with at least one topically acceptable carrier material, with the proviso that no it contains ethylsulfonylmethane or cetomacrogol.

[0048] Allopurinol is a compound very poorly soluble in water and alcohol; practically insoluble in chloroform and ether; dissolves in dilute alkaline hydroxide solutions. It can be used as such, or a salt such as sodium salt can be used instead of a base to increase water solubility.

[0049] In topically applied compositions of the invention, allopurinol or a salt thereof is usually present in an amount of atoms of about 1 to 10%, in particular from 1-8%, more particularly from 1-6%, especially from 1 to 5%. Allopurinol concentrations below 1% are not sufficient for effective treatment or prevention of PPE. At concentrations above 10%, allopurinol may have undesirable side effects on the patient's skin.

[0050] A preferred range is from 2 to 5%, more preferably, from 2-4% by weight of the total composition. An amount of about 3% has given good results and is particularly preferred. All percentages mentioned are percentages by weight% (w / w), unless otherwise stated.

[0051] Pharmaceutical compositions of the invention suitable for topical administration to the hands and feet, preferably, to the hands and soles, are, for example, creams, lotions, ointments, microemulsions, fatty ointments, gels, emulsions-gels, pastes, foams, tinctures, solutions, dressings, bandages and transdermal therapeutic systems. Creams or gel emulsions are most preferred.

[0052] Creams or lotions are oil-in-water emulsions. The oil base that can be used is made up of fatty alcohols, especially those containing from 12 to 18 carbon atoms, e.g. lauryl, cetyl or stearyl alcohol, fatty acids, especially those containing from 10 to 18 carbon atoms, e.g. palmitic acid or stearyl acid , fatty acid esters, e.g. glycerol tricaprylodecanoate (neutral oil) or cetyl palmitate, liquid or solid waxes, for example isopropyl myristate, wool wax or beeswax, and / or hydrocarbons, especially liquid, semi-solid or solid substances or mixtures thereof, e.g. petroleum jelly (microcrystalline paraffin, petroleum jelly) or

EP 2 035 006 B1 paraffin oil. Suitable emulsifiers are surface-active substances having mainly hydrophilic properties, such as suitable non-ionic emulsifiers, for example fatty acid and polyalcohol esters and / or their ethylene oxide addition compounds, particularly suitable fatty acid esters with (poly) ethylene glycol, (poly) propylene glycol or sorbitol, fatty acid units containing especially from 10 to 18 carbon atoms, especially partial fatty acid and glycerol esters or partial polyhydroxyethylene fatty acid esters of sorbitan, such as polyglycerol fatty acid esters or polyoxyethylene sorbitol fatty acid esters (Tweens), as well as polyoxyethylene fatty alcohol ethers or fatty acid esters, particularly fatty alcohol units containing from 12 to 18 carbon atoms and fatty acid units, especially from 10 to 18 carbon atoms, such as polyhydroxyethylene glycerol fatty acid ester (e.g. Tagat S), or suitable ionic emulsifiers such as alkali metal salts of fatty alcohol sulfates, especially having from 12 to 18 carbon atoms in the fatty alcohol unit, e.g. sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are, inter alia, anti-drying agents for creams, e.g. humectants, such as polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, as well as preservatives, fragrances, gelling agents, etc.

[0053] Ointments are water-in-oil emulsions containing up to 70%, and preferably from approximately 20% to approximately 50%, of water or an aqueous phase. Hydrocarbons, e.g. petrolatum, paraffin oil and / or hard paraffins, are particularly suitable for the fat phase, which, in order to improve the water binding capacity, preferably contain suitable hydroxyl compounds such as fatty alcohols or their esters, e.g. cetyl alcohol or alcohols wool waxes, or wool waxes or beeswax. Emulsifiers are suitable lipophilic substances, for example of the type indicated above, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and / or sorbitan isostearate. Additives to the aqueous phase are, among others, humectants, such as polyalcohols, e.g. glycerol, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances, etc.

[0054] Microemulsions are isotropic systems based on the following four components: water, surfactant, for example surfactants, lipid components such as non-polar or polar oil, for example paraffin oil, natural oils such as olive oil or corn oil, and alcohol or polyalcohol containing lipophilic groups, for example 2-octyldodecanol or ethoxylated glycerol or polyglycerol esters. If necessary, other additives may be added to the microemulsion. Microemulsions have micelles or particles smaller than 200 nm and are transparent or translucent systems, spontaneously formed, and are stable.

[0055] Fatty ointments are anhydrous and contain as a base particularly hydrocarbons, for example, paraffin, petrolatum and / or liquid paraffins, also natural or partially synthetic fats, such as glycerol fatty acid esters, for example triglycerides of coconut fatty acids, or preferably, oils hardened, for example hydrogenated peanut oil, castor oil or waxes, also partial glycerol fatty acid esters, for example glyceryl mono- and distearate, and also, for example, fatty alcohols that increase water absorption capacity, emulsifiers and / or additives mentioned in connection with ointments.

[0056] As for gels, a distinction is made between aqueous gels, anhydrous gels and low water gels, which gels consist of swellable, gel forming materials. Particularly transparent hydrogels based on inorganic or organic macromolecules are used. High molecular weight inorganic components having gel forming properties are mainly water-containing silicates, such as aluminum silicates, e.g. bentonite, magnesium aluminum silicates, e.g. Veegum, or colloidal silicic acid, e.g. Aerosil. For example, natural, semi-synthetic or synthetic macromolecules are used as high molecular weight organic substances. Natural and semi-synthetic polymers are derived, for example, from polysaccharides containing various hydrocarbon components, such as celluloses, starches, tragacanth, acacia and agar-agar, and gelatin, alginic acid and their salts, e.g. sodium alginate, and their derivatives, such as lower alkyl celluloses, for example methyl or ethyl cellulose, carboxy or lower hydroxy alkyl celluloses, for example carboxymethyl or hydroxyethyl cellulose. The components of the synthetic gel-forming macromolecules are, for example, suitably substituted

Unsaturated aliphatic compounds such as vinyl alcohol, vinylpyrrolidine, acrylic acid or methacrylic acid.

[0057] Emulsion gels - also called "emulgels" - are topical compositions that combine the properties of a gel with the properties of an oil-in-water emulsion. Unlike gels, they contain a lipid phase, which thanks to its fat regenerating properties enables massaging and at the same time direct absorption into the skin is felt as their beneficial property. In addition, increased solubility of active lipophilic components can be observed. One of the advantages of the emulsion-gel system over oil-in-water emulsions is the increased cooling effect that is caused by the cooling as a result of evaporation of the additional alcoholic component, if present.

[0058] Foams are fed, for example, from pressurized containers, are oil-in-water liquid emulsions in the form of an aerosol; unsubstituted hydrocarbons such as alkanes, for example propane and / or butane, are used as the propellant. As the oily phase, hydrocarbons, e.g. paraffin oils, fatty alcohols, e.g. cetyl alcohol, fatty acid esters, e.g. isopropyl myristate and / or other waxes are used, among others. As emulsifiers, mixtures of emulsifiers having mainly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and emulsifiers having mainly lipophilic properties such as sorbitan fatty acid esters (Spans) are used, among others. The usual additions, such as preservatives, etc. are also added.

[0059] Tinctures and solutions generally have an ethanol base to which water may be added and to which polyalcohols, for example glycerol, glycols and / or polyethylene glycol, such as humectants (humectants) to reduce evaporation are added , and fat renewing substances, such as fatty acid esters with low molecular weight polyethylene glycols, propylene glycol or glycerol, in other words lipophilic substances, soluble in aqueous mixtures as substitutes for fatty substances removed from the skin by ethanol, and, if necessary, other additives and additives. Appropriate tinctures or solutions can also be used in the form of an aerosol using appropriate devices. In this case, because of allopurinol solubility problems, its salt is more suitable for tinctures and solutions.

[0060] Transdermal therapeutic systems - in particular - with topical delivery of allopurinol contain an effective amount of allopurinol, optionally together with a carrier. Useful carriers include absorbable appropriate pharmacological solvents to assist the passage of the active ingredient through the skin. Transdermal delivery systems are, for example, in the form of dressings comprising (a) a substrate (= primer layer or film), (b) a matrix containing the active ingredient, optionally carriers and any (but preferably) special patch to attach the system to the skin, and usually ( c) protective film (= removable part). The matrix (b) usually occurs as a mixing of all components or can consist of separate layers.

[0061] All these systems are well known to those skilled in the art. The production of topically administered pharmaceutical preparations is carried out in a known manner, for example by dissolving or suspending allopurinol in the base or, if necessary, in part.

[0062] The compositions of the invention may also contain conventionally used additives and adjuvants for dermatological applications, such as preservatives, especially paraben esters, such as methylparaben, ethylparaben, propylparaben, butylparaben, or quaternary ammonium compounds, such as benzalkonium chloride, or formaldehyde donors, such as imidazolidinyl urea, or alcohols such as benzyl alcohol, phenoxyethanol or acids such as benzoic acid, sorbic acid; acids or bases used as pH buffering excipients; antioxidants, especially phenolic antioxidants, such as hydroquinone, tocopherol and their derivatives, as well as flavonoids, or various antioxidants, such as ascorbic acid, ascorbic acid palmitate; fragrances; fillers such as kaolin or starch; pigments or dyes; UV shielding compounds; humidifiers, especially glycerin, butylene glycol, hexylene glycol, urea, hyaluronic acid or their derivatives, compounds that inhibit free radicals such as vitamin E or its derivatives; penetration enhancers, especially propylene glycol; ethanol; isopropanol; dimethyl sulfoxide; N-methyl-2-pyrrolidone; fatty acids / alcohols such as oleic acid, oleyl alcohol; terpenes such as limonene, menthol, 1-8 cineol; alkyl esters such as ethyl acetate, butyl acetate; ion-evaporating compounds such as salicylic acid.

[0063] Further details on suitable formulations for topical use can be obtained from standard references, such as Banker and Rhodes (Ed) Modem Pharmaceutics 4th ed. (2002), published by Marcel Dekker Inc .;

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Harry's Cosmeticology (2000), 8th Edition, Chemical Publishing Co .; Remington's

Pharmaceutical Sciences 20th ed Mack Publishing Co. (2000).

[0064] In a preferred embodiment, allopurinol is obtained as a cream, preferably based on emollients, provided that the emollient base is suitable for topical application to the skin, is substantially non-toxic, and a suitable carrier for allopurinol or pharmaceutically acceptable salts thereof. A properly selected softener base can also provide relief as such. In a particular case, a moisturizer is preferred as a base.

[0065] The emollients may be, for example, fatty alcohols, hydrocarbons, triglycerides, waxes, esters, silicone oils and products containing lanolin. Fatty alcohols are e.g. cetyl alcohol, octyldodecanol, stearyl alcohol and oleyl alcohol. Hydrocarbons include mineral oil, petrolatum, paraffin, squalene, polybutene, polyisobutene, hydrogenated polyisobutene, ceresin and polyethylene. Triglycerides are e.g. castor oil, octane / decanoate triglycerides, hydrogenated vegetable oil, sweet almond oil, wheat germ oil, sesame oil, hydrogenated cottonseed oil, coconut oil, wheat germ glycerides, avocado oil, corn oil, trilaurine, hydrogenated castor oil , shea butter, coconut butter, soybean oil, mink oil, sunflower oil, thistle oil, macadamia nut oil, olive oil, apricot kernel oil, hazelnut oil and borage oil. Waxes include, e.g., carnauba wax, beeswax, candelilla wax, paraffin, Japanese wax, microcrystalline wax, jojoba oil, cetyl ester waxes and synthetic jojoba oil. Esters include, for example isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl linolate, 12-15 alcohol benzoates, cetyl palmitate, myristyl myristate, myristyl lactate, cetyl acetate, dipropylene glycol octanoate / decanoate, decyl olinate, diaryl stearate, and styrene stearate . Silicone oils are e.g. dimethicone (dimethyl polysiloxane) and cyclomethicone. Products containing lanolin are e.g. lanolin, lanolin oil, isopropyl lanolate, acetylated lanolin alcohol, acetylated lanolin, hydroxylated lanolin, hydrogenated lanolin and lanolin wax.

[0066] In a preferred embodiment, allopurinol is obtained by mixing it with a commercially available "Basic" base cream, such as Bag Balm or Basiscreme DAC (Deutsches Arzneimittel codex).

[0067] The daily dose of a topically administered formulation containing allopurinol or pharmaceutically acceptable salts thereof may depend on various factors such as gender, age, weight and individual condition of the patient as well as the chemotherapy being performed or planned.

[0068] Topical pharmaceutical compositions, e.g. in the form of creams, gel emulsions or gels, may be administered once, two or three times a day, and even more frequent applications, such as 5 to 10 times a day, are possible provided they do not appear symptoms of PPE. The dose may vary, depending on the severity of the PPE symptoms or cycles, or the doses of chemotherapeutic treatment.

[0069] The pharmaceutical composition of the invention is administered to patients already suffering from PPE at varying degrees of severity or as a preventative measure against patients susceptible to developing PPE as a result of undergoing chemotherapy or about to receive chemotherapy.

[0070] Administration can be intensified shortly before, during and after chemotherapy, when the risk of developing PPE is high and can be reduced during rest periods between cycles.

[0071] The invention will now be illustrated by way of examples, but they should not be considered as limiting the scope of protection of the invention as defined in the claims.

EXAMPLES

Example 1

Preparation of a formulation containing allopurinol for topical administration [0072] The formulation was prepared by suspending allopurinol base (3% by weight of total formulation) in 5% water, followed by the addition of Basiscreme DAC cream (92%) and mixing.

[0073] The composition of the Basic DAC basic cream is as follows:

Glycerol monostearate: 4.0

Cetyl alcohol: 6.0

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Medium chain triglyceride: 7.5 White petroleum jelly: 25.5

Polyoxyethylene glycerol monostearate: 7.0 Propylene glycol: 10.0 Water: 40.0 [0074] The resulting cream is distributed into appropriate containers and stored. The cream is easy for patients to use.

Example 2

Treatment of palmar-plantar erythrodysaesthesia [0075] Patients with colorectal cancer were treated with chemotherapy (adjuvant or palliative adjuvant) using the usual protocol. Immediately after the first symptoms of palmar-plantar erythrodysaesthesia appeared, after the start of chemotherapy, patients were given the cream obtained in Example 1.

[0076] The characteristics of the patients treated with the cream and subjected to the chemotherapy regimen were as follows:

Patients with advanced colorectal cancer or metastases: 8

Phase III resection patients with colon cancer: 2

Chemotherapy:

[0077]

Shock dose (bolus) 5FU + LV (Mayo protocol): 1 patient Infusion 5FU + LV (AIO protocol): 7 patients

Single capecitabine therapy: 2 patients

[0078] The cream was applied 5 times a day to the hands and feet as long as chemotherapy was carried out. The frequency was lowered between cycles and increased shortly before and during chemotherapy.

[0079] Results: After topical treatment with allopurinol, the symptoms of PPE disappeared and chemotherapy could be completed without any dose reduction or delayed treatment with PPE. This is particularly important in patients receiving high doses of 5FU24H + leucovorin, for whom the incidence of PPE has been as high as 34%.

Example 3

Treatment of palmar-plantar erythrodysaesthesia [0080] Patients suffering from colon cancer or breast cancer underwent the following standard chemotherapy from January 2005 to March 2007:

• AJO protocol for high dose 5FU24H + leucovorin • FOLFOX 4: 1 day: oxaliplatin, 85 mg / m² and leucovorin, 200 mg / m², concurrently iv, then 5-FU, 400 mg / m² IV bolus followed by 600 mg / m² continuously iv; Day 2: Leucovorin, 200 mg / m² iv, then 5-FU, 400 mg / m²IV bolus followed by 600 mg / m² iv continuous; repeated every 2 weeks.

• Oral capecitabine.

[0081] Patient characteristics are summarized in Table 1.

Table 1. Patient characteristics

<td></td><td>n</td>

<td>patients</td><td> 35</td>

<td>Age</td><td></td>

<td>Median</td><td> 67</td>

<td>Range</td><td> (42-83)</td>

<td>ECOG results</td><td></td>

<td> 0</td><td> 21</td>

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<td></td><td>n</td>

<td> 1</td><td> 14</td>

<td> 2</td><td> 0</td>

<td>Sex</td><td></td>

<td>Men</td><td> 11</td>

<td>Women</td><td> 24</td>

<td>Type of cancer</td><td></td>

<td>Breast cancer</td><td> 8</td>

<td>Colon cancer</td><td> 27</td>

<td>Prior chemotherapy</td><td></td>

<td>Yes</td><td> 10</td>

<td>No</td><td> 25</td>

<td>Therapy regime</td><td></td>

<td>5-FU: AIO</td><td> 16</td>

<td>FOLFOX 4</td><td> 7</td>

<td>capecitabine</td><td> 12</td>

[0082] Palmar-plantar erythrodysaesthesia (PPE) appeared in 30% of patients treated with 5-FU and in 66% of patients receiving capecitabine. The time of onset and severity of the case varied, the results are summarized in Table 2.

Table 2. Palmar-plantar erythrodysesthesia

<td></td><td>n</td><td> %</td>

<td>patients</td><td></td><td></td>

<td>Total number</td><td> 35</td><td></td>

<td>PPE symptoms</td><td> 15(35)</td><td> 42%</td>

<td>AIO</td><td> 5(16)</td><td> 31%</td>

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<td></td><td>n</td><td> %</td>

<td>FOLFOX 4</td><td> 2(7)</td><td> 28%</td>

<td>capecitabine</td><td> 8(12)</td><td> 66%</td>

<td>Degree of toxicity PPE (NCI)</td><td></td><td></td>

<td> 1</td><td> 1</td><td> 6,6%</td>

<td> 2</td><td> 5</td><td> 33%</td>

<td> 3</td><td> 9</td><td> 60%</td>

<td>Cumulative doses with a 5-FU regimen to appear EPP</td><td></td><td></td>

<td>AIO</td><td></td><td></td>

<td>Median</td><td>42,000 mg</td><td></td>

<td>Range</td><td>(23,000 mg - 64,800 mg)</td><td></td>

<td>FOLFOX 4</td><td></td><td></td>

<td>Median</td><td>40,000 mg</td><td></td>

<td>Range</td><td>(38,000 mg - 42,000 mg)</td><td></td>

<td>Cumulative doses with capecitabine until onset EPP</td><td></td><td></td>

<td>Median</td><td>81.000 mg</td><td></td>

<td>Range</td><td>(35,000 mg - 180,000 mg)</td><td></td>

[0083] These data are well correlated with documented PPE morbidity.

[0084] The cream containing allopurinol, obtained as in Example 1, was applied topically by patients 4-5 times a day, on hands and feet. In the absence of response to this treatment and persistent PPE symptoms, the chemotherapy dose was reduced and chemotherapy was discontinued in some cases. The answer is summarized in Table 3.

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Table 3. Response to allopurinol treatment

<td></td><td>n</td><td> %</td>

<td>PPE patients</td><td> 15</td><td></td>

<td>(TR)</td><td> 13</td><td> 86,6%</td>

<td>(CR)</td><td> 10</td><td> 66,6%</td>

<td>(PR)</td><td> 3</td><td> 20,0%</td>

<td>(NR)</td><td> 2</td><td> 13,3%</td>

<td>AIO</td><td> 5</td><td></td>

<td>(TR)</td><td> 5</td><td> 100%</td>

<td>(CR)</td><td> 4</td><td> 80%</td>

<td>(PR)</td><td> 1</td><td> 20%</td>

<td>(NR)</td><td> 0</td><td> 0%</td>

<td>FOLFOX-4-</td><td> 2</td><td></td>

<td>(TR)</td><td> 1</td><td> 50%</td>

<td>(CR)</td><td> 0</td><td></td>

<td>(PR)</td><td> 1</td><td> 50%</td>

<td>(NR)</td><td> 1</td><td> 50%</td>

<td>capecitabine</td><td> 8</td><td></td>

<td>(TR)</td><td> 7</td><td> 87%</td>

<td>(CR)</td><td> 5</td><td> 62,5%</td>

<td>(PR)</td><td> 2</td><td> 25%</td>

<td>(NR)</td><td> 1</td><td> 12,5</td>

<td colspan="3">TR: complete response. CR: complete resolution of symptoms PR: Partial remission NO: no response</td>

[0085] In 86% of patients response to treatment was noted, with a reduction of symptoms in 20% and a complete disappearance in 66%.

[0086] No toxic effects associated with topical allopurinol treatment were noted, and patient compliance and improvement in PPE symptoms were surprising. As a result, their quality of life has significantly improved.

[0087] In 86% of patients with this PPE, treatment with allopurinol allowed for scheduled completion of chemotherapy.

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