Using allopurinol for treating palmar-plantar erythrodysesthesia syndrome

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry and represents a therapeutic agent used for treating or preventing palmar-plantar erythrodysesthesia syndrome (PPES) induced by a multifunction kinase inhibitor (MKI) therapy and containing a therapeutically effective amount of allopurinol or its pharmaceutically acceptable salt.

EFFECT: invention provides extending the range of products for treating or preventing palmar-plantar erythrodysesthesia syndrome (PPES) induced by the multifunction kinase inhibitor (MKI) therapy.

21 cl, 5 ex

 

The SCOPE of the INVENTION

The present invention relates to the field of therapy, especially in Oncology. It refers to the use of allopurinol or pharmaceutically acceptable salts for the treatment or prevention of hand-foot syndrome (LPS) caused by multi-kinase inhibitors (MIC). It also relates to a method of treatment of LPS.

BACKGROUND of the INVENTION

Malignant neoplasms are a group of diseases in which abnormal cells are able to uncontrolled division. Cancer cells can invade nearby tissues and can spread through the bloodstream and lymphatic system to other parts of the body. There are several types of malignant tumors. Carcinoma is a malignant tumor that develops in the skin or in tissues that restrict or cover internal organs. Sarcoma is a malignant tumor that develops in the bone, cartilage, adipose tissue, muscle, blood vessels, or other connective or supportive tissues. Leukemia is a malignant neoplasm originating from hematopoietic tissues, such as bone marrow, leading to the formation and enters the bloodstream of a huge number of atypical blood cells. Lymphoma and multiple myeloma are C kachestvennymi neoplasms, which develop from cells of the immune system.

Regarding malignant tumors there are several methods of treatment, including surgical treatment and radiation therapy for localized disease, and drugs that destroy cancer cells (chemotherapy). Chemotherapy plays a significant role in the treatment of malignant tumors, because it is required in the treatment of advanced stages of malignant tumors with distant metastases and often contributes to the reduction of tumor volume before surgery (neoadjuvant therapy). It is also used after surgery or radiation (adjuvant therapy) to destroy any residual cancer cells or prevent recurrence of malignant tumors.

Many anticancer drugs are created with the involvement of different mechanisms of their action: the most commonly used alkylating agents influencing directly on the DNA (such as cisplatin, carboplatin, oxaliplatin, busulfan, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine; antimetabolites, preventing DNA synthesis and RNA (such as 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine (Ara-C), fludarabine); anthracyclines, preventing the enzymes involved the military in DNA replication (such as daunorubicin, doxorubicin, epirubicin, idarubitsin, mitoxantrone); substances razrushayushie microtubules (taxanes, such as paclitaxel and docetaxel, or Vinca alkaloids such as vinblastine, vincristine and vinorelbine); topoisomerase inhibitors (such as etoposide, doxorubicin, topotecan and irinotecan); means for hormonal therapy (such as tamoxifen, flutamide) and recently introduced tools for targeted therapy (such as EGFR inhibitors cetuximab and gefitinib or inhibitor of protein tyrosine kinase imatinib).

The development of chemotherapy in recent decades has significantly improved the treatment of malignant tumors that have led to effective recovery of certain types of malignant tumors and improved survival or time to disease progression in other forms. Currently, most chemotherapeutic agents are administered intravenously; however, a chemotherapeutic drug for oral administration are becoming more commonly used.

Unfortunately, most chemotherapeutic agents are unable to distinguish between malignant and healthy cells. Therefore, chemotherapy is often impairs normal organs and tissues of the body, which leads to complication of treatment or side effects. In addition to caused difficulties, side effects can not ozbolat doctors to follow the prescribed dose of chemotherapy, that reduces the likelihood of adequate treatment of malignant neoplasms. The most frequent side effects are anemia, neutropenia, thrombocytopenia, fatigue, alopecia, nausea and vomiting, inflammation of the mucous membranes and pain.

One of the side effects associated with certain chemotherapeutics, especially with 5-fluorouracil and its prodrug by involving capecitabine is Palmar-plantar erythrodysesthesia (let), erythematous rash on the hands and feet, also known as acrolina erythema (AE). Let is a characteristic and relatively frequent toxic reaction. It is a painful swelling and erythematous rash, localized on the hands and feet, often accompanied by disturbances of sensation, usually in the form of tingling, and is often associated with edema. The rash may become bullous and then otshelushivatsya without scarring with a gradual worsening of pain. Erythema may also appear in the area of the nail bed. Usually it is restricted by the arms and legs, the arms usually are affected stronger than his legs.

Histological analysis let reveal moderate interstitial edema, diffuse necrotic and devoid of keratin, keratinocytes, and vacuole-type degeneration of the basal layer. In Tricone changes in most cases include dilated blood vessels, edema of the papillary layer and the diffuse superficial perivascular lymphohistiocytic infiltration found in varying degrees in the epidermis.

Let clearly differs from other adverse skin reactions and are described in detail inNagore E. et al., Am J. Clin. Dermatol. 2000, 1(4), 225-234.Despite the frequency of its causes are largely unknown.

The emergence in recent decades of molecular targeted therapy has changed the nature of the treatment of malignant tumors. Among the methods targeted therapy of malignant neoplasms increased interest in the development of medications that suppress angiogenesis - the process by which the formation of new blood vessels. The formation of tumor vessels can stop and even reverse, by suppressing the activity of receptors, such as platelet growth factor (DERIVED) and growth factor receptor vascular endothelial (VEGFR), or by inhibition of components of their signaling cascades. Some of these targets are universal cascade of mitogen-activated protein kinase (MAPK) and the cascade Raf/MEK/ERK, also including signaling through MAPK and controlling the growth and survival of human tumors through regulation of the angiogenic cascade. Solid tumors are often characterized by activating oncogenic mutations in Ras and/or Sergachev what she Raf-1 kinase, leading to dysregulation of signaling through the MAPK cascade and the subsequent proliferation of tumor cells and angiogenesis.

Such a reasonable approach to the treatment of malignant tumors leads to the development of second generation inhibitors tyrosinekinase, which is capable of hitting multiple targets or cascades. Extremely attractive funds are aimed at many stages of tumor growth, potentially having effects of combination therapy in a single tool. Most of these new means inhibits more than one tyrosinekinase receptor and may have a unique profile of inhibition. Among multi-kinase inhibitors (MIC) sorafenib and sunitinib already approved for use, and vandetanib, motesanib, ABT-869 and some other compounds are still under development.

Sorafenib (Nexavar®) is an oral drug, is able to suppress several tyrosinekinase receptors involved in tumor progression and angiogenesis. Sorafenib blocks the Raf gene products (serine-treoninove kinases), including mutant B-Raf, along with produced platelet-growth factor-beta (DERIVED-β), FLt3, receptioni growth factor vascular endothelial-2 and 3 (VEGFR-2 and 3). In 2005, sorafenib is approved by the FDA, and in 2006, approved by the EMEA for the treatment of meta is teticheskoi pochernkletocny carcinoma and advanced stages of liver carcinoma.

Sunitinib (Sutent®) is an oral drug, multipurpose inhibitor tyrosinekinase that blocks VEGFR-1, 2 and 3, DERIVED α and β, Ret, c-Kit and FLT3. In 2006 it was approved by the FDA and EMEA for use in patients with gastrointestinal stromal tumors (GIST) that cannot tolerate or unresponsive to of imatinib mesilate, as well as in patients with metastatic pochernkletocny carcinoma. It is usually prescribed courses of 4 weeks with 2-week intervals in order to allow patients to recover from possible toxic effects.

MCI, such as sorafenib and sunitinib, have side effects, the most frequent of which are fatigue, hypertension, nausea, and diarrhea. However, the level of their security, as a rule, more preferable compared to many standard chemotherapeutic agents.

However, like other inhibitors tyrosinekinase, MICK associated with significant dermatological adverse reactions. Palmar-plantar syndrome (LPS) is the most significant clinical terms (Rosenbaum SE et al. Support Care Cancer (2008) 16:557-566 "Dermatological reactions to the multitargeted tyrosine kinase inhibitor sunitinib"; Robert C et al. J. Am. Acad. Dermatol. 2009, vol. 60 no. 2, 299-305 "Dermatological symptoms associated with the multikinase inhibitor sorafenib").

Palmar-plantar syndrome (LPS) is a certain limited skins is th reaction, particularly on the palms and/or soles, characterized by erythema, numbness, tingling and other dysesthesia or paresthesia. Histological examination it is characterized by thickening, pronounced be accompanied lesions, often affecting joints of the toe area. It develops within the first 2-4 weeks after the appointment of MICK. After a few weeks of lesion, with or without blisters, supplemented painful areas of thickening or hyperkeratosis of the skin that looks like skin blisters.

LPS is described in:Lacouture ME, et al. The Oncologist 2008, 13, no. 9, 1001-1011: "Evolving Strategies for the management of Hand-Foot Skin Reaction associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib"; Beldner M et al. The Oncologist 2007 12:1178-1182 "Localized Palmar-Plantar epidermal hyperplasia: a previously undefined dermatological toxicity to sorafenib"; Yang CH, et al. British journal of Dermatology 2008, 158 592-596 "Hand-Foot skin reaction in patients treated with sorafenib: a clinopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy"; Porta C, et al. Clin Exp Med 2007, 7:12-134 Uncovering Pandora's vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib"; L. Wood et al. Community Oncology 2010, vol. 7, no. 1 pages 23-29: "Practical Considerations in the Treatment of Hand Foot Skin Reaction caused by Multikinase Inhibitors".

As indicated in these publications, Palmar-plantar syndrome clinically and histologically different from Palmar-plantar erythrodysesthesia (let) [also known as acrolina erythema (AE)] caused by chemotherapy such as 5-FU, capacit the binomial or paglierani liposomal doxorubicin.

Both conditions demonstrate Palmar-plantar localization, sensitivity disorders, pain and reduction of lesions after discontinuation of the drug.

However, LPS from let distinguishes the typical picture be accompanied localized lesions surrounded by erythematous areas where there are symmetric paresthesias, diffuse painful erythema and swelling. Moreover, LPS can affect and outside the region, such as the membrane between the fingers of the hands and feet and side surfaces of the feet. In the pathogenetic aspect MICK cause vacuole-type degeneration of keratinocytes in the spinous layer together with epidermal acanthosis, while caused by chemotherapy let demonstrates inflammation on the edge of the internal layer of the skin and epidermis, as well as using the degeneration of basal keratinocytes. The main histological changes observed in LPS, are considered to be impaired maturation of cells with abnormalities in the differentiation of keratinocytes, the potential increase in the level of apoptosis in this cell population, as well as specific inflammation. When FSC speed doubling epidermal cells significantly increased in areas of active lesions. The main histopathological characteristics relevant to the FSC, is damage to keratinocytes, which is manifested in the appearance is unique to this state of intracellular eosinophilic cells. The mechanism of occurrence of LPS is unknown.

The frequency of occurrence of LPS high. The meta-analysis showed that the total frequency FSC in patients receiving sorafenib, is to 33.8% for stages 1-3 and 8.9% in stage 3 (Chu D., Lacouture ME et al. Acta Oncologica 2008; 4 16-186: "Risk of Hand Foot Skin Reation with Sorafenib: A systematic Review and Meta-Analysis"). For sunitinib total frequency calculated as of 18.9% for stages 1-3 and 5.5% in stage 3 (Chu D. Lacouture ME, et al. Clinical Genitourinary Cancer 2009, no. 1 11-19: "Risk of Hand Foot Skin Reation with the Multitargeted Kinase Inhibitor Sunitinib in patients with Renal Cell and Non-Renal Cell carcinoma: a Meta-analysis"). In patients receiving MICK, such as sorafenib and sunitinib, LPS could negatively affect normal quality of life and everyday life.

The severity of LPS is a major component of the widely used Common terminology criteria for adverse effects of the National cancer Institute (NCI-CTCAE v. 3,0). Clinical signs of each stage are:

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

2. Skin changes (e.g., peeling, blisters, bleeding, edema) or pain; without disrupting your everyday life;

3. Ulcerative dermatitis or painful skin changes; break everyday life of the patient.

It can also be classified according to the modified criteria more appropriate draconically practice ( Porta C, et al. Clin Exp Med 2007, 7:12-134):

1. Numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema or discomfort in the arms or legs, do not disrupt the normal activity of the patient;

2. One or more of the following symptoms: painful erythema, swelling, hyperkeratosis of the hands or feet, discomfort, disrupt the normal activity of the patient;

3. One or more of the following symptoms: moist desquamation, ulceration, blisters, hyperkeratosis, severe pain in the hands and feet, severe discomfort, which do not allow the patient to work or to conduct everyday life.

Currently there is no effective treatment of LPS. Before MICK therapy is recommended to remove the existing be accompanied plots and corn. In the case of skin reaction after the start of therapy MICK may be offered some of the following treatments: cold compresses or ice packs, to avoid pressure on the hands or feet; skin hydration; skin softening cream, ointment clobetasol or local anesthetics. For more severe stages (2-3) recommended dose reduction or treatment discontinuation by MICK. Also taken into consideration creams containing urea, fluorouracil, tazarotene, because these environments is TBA inhibit the proliferation of keratinocytes ( Lacouture ME, et al. The Oncologist 2008, vol. 13, no. 9, 1001-1011: "Evolving Strategies for the management of Hand-Foot Skin Reaction associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib", Anderson et al. The Oncologist 2009, vol. 14, no. 3, 291-302: "Search for evidence-based approaches for the prevention and palliation of Hand-foot Skin Reaction (HFSR) caused by the Multikinase Inhibitors"); L. Wood et al. Community Oncology 2010, vol. 7, no. 1 opages 23-29: "Practical Considerations in the Treatment of Hand Foot Skin Reaction caused by Multikinase Inhibitors").

None of the currently proposed treatment methods are not able to effectively treat or prevent LPS. This is a serious problem for the patient, because in addition to the internal discomfort and pain in advanced stages it leads to reduction or cessation of chemotherapy through the MIC, which has a negative impact on the survival and/or time to progression of malignant neoplasms in the treatment process. Obviously still needs to create an effective treatment of LPS in order to realize the full potential multikinase inhibitors, different treatment regimens and combinations in which they can and will be used.

Allopurinol is a structural isomer gipoksantina, it inhibits xanthine oxidase, an enzyme that transforms oxypurine in uric acid. By blocking the production of uric acid, this tool reduces the concentration of uric acid in serum and urine, thereby providing protection from uric acid terminal defeat the body is in the States, associated with excessive production of uric acid. For many years it is used for the treatment or prevention of gout, hyperuricemia and kidney stones through oral or parenteral systemic administration.

It has been shown the use of allopurinol for the treatment of mucositis is widespread and caused by chemotherapy or radiation therapy defeat bystrogasjashchejsja cells lining the mouth, throat and gastro-intestinal tract (GIT). Allopurinol is used in the form of liquids for rinsing of the mouth (dispersion in water) (Porta C. et al., Am J. Clin. Oncol. 1994, Vol 17, no.3, 246-247). Improved composition of liquids for rinsing of the mouth, including allopurinol, carboxymethylcellulose and water described in the patent JP-3106817.Hanawa et al.inDrug Dev Ind Pharm 2004, 30(2) 151-161describe other liquid for rinsing the mouth, including allopurinol, polyethylene oxide and carrageenan.Kitagawa et al.note inJ. Radiation Research, 2008, vol. 49, no. 1, 49-54that gel allopurinol decreases caused by radiation therapy mucositis and dermatitis in rats.Dagher et al., Canadian Journal of Hospital Pharmacy, vol. 40, no.5 1987, page 189indicate the use of a fluid for rinsing the mouth with allopurinol and 0.1% vaginal cream for the treatment of mucositis induced by 5-FU.

Patents WO 94/05293 and WO 94/05291 describe a synergistic composition comprising methylsufonylmethane (MSM) and at m is re, one of oxipurinol or allopurinol, and their use for the treatment of skin conditions, diseases and injuries, such as burns, dermatitis, hyperkeratosis, sun exposure, aging, etc. Oxypurinol and allopurinol described as a means of enhancing the healing of skin or reducing properties of MSM.

Patent WO 2007/138103 describes and provides examples of the use of allopurinol, in particular, a topical cream for the treatment of Palmar-plantar erythrodysesthesia or acrelno erythema caused by chemotherapy torpedinidae (5-FU and involving capecitabine). However, the specialist is known that at the molecular level ftorpirimidinu and multi-kinase inhibitors work by completely different mechanisms, and, as noted above, their toxic effects on the skin differ both clinically and histologically.

In fact, an interdisciplinary team of specialists in theWood et al. Community Oncology)on page 1 resolved that:

"MICK-associated LPS represents a toxic effect on the skin, clinical and pathomorphological different from the AE observed in the case of the earlier chemotherapeutic agents".

None of the cited document does not imply or suggest that allopurinol can be used for the treatment or prevention of hand-foot syndrome LPS).

The INVENTION

Inventor unexpectedly found that in the case of local application, particularly on the palms and feet of the patient, allopurinol extremely effective in the treatment and prevention of hand-foot syndrome (LPS) caused by multi-kinase inhibitors (MIC). As shown in the examples, the local use of allopurinol in patients with malignancies receiving MICK and have developed this condition, leads to the complete disappearance of the symptoms and prevent further occurrence of LPS. This is more pronounced in patients with typical FSC developed hyperkeratosis, as should be expected that local effects on fat orogovevshi layer located on the hands and feet, as well as the process and return the skin to its normal state in a short period of time with the disappearance of hyperkeratosis, as shown in one of the examples, it will be extremely difficult.

Thus, in one aspect the invention relates to a medicinal product containing allopurinol or pharmaceutically acceptable salt, for use in the treatment or prevention of hand-foot syndrome caused by multi-kinase inhibitor (MIC).

In the second aspect, the invention relates to the use of allopurinol, Riego pharmaceutically acceptable salts in the manufacture of a medicinal product for the treatment or prevention of hand-foot syndrome, called multi-kinase inhibitor.

In the third aspect, the invention relates to a method for the treatment or prevention of hand-foot syndrome caused by multi-kinase inhibitor in a patient affected or prone to this condition, including local application of a therapeutically effective amount of allopurinol or pharmaceutically acceptable salt.

Additional embodiments of the invention defined in the claims.

DETAILED description of the INVENTION

As used herein, the term "multipurpose inhibitor tyrosinekinase receptor" refers to compounds having a profile of binding to receptors, such as the selectivity to many receptors, which shows the important role in the process of angiogenesis.

In the context of the present invention, the term "hand-foot syndrome (LPS) defines a side effect on the skin of the hands and feet of a patient with malignant neoplasm receiving multipurpose inhibitor tyrosinekinase receptors. The clinical and histological features, as well as his stage described above. As was explained, it differs from Palmar-plantar erythrodysesthesia (let), also known as acrolina erythema (AE), caused by other chemotherapeutics,such as 5-FU and capecitabine.

In the context of the present invention, the term "allopurinol" refers to various tautomeric compounds, since it is a tautomeric mixture of 1H-pyrazolo-(3,4-d)-pyrimidine-4-ol and 1,5-dihydro-4H-pyrazolo(3,4-d)pyrimidine-4-it:

As indicated above, it has been unexpectedly found that local administration of allopurinol or pharmaceutically acceptable salt is suitable for the treatment and prevention of LPS caused MICK.

Thus, in one aspect the invention relates to the use of allopurinol or pharmaceutically acceptable salts in the manufacture of a medicinal product for the treatment or prevention of LPS induced therapy multi-kinase inhibitor.

In one of the embodiments, the drug is in the form of a cream. Preferably, the cream is a hydrophilic cream.

In another embodiment, the drug is intended for treatment of LPS caused MICK sorafenib alone and in combination with other agents.

In another embodiment, the drug is intended for treatment of LPS caused MICK sunitinib, both independently and in conjunction with other tools.

Thus, a drug suitable for the treatment of patients suffering from malignant neoplasm, preferably pochernkletocny carcinoma, liver carcinoma, breast cancer, stromal tumors of the gastrointestinal tract (GIST), small cell lung cancer (NSCLC), melanoma and receiving MICK therapy as adjuvant, neoadjuvant or palliative. Examples of patients and treatments, causing LPS, was discussed in the section "Background of the invention".

Drug for the treatment of LPS containing allopurinol, especially suitable for patients receiving or planning to receive sorafenib, sunitinib or other MICK, both independently and in conjunction with other tools.

Local application of allopurinol ensures effective treatment of affected areas and prevents toxic effects and complications that can cause systemic introduction of allopurinol patients with malignant neoplasms. This allows you to avoid a negative impact on therapy of malignant tumors.

Allopurinol is a compound that is poorly soluble in water and alcohol; practically insoluble in chloroform and in simple ether; it dissolves in dilute solutions of hydroxides of alkali metals. It can be used in native form, or instead, you can use salt, such as sodium salt, to improve rest is remote in the water.

In a preferred embodiment, the drug is in the form of local pharmaceutical composition for the treatment of hands and feet, including allopurinol or its pharmaceutically acceptable salt together with at least one material carrier that is acceptable for local use.

Local compositions used for the treatment of LPS, allopurinol or its salts are usually present in amounts from about 1 to 10%, in particular 1 to 8%, more specifically 1 to 6%, in particular from 1 to 5%. Concentration of about 1%, about 3% and about 8% are preferred.

The preferred range is from 2 to 5%, preferably 2-4% by weight of the total composition. Content of about 3% gives good results and is particularly preferably. Unless otherwise stated, all percentage specified as wt.% (mass./mass.).

Pharmaceutical compositions suitable for topical application to the hands and feet, more preferably in the affected areas of the palms and soles, are, for example, creams, lotions, ointments, micro-emulsions, fatty ointments, gels, emulsion-gels, pastes, foams, tinctures, solutions, plasters, bandages and transdermal therapeutic systems. Most preferred are the cream or emulsion-gels.

Creams or lotions are emulsions of oil-in-water". Suitably the oil and the basics are fatty alcohols, especially containing from 12 to 18 carbon atoms, for example lauric, cetyl or stearyl alcohol, fatty acids, particularly those containing from 10 to 18 carbon atoms, such as palmitic or stearic acid, esters of fatty acids, for example glyceryltrinitrate (neutral oil) or cetylpalmitate, liquid paraffins, such as isopropylmyristate, lanolin or beeswax, and/or hydrocarbons, especially liquid, semi-solid or solid substances or mixtures, such as petroleum jelly (petrolatum, petrolatum) or paraffin oil. Suitable emulsifiers are surface-active substances having predominantly hydrophilic properties, such as corresponding non-ionic emulsifiers, for example esters of fatty acid and polyalcohol and/or products with the addition of ethylene oxide, in particular, the corresponding esters of fatty acids, (poly)ethylene glycol, (poly)propylene glycol or sorbitol, in particular, residues of fatty acids containing from 10 to 18 carbon atoms, in particular partial esters of glycerol and fatty acids or partial esters of fatty acids and polyhydroxyethylmethacrylate, such as polyglyceryl esters of fatty acids or esters of polyoxyethylenesorbitan and fatty acids (Tweens), and polyoxyethylene ethers LM is different alcohols or esters of fatty acids, residues of fatty alcohols containing in particular from 12 to 18 carbon atoms and residues of fatty acids, in particular from 10 to 18 carbon atoms, such as esters of polyhydroxyalkanoates and fatty acids (for example, Tagat S), or corresponding ionic emulsifiers, such as alkali metal salts of sulfates of fatty alcohols, in particular having from 12 to 18 carbon atoms in the residue of a fatty alcohol, such as lauryl sulfate, tamilselvam sodium or sterilant sodium, which are usually used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are, among other means, to protect the cream from drying out, for example humectants, such as a polyalcohol such as glycerin, sorbitol, propylene glycol and/or polyethylene glycol, as well as preservatives, fragrances, gel-forming means, and so on

Creams are emulsions of water in oil, containing up to 70%, but preferably from about 20% to about 50% water or aqueous phase. Suitable oily phase are, in particular, hydrocarbons, for example petroleum jelly, paraffin oil and/or hard paraffins, which, in order to improve the ability to bind water, preferably contains suitable hydroxyl compounds such as fatty alcohols or their esters, which for example cetyl alcohol, or lanolin alcohols or lanolin or beeswax. Emulsifiers are appropriate lipophilic substances, for example, from the above, such as esters of sorbitol and fatty acids (Spans), such as sorbifolia and/or serbianization. Additives to the aqueous phase, among others, are moisturizers such as a polyalcohol such as glycerin, propylene glycol, sorbitol and/or polyethylene glycol, as well as preservatives, flavorings, etc.

Microemulsions are homogeneous system, based on the following four components: water, surfactant, non-polar or polar lipid, for example paraffin oil, natural oils, such as olive or corn oil, and alcohol or propertystorage lipophilic group, for example 2-octyldodecanol, or ethoxylated glycerol, or polyglyceryl esters. If desired, the microemulsions can be added other additives. Microemulsions containing micelles or particles smaller than 200 nm and are spontaneously formed, stable, transparent or translucent systems.

Fatty ointments are anhydrous and as a basis contain, in particular, hydrocarbons, for example paraffin, petroleum jelly and/or liquid paraffins, also natural or partially synthetic fats, such as complex EF the market glycerol and fatty acids, for example, triglycerides of fatty acids of coconut oil, or preferably hydrogenated oils such as hydrogenated peanut oil, castor oil or paraffin, also fragments of esters of fatty acids and of glycerol, for example glycerol mono - and distearate, as well as, for example, fatty alcohols, increase the ability to bind water, emulsifiers and/or additives indicated in the case of ointments.

In the case of gels the differentiation between aqueous gels, anhydrous gels and gels with low water content, which consist of swelling gel-forming materials. In particular, the use of transparent hydrogels based on inorganic or organic macromolecules. Inorganic components with high molecular weight, having gel-forming properties are predominantly water-containing silicates such as aluminum silicates such as bentonite, silicates of magnesium and aluminum, such as Veegum, or colloidal silica, such as Aerosil. As organic substances with high molecular weight is used, for example, natural, presintations or synthetic macromolecules. Natural and semisynthetic polymers receive, for example, of polysaccharides containing a large variety of carbohydrate fragments, such as cellulose, starch, t is agakhanova gum, Arabian gum and agar-agar, gelatin, alginic acid and its salts, such as sodium alginate and its derivatives, such as lower alkylaryl, for example methyl - or ethylcellulose, lower carboxy - or hydroxyethylcellulose, for example carboxymethyl or hydroxyethylcellulose. Fragments of synthetic gel-forming macromolecules are, for example, the corresponding substituted unsaturated aliphatic compounds such as vinyl alcohol, vinylpyrrolidone, acrylic or methacrylic acid.

Emulsion-gels - also called "emulgel" - represent the local composition, combining the properties of the gel and emulsion oil-in-water". Unlike gels they contain lipid phase, which due to its ability to restore fat allows you to RUB the composition, while the direct absorption into the skin is perceived as pleasant. In addition, everyone can observe an increased absorption of lipophilic active ingredients. One of the advantages of emulsions gels before emulsions oil-in-water" is enhanced cooling effect that can be achieved by cooling due to evaporation of the auxiliary alcohol component, if any.

The foam is applied, for example, from pressurized containers and they are a Jew is their emulsions are oil-in-water" in the form of aerosols; as the spray substance use unsubstituted hydrocarbons, such as alkanes, for example propane and/or butane. As the oil phase used among other hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, esters of fatty acids, such as isopropylmyristate and/or other waxes. As emulsifiers are used, among others, a mixture of emulsifiers having predominantly hydrophilic properties, such as esters of polyoxyethylenesorbitan and fatty acids (Tweens), and emulsifiers, with predominantly lipophilic properties, such as esters of sorbitol and fatty acids (Spans). Also use standard additives, such as preservatives, etc.

Tinctures and solutions generally have a basis from ethanol, to which you can add water, and which adds, among others, a polyalcohol such as glycerol, glycols and/or polyethylene glycol, as humectants for reducing evaporation, and reducing oiliness agents such as esters of fatty acids with low molecular weight and polyethylene glycol, propylene glycol or glycerol, in other words, lipophilic soluble in aqueous mixtures of substances as substitutes for fatty substances removed from the skin by ethanol, and, if necessary, other auxiliary means and obuvki. Acceptable tinctures or solutions can also be applied in the form of a spray by means of a suitable device. Due to problems with solubility of allopurinol, in this case, the salt is more suitable for tinctures or solutions.

Transdermal therapeutic system, in particular, with local delivery allopurinol contain an effective amount of allopurinol optionally together with a carrier. Suitable carrier materials include absorbable pharmacologically acceptable solvents to facilitate penetration of the active ingredient through the skin. Transdermal delivery systems are, for example, the patch comprising (a) a substrate (supporting layer or film), (b) a basis containing the active ingredient, optionally carriers and optionally (but preferably) a special binder for attaching the system to the skin, and usually (c) protective coating (deleted thin film). Base (b) is typically present in the form of a mixture of all components, or may consist of separate layers.

All these systems are well known to specialists in this field. The pharmaceutical topical application in some sense by itself effectively, for example, by dissolving or distribution of allopurinol in basis or, if necessary, in its part.

The composition can so is e to include standard additives and adjuvants for dermatological applications, such as preservatives, in particular esters of parabens, 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; acid or base is used as the excipients pH buffer; antioxidants, in particular phenolic antioxidants, such as hydroquinone, tocopherol and derivatives thereof, as well as flavonoids, or a combination of antioxidants, such as ascorbic acid, ascorbyl palmitate; fragrances; fillers such as kaolin or starch; pigments or dyes; a means of protecting against UV light; humidifiers, in particular glycerol, butyleneglycol, hexyleneglycol, urea, hyaluronic acid or derivatives thereof; anti-free radicals, such as vitamin E or its derivatives; amplifiers permeability, in particular, propylene glycol; ethanol; isopropanol; dimethylsulfoxide; N-methyl-2-pyrrolidone; fatty acids/alcohols such as oleic acid, alerby alcohol; the terpenes such as limonene, menthol, 1,8-cineole; alkyl esters, such as ethyl acetate, butyl acetate; means forming ion pairs, such as salicylic KIS the PTA.

Additional features about the appropriate local structures can be obtained in standard manuals such asBanker and Rhodes (Ed) Modern Pharmaceutics 4th ed. (2002)published by Marcel Dekker Inc.;Harry's Cosmeticology (2000), 8th Edition, Chemical Publishing Co.; Remington''s Pharmaceutical Sciences, 20th ed Mack Publishing Co. (2000).

In a preferred embodiment, allopurinol enclosed in a cream composition, preferably based softening means, offer the basis of a cushioning means suitable for local application to the skin, virtually non-toxic and provides a suitable media for allopurinol or its pharmaceutically acceptable salt. Correctly selected the basis of the cushioning means may also by itself, to provide a slight calming effect. In the special case, moisturizer is the preferred basis.

Emollients can be, for example, fatty alcohols, hydrocarbons, triglycerides, waxes, esters, silicone oils and lanolin-containing products. Fatty alcohols are, for example, cetyl alcohol, artillerivej alcohol, stearyl alcohol and alerby alcohol. Hydrocarbons include mineral oil, petrolatum, paraffin, squalene, polybutene, polyisobutene, hydrogenated polyisobutene, ceresin and polyethylene. Triglycerides are, for example, castor oil, Caprylic/is April triglyceride, hydrogenated vegetable oil, sweet almond oil, wheatgerm oil, sesame oil, hydrogenated cottonseed oil, coconut oil, glycerides wheat germ oil, avocado oil, corn oil, Triowin, hydrogenated castor oil, oil from the seeds of Shea, cocoa butter, soybean oil, mink oil, sunflower oil, safflower oil, oil of Australian walnut, olive oil, oil of apricot pits, hazelnut oil and borage oil. Waxes include, for example, Carnauba wax, beeswax, wax candelilla, Japanese wax, microcrystalline wax, jojoba oil, celestedowy wax and synthetic jojoba oil. Esters include, for example, isopropylmyristate, isopropyl, octylpyrimidine, isopropyl linoleate, benzoate alcohols 12-15, cetylpalmitate, myristoleate, myristylated, cetilistat, propilenglikolstearat/capret, decillia, steuergeraet, diisostearate, activitiesthat and isopropyltoluene. Silicone oils are, for example, Dimethicone (dimethylpolysiloxane) and cyclomethicone. Lanolin-containing products are, for example, lanolin, lanolin oil, isopropylmalate, acetylated lanolin alcohol, acetylated lanolin, gidroksilirovanii lanolin, gidrogenizirovannye and lanolin wax.

In a preferred embodiment, allopurinol treated by mixing it with ordinary commercial cream, such as Bag Balm or Basiscreme DAC (Deutsches Arzneimittel codex).

The daily dosage of the local composition comprising allopurinol or its pharmaceutically acceptable salt may depend on various factors such as gender, age, weight and individual characteristics of the patient, as well as chemotherapy, which he receives or will receive, and the severity of LPS.

Local pharmaceutical compositions, for example, in the form of creams, emulsions, gels or gels can be applied once, twice or three times a day, it is also possible and more frequent application, from 5 to 10 times per day, provided that the symptoms LPS are eliminated or avoided. The dosage can be varioface depending on the severity of symptoms LPS, or courses or dosages therapy MICK. It is recommended to apply one tip of the finger or toe.

The pharmaceutical composition according to the invention is administered to patients already suffering from various stages of the FSC or as a prophylactic treatment in patients predisposed to the development of the FSC as a consequence of therapy MICK they receive or expect to receive.

The reception can be increased shortly before, during and after chemotherapy, when the risk of FSC above, and can be reduced during periodontia between courses.

The invention will be further illustrated by examples, which should not be construed as limiting the scope of invention defined by the claims.

EXAMPLES

EXAMPLE 1

Get the local composition comprising allopurinol.

The composition was obtained by suspension basics of allopurinol (3% by weight of the total composition) in 5% water and then adding Basiscreme AC (92%) and mixing.

The cream Basic DAC is as follows:

Glycerylmonostearate: 4,0

Cetyl alcohol 6,0

Medium chain triglycerides 7,5

White petrolatum 25,5

Poliauxietilenglikola 7,0

Propylene glycol 10,0

Water 40,0

The resulting cream is transferred into suitable containers and stored. The cream is easily applied by the patient.

EXAMPLE 2

Treatment of Palmar-plantar syndrome

The patient is male (65 years), have developed metastatic pochernkletocny carcinoma ((MRCC), was operated on and after the development of metastases received Nexavar® (sorafenib) as palliative therapy in reduced doses (200 mg 2 times a day). After 7 months, the treatment was stopped due to LPS, fatigue, loss of appetite and diarrhea. Try to spend palliative therapy third/second line was performed using Sutent® (sunitinib) in a reduced dosage of 37.5 mg daily for 1-28 days every 6 weeks.

In hoteleshanya with sorafenib, the patient developed LPS with extremely thick hyperkeratosis and pain in the hands and feet, which did not disappear when changing treatment from sorafenib on sunitinib. With the aim of improving its status, and in order to prevent disruption to the treatment of malignant neoplasms, proceeded to the local treatment obtained in example 1, the cream was applied 3 times daily.

Results: in the process of local administration of allopurinol almost completely disappeared symptoms LPS and therapy sunitinib managed to finish without any reduction in dosage or treatment delay due to LPS. Showed no toxic effects associated with the local use of allopurinol.

Surprisingly, after only one week of treatment with allopurinol symptoms LPS applied from stage 3 to stage 1 and 0 in most parts of the affected areas. The most significant was the disappearance of thick hyperkeratosis. Treatment sunitinib and cream allopurinol continued until the cessation of treatment due to tumor progression.

EXAMPLE 3

Treatment of Palmar-plantar syndrome.

The patient is male (74 years old), who have developed liver carcinoma (HCC), began to receive palliative therapy with sorafenib initially reduced dosage (200 mg 2 times a day). After 2½ months he developed stage 1 LPS. He was treated with cream allopurinol as described in example 1, and symptoms L Is With disappeared after 7 days.

The dosage of sorafenib increased to the recommended dose of 400 mg 2 times a day. Identified no additional symptoms LPS, despite the presence of other modifiable side effects such as diarrhea. The patient continued treatment with sorafenib on the planned scheme.

EXAMPLE 4

Patients (56 years) with metastatic pochernkletocny carcinoma ((MRCC) in August 2008 and was diagnosed with metastases in bones and lungs. He was initially treated with intravenous Torisel for 6 months. After the progression of metastases and nephrectomy of the right kidney, he was appointed Sutent® (sunitinib) as palliative therapy in standard dose 50 mg daily for 1-28 days every 6 weeks.

During treatment sunitinib the patient has developed an FSC with keratosis (scaling and defeat the fingertips and pain in the hands and feet, which did not disappear after treatment emollient cream. With the aim of improving its status, and in order to prevent disruption to the treatment of malignant neoplasms, proceeded to the local treatment obtained in example 1, the cream was applied 3 times daily.

Results: as a result of local administration of allopurinol almost completely disappeared symptoms LPS and therapy sunitinib managed to finish without any reduction in dosage or what dedimania treatment due to LPS. Showed no toxic effects associated with the local use of allopurinol.

After only one week of treatment with allopurinol symptoms LPS applied from stage 2 to stage 1 and 0 in most parts of the affected areas. Treatment sunitinib and cream allopurinol is still in progress.

EXAMPLE 5

The patient (71) with pochernkletocny carcinoma, first identified in 2001, underwent surgery. In 2005 she developed metastatic pochernkletocny carcinoma ((MRCC) (liver metastases and local), and following the progression of metastases were treated with Nexavar® (sorafenib) as palliative therapy (400 mg 2 times a day). Therapy was interrupted in September 2007 due to toxicity (LPS, diarrhea). Palliative second-line therapy began with Sutent® (sunitinib) at a dose of 50 mg daily for 1-28 days every 6 weeks. It had to be interrupted after a month due to more problems with toxicity than in the case of Nexavar (edema, depression, allergies), and back to the treatment Nexavar (sorafenib), which after a month complements the cream allopurinol example 1 and loperamide for the treatment of LPS and diarrhea. The treatment helped to keep LPS, but not diarrhea for almost two years (November 2007 - September 2009). Treatment was interrupted after the progression of malignant tumors. the ATEM within a short period of time she received a course of Afinitor (everolimus) 10 mg per day (September 2009 - March 2010), which was interrupted due to the lack of response to therapy and tumor progression. In the absence of alternative treatment in March 2010 resumed treatment with Nexavar (sorafenib) in a reduced dosage. After the development of LPS in one month treatment again complements the cream of allopurinol.

Results: as a result of local administration of allopurinol almost completely disappeared symptoms LPS and it was possible to continue therapy with Nexavar. Showed no toxic effects associated with the local use of allopurinol.

As shown in the examples, four patients developed LPS treatment allopurinol facilitated for FSC and allowed to complete therapy MICK according to the planned scheme.

1. Drug for the treatment or prevention of hand-foot syndrome (LPS) - induced therapy multipurpose inhibitor kinase (MICK), containing a therapeutically effective amount of allopurinol or pharmaceutically acceptable salt.

2. Drug under item 1, where hand-foot syndrome caused by sunitinib.

3. Drug under item 1, where hand-foot syndrome caused by sorafenib.

4. Drug under item 1, where the drug is intended for topical application, preferably for topical application on the skin of the arms or legs.

5. Drug under item 4, where the medicinal product is a cream, preferably hydrophilic cream.

6. The drug according to any one of paragraphs.1-5, where the medicinal product contains from about 1-10% by weight of the composition of allopurinol or pharmaceutically acceptable salt, preferably from about 1% to about 8%, more preferably from about 2 to about 5% by weight.

7. Drug under item 1, where the medicinal product contains approximately 3% by weight of the composition of allopurinol or pharmaceutically acceptable salt.

8. The use of allopurinol or pharmaceutically acceptable salts in the manufacture of a medicinal product for the treatment or prevention of hand-foot syndrome (LPS) - induced therapy multipurpose inhibitor kinase (MICK).

9. The use of allopurinol in the treatment or prevention of hand-foot syndrome (LPS) - induced therapy multipurpose inhibitor kinase (MICK).

10. The use of allopurinol in the treatment or prevention of hand-foot syndrome (LPS) - induced sunitinib.

11. The use of allopurinol in the treatment or prevention of hand-foot syndrome (LPS) induced by sorafenib.

12. Method for the treatment or prevention of hand-foot syndrome (LPS), calling the spent therapy multipurpose inhibitor kinase (MICK), we need in this patient, comprising the administration to a patient of a medicinal product containing a therapeutically effective amount of allopurinol or pharmaceutically acceptable salts for the treatment or prevention of hand-foot syndrome.

13. The method according to p. 12, where FSC is caused by sorafenib.

14. The method according to p. 12, where LPS-induced sunitinib.

15. The method according to p. 12, where the drug is applied topically to the skin.

16. The method according to p. 15, where the drug is applied topically to the skin of the arms or legs.

17. The method according to p. 12, where the medicinal product is a cream.

18. The method according to p. 17, where the medicinal product is a hydrophilic cream.

19. The method according to p. 12, where the medicinal product contains from about 1% to about 10% by weight of the composition of allopurinol or pharmaceutically acceptable salt.

20. The method according to p. 19, where the medicinal product contains from about 1% to about 5% by weight of the composition of allopurinol or pharmaceutically acceptable salt.

21. The method according to p. 20, where the medicinal product contains approximately 3% by weight of the composition of allopurinol or pharmaceutically acceptable salt.



 

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