Using 5-aminolevulinic acid and derivatives thereof in solid form for photodynamic treatment and diagnostics

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a solid pharmaceutical product for oral administration which contains a photosensitiser representing a compound of general formula I:

wherein R¹ represents a substituted or unsubstituted unbranched, branched or cyclic alkyl group, and each R² independently represents a hydrogen atom or optionally a substituted alkyl group or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient. The above pharmaceutical product is presented in the form of a tablet, a pill or a capsule having an enteric and gastroresistant coating, or in the form of the tablet or the capsule containing a number of balls, drops, granules or mini-pills with an enteric and gastroresistant coating. The above coating disintegrates in the lower gastrointestinal tract. The invention also refers to using the above photosensitiser in preparing the solid pharmaceutical product applicable in photodynamic treatment or diagnostics of a cancer condition in the lower gastrointestinal tract. What is also described is a photodynamic method of treating or diagnosing the cancer condition in the lower gastrointestinal tract by administering the solid pharmaceutical product containing the photosensitiser.

EFFECT: invention provides photosensitiser delivery to the lower gastrointestinal tract, and homogenous distribution of the photosensitiser in the target region, thereby improving the response to photodynamic treatment or diagnostics.

20 cl, 2 dwg, 2 tbl, 54 ex

This invention relates to a method of photodynamic therapy and diagnosis of conditions such as cancer, and in particular for use in such methods of solid pharmaceutical products containing the photosensitizer, which is a 5-aminolevulinic acid (5-ALA) or its precursor or derivative (for example an ester of 5-ALA). Described here pharmaceutical products particularly suitable for use in the treatment and diagnosis of cancerous and benign conditions of the lower section of the gastrointestinal tract (mainly the lower part of the small intestine, colon and rectum) and organs of the female reproductive system (uterus, cervix, vagina).

Photodynamic therapy (PDT) is a relatively new technique that is used in the treatment of various cancers and other diseases. PDT involves the introduction of a photosensitizing agent followed by exposure photoactivation light to activate a photosensitizing agents and their transformation into a cytotoxic form, which leads to the destruction of cells and thereby to cure the disease. Known and described in the literature several photosensitizing agents, including 5-aminolevulinic acid (5-ALA) and some of its derivatives, for example esters of 5-ALA.

Currently clinical when is the change in (PDT) and photodynamic diagnosis (PDD) have three pharmaceutical drug, containing 5-ALA or its ester. This Metvix® and Hexvix®, developed by Photocure ASA (Oslo, Norway), and Levulan Kerastick®, developed DUSA Pharmaceuticals (Canada). Metvix® is a skin medication for the treatment of senile keratosis and basal cell carcinoma, which contains the methyl ester of ALA in the form of an emulsion (cream). Hexvix® is a water solution containing hexyl ester of ALA, for instillation into the bladder in the diagnosis of bladder cancer. Levulan Kerastick® is a two component product for the preparation of a solution of 5-ALA immediately before use. This drug can be used for the treatment of skin diseases.

Although these drugs are useful in clinical practice, they all have the disadvantage associated with the instability of 5-ALA. 5-ALA and its esters are susceptible to a wide range of decomposition reactions that limit shelf life of pharmaceutical products containing these compounds.

To overcome this problem it was suggested several different ways. For example, for a product Metvix® the problem is solved by storing cream at low temperature, and the product Levulan Kerastick® is supplied separately from its solvent, and the solution thus introduced the subject, prepared just before use. Hexvix® is supplied as a lyophilized powder and is soluble in odnomestnoi immediately before use.

These approaches, however, have drawbacks. For example, it is not always convenient to transport and store medications at low temperature. In addition, preferably, as a rule, to supply the pharmaceutical composition in a ready to use form, as it is much easier for practitioners. Delivery of ready to use forms also allows you to ensure the correct and exact concentration of the resulting compositions. This is especially essential in the treatment and diagnosis of many diseases, including cancer, where the correct dosage injected drugs may be critical.

US 2003/125388 describes an alternative approach to the stability of the drugs 5-ALA, where 5-ALA or its derivative is dissolved or dispersed in non-aqueous liquid having a dielectric constant less than 80 at 25°C., and which acts as a stabilizer. It is assumed that the use of non-aqueous liquid promotes the formation of enol forms of 5-ALA and thereby preventing its collapse. Examples of suitable non-aqueous liquids, referred to in the US 2003/125388 include alcohols, ethers and esters, poly(alkalophile), phospholipids, DMSO (dimethylsulfoxide), N-vinyl pyrrolidone and N,N-dimethylacetamide. This composition may be part of a kit for therapeutic or diagnostic is th use. Another part of the set is a composition containing water. In this case, the two parts of set mixed before using.

Thus, the approach proposed in US 2003/125388, has the same drawback, that Levulan Kerastick®, since in General it is undesirable to deliver drugs in a form that requires the practitioner to prepare directly input pharmaceutical drug. Moreover, the introduction of non-aqueous liquid animal may not always be desirable.

The next disadvantage possessed by all of the above, is that the drugs in the form of liquids and creams difficult to use for treatment, especially local, many areas of the body. This disadvantage is particularly evident in the case of treatment of cancer, because the disease affects different parts of the body.

Areas of the body that are difficult to treat using traditional methods PDT and PDD include the lower part of the gastrointestinal tract and female reproductive system (uterus, cervix, vagina). There are currently no products available for clinical use in photodynamic diagnosis or therapy of these body parts. This is a serious problem, especially in respect of the colon and rectum, which can be exposed to serious and dangerous on the I-life diseases, such as colitis, colorectal cancer, Crohn's disease, irritable bowel syndrome, and a variety of local infections, and in relation to the cervix, which may be exposed to infectious diseases and cervical cancer. There remains a medical need for methods of early diagnosis of these diseases, in particular colorectal cancer and cervical cancer.

Modern methods of diagnosis of colorectal cancer include the monitoring of such clinical symptoms as the presence of blood in the stool, pain in the lower abdomen, weight loss, coloscopy and fluoroscopy. The prognosis for patients with colorectal cancer depends; as with most other forms of cancer, stage of disease at diagnosis and, in particular, from the presence of the patient's extensive distant metastases. Currently in clinical use, there are several therapeutic drugs for the treatment of colorectal cancer, however, these funds have clinical limitations and therefore remains a medical need for other treatment regimens and alternative methods of early diagnostics.

One of the most serious infections, cervical cancer is the human papilloma virus (HPV)that can cause cervical cancer. The HPV infection is a common factor in almost all cases the development of cervical cancer. Estimates of the prevalence of HPV infection vary, but are usually about 30% among all women. Recently developed vaccine against HPV, for example, Gardasil® and Cervarix®. However, cervical cancer remains a life-threatening disease. Unfortunately, cancer is often diagnosed late, as symptoms may not appear until until the cancer reaches an advanced stage. One of the possible early signs of cervical cancer is vaginal bleeding. Diagnosis of cervical cancer based on biopsy. The main method of treatment is surgery, however, in the later stages of the disease can be applied radiation and chemotherapy. The prognosis for patients with cervical cancer depends on the stage of disease at diagnosis.

Intended for oral administration of a composition containing 5-ALA and its derivatives, such as solutions, suspensions, classic tablets and capsules (containing water composition) have several disadvantages when used in the diagnosis and/or treatment of cancer and benign diseases of the lower section of the gastrointestinal tract. This refers to the stability during storage of the pharmaceutical product, stability product in vivo during the passage through the gastrointestinal tract and systemic toxicity by suction 5-ALA is its derivative. In turn, the systemic absorption of 5-ALA leads to a reduction in clinical effectiveness in the area requiring treatment.

Therefore, there is still a need for alternative methods of photodynamic treatment and/or diagnosis of such conditions as, for example, cancer. In particular there is a need for improved methods of diagnosis and/or treatment of cancer and benign lesions in the lower part of the gastrointestinal tract, especially in the lower part of the small intestine, the colon and the rectum. There is also a need for improved methods of diagnosis and/or treatment of cancer and benign lesions of the female reproductive system (uterus, cervix and vagina), especially of the cervix.

Unexpectedly, it was found that some solid pharmaceutical products containing 5-ALA or a derivative (e.g. an ALA ester), do not have the problems known from the prior art preparations. Solid pharmaceutical products are stable at room temperature, easy to handle, easy to use and can be quickly delivered to the lower part of the gastrointestinal tract, especially in the lower part of the small intestine and the entire colon-and rectum. They can also be quickly and locally delivered to the organs of the female reproductive system, in particular to the neck mA is key. Such products also solve the problem of reducing the efficiency of the known compositions, when applied to the above areas of the body. More precisely, they are able to provide an effective concentration of 5-ALA or its derivatives in the area requiring treatment (e.g., in the lower part of the gastrointestinal tract or in the female reproductive system). They can also provide an essentially homogeneous (i.e. uniform) distribution of active photosensitizing agent in the desired area, thereby improving the result of the application of PDT and PDD.

Thus, one aspect of the invention provides the use of a photosensitiser which is 5-ALA or a precursor or derivative (for example an ester of 5-ALA) in the manufacture of a pharmaceutical product for use in the photodynamic treatment or diagnosis (e.g. treatment) of cancer, infections associated with cancer or in the treatment or diagnosis of a benign condition where the specified pharmaceutical product is in the form of solids. Preferably the product is intended for use in the photodynamic treatment or diagnosis of cancer or a benign condition in the lower part of the gastrointestinal tract or female reproductive system.

Another aspect of the invention provides for primenenia.nebolshie, which is 5-ALA or a precursor or derivative (for example an ester of 5-ALA), in the manufacture of a pharmaceutical product for use in the photodynamic treatment of cancer is in the lower part of the gastrointestinal tract, where specified pharmaceutical product is in the form of solids.

The subsequent aspect of the invention provides the use of a photosensitiser which is 5-ALA or a precursor or derivative (for example an ester of 5-ALA), in the manufacture of a pharmaceutical product for use in photodynamic diagnosis of cancer is in the lower part of the gastrointestinal tract, where specified pharmaceutical product is in the form of solids.

Another aspect of the invention provides the use of a photosensitiser which is 5-ALA or a precursor or derivative (for example an ester of 5-ALA), in the manufacture of a pharmaceutical product for use in photodynamic diagnosis of a benign condition in the lower part of the gastrointestinal tract, where specified pharmaceutical product is in the form of solids.

Another aspect of the invention provides the use of a photosensitiser which is 5-ALA or a precursor or derivative (for example an ester of 5-ALA), in the manufacture of headlights is aceticism product for use in the photodynamic treatment of a benign condition in the lower part of the gastrointestinal tract, where specified pharmaceutical product is in the form of solids.

An alternative aspect of the invention provides the use of a photosensitiser which is 5-ALA or a precursor or derivative (for example an ester of 5-ALA), in the manufacture of a pharmaceutical product for use in the photodynamic treatment of the female reproductive system (e.g. cervical cancer), where the specified pharmaceutical product is in the form of solids.

Another aspect of the invention provides the use of a photosensitiser which is 5-ALA or a precursor or derivative (for example an ester of 5-ALA), in the manufacture of a pharmaceutical product for use in photodynamic diagnosis of cancer of the female reproductive system (e.g. cervical cancer), where the specified pharmaceutical drug has a solid form.

The subsequent aspect of the invention provides the use of a photosensitiser which is 5-ALA or a precursor or derivative (for example an ester of 5-ALA), in the manufacture of a pharmaceutical product for use in photodynamic diagnosis of a benign condition of the female reproductive system where the specified pharmaceutical drug has a solid form.

Another aspect of the invention Ave is envisages the use of a photosensitizer, which is 5-ALA or a precursor or derivative (e.g. an ester of 5-ALA) in the manufacture of a pharmaceutical product for use in the photodynamic treatment of benign status of the female reproductive system where the specified pharmaceutical drug has a solid form.

Described here are the methods of diagnosis can also be performed during the surgical intervention, in which the patient is given a diagnostic agent, and then the operation is performed under a blue light. The fact that the area of lesion or disease flyuorestsiruyut under blue light helps the surgeon to determine the surgical border" and thus allows to produce electoral resection of the affected area (such as tumors). The application described here photosensitizing surgical methods is another aspect of the invention.

Therapeutic and diagnostic methods described herein can also be used in the form of combination therapy. For example, over the course of PDT against cancer or benign conditions, carried out using any of the methods described here can then follow the PDD method (for example, to determine the effectiveness of PDT and/or to detect recurrence of the condition).

Thus, another aspect of the invention provides skin is of a photosensitizer, which is 5-ALA or a precursor or derivative (for example an ester of 5-ALA), in the manufacture of a pharmaceutical product, which is in the form of solids, for use in the method comprising the stage of: (1) conducting photodynamic treatment of cancer or a benign condition of the lower section of the gastrointestinal tract or of the female reproductive system of the patient; and (2) conducting photodynamic diagnosis of the specified patient. At least one of the stages (1) and (2) is carried out after the introduction of the indicated patient photosensitizer, which is 5-ALA or a precursor or derivative (for example an ester of 5-ALA). Preferably both stages (1) and (2) is carried out after the introduction of such a photosensitizer.

The subsequent aspect of the invention provides a method of photodynamic treatment or diagnosis of cancer, infections associated with cancer, or a benign condition, comprising the following stages:

(a) introducing into the organism a pharmaceutical product, as defined above;

(b) you can wait for a period of time necessary to achieve the effective concentration of the photosensitizer in the tissue in the desired area; and

(C) the photo-activation of the photosensitizer.

Another aspect of the invention provides photodynamics is th way to diagnose cancer, infections associated with cancer, or a benign condition of the animal, which was previously introduced pharmaceutical product, as defined above, including:

(1) you can wait for a time necessary to achieve the effective concentration of the photosensitizer in the desired area;

and

(2) the photo-activation of the photosensitizer.

Another aspect of the invention provides a solid pharmaceutical product containing the photosensitizer, which is 5-ALA or a precursor or derivative and at least one pharmaceutically acceptable carrier or excipient where specified pharmaceutical product is a suppository, a capsule, a pill or tablet. Preferably specified pharmaceutical product is a suppository, pill or tablet.

The above-defined solid pharmaceutical product for application in medicine is another aspect of the invention.

In this document, the term "pharmaceutical product" refers to the object that is actually administered to the subject.

In this document, the term "solid" refers to the physical condition of the described object (i.e. representing a solid and not a liquid or gas). Thus, liquids, solutions, gels and creams are not covered by the Tim the term. Typical examples of solid pharmaceutical products that are covered by the invention include capsules, tablets, pills, pessaries and suppositories.

The pharmaceutical products according to the invention are solid at introduction. Preferred solid pharmaceutical product according to the invention are solid at a temperature at least 20°C., more preferably at a temperature at least 30°C., even more preferably at a temperature of at least 37°C (i.e. at body temperature) and most preferably at a temperature of at least 40°C.

In this document, the term "pharmaceutical product" refers to a mixture of at least two different components. Thus, acid 5-ALA or a derivative ALA themselves do not constitute a pharmaceutical product. Preferred pharmaceutical products contain at least one pharmaceutically acceptable carrier or excipient.

In this document, the term "treatment" includes both radical treatment and prophylactic treatment.

The term "precursor" in this document refers to the precursors of 5-ALA, which in the metabolism into it and so essentially it is equivalent. Thus, the term "precursor" includes biological precursors of protoporphyrin in m is tablescan the heme biosynthesis pathway. The term "derivative" includes pharmaceutically acceptable salts and chemically modified agents, such as esters, such as esters of 5-ALA.

The use of 5-ALA and its derivatives (such as esters of 5-ALA) PDT is well known in the scientific and patent literature (see, for example, WO 2006/051269, WO 20051092838, WO 03/011265, WO 02/09690, WO 02/10120 and US 6034267, the contents of which are incorporated herein by reference). All such derivatives of 5-ALA and their pharmaceutically acceptable salts are suitable for use in the ways described here.

Useful in accordance with the invention, derivatives of 5-ALA can be any derivative of 5-ALA, which is able to form protoporphyrin IX (PpIX) or any other photosensitizer (e.g derived PpIX) in vivo. Typically, these derivatives will be the precursor of PpIX or its derivative (for example, ester PpIX) in the heme biosynthesis pathway and, therefore, they are able to induce the accumulation of PpIX in the field of disease after administration in vivo. Suitable precursors of PpIX and its derivatives include prodrugs of 5-ALA, which may be capable of forming 5-ALA in vivo as an intermediate compound in the biosynthesis of PpIX, or which can be transformed (e.g. enzymatic) in the porphyrins without the formation of 5-ALA as intermediate compounds. It is preferred to use, as described, is here how compounds include esters of 5-ALA and their pharmaceutically acceptable salts.

Esters of 5-aminolevulinic acid and their N-substituted derivatives are preferred photosensitizers for use according to the invention. Especially preferred are those compounds in which the 5-amino group is unsubstituted (i.e., the esters of ALA). Such compounds are widely known and described in the literature (see, for example, WO 96/28412 and WO 02/10120 from Photocure ASA, the contents of which are incorporated herein by reference).

Esters of 5-aminolevulinic acid with a substituted or unsubstituted, preferably substituted, alkanols, i.e. alkalemia esters or, more preferably, substituted alkalemia esters are especially preferred photosensitizers for use according to the invention. Examples of such compounds include compounds of General formula I

(where R¹represents a substituted or unsubstituted, preferably substituted, unbranched, branched or cyclic alkyl group (such as substituted unbranched alkyl group); and each R²independently represents a hydrogen atom or a possibly substituted alkyl group, such as group R¹) and their pharmaceutically acceptable salts.

In this document, unless otherwise indicated, the term "alkyl" includes any cyclic, unbranched or razvetvlenno the aliphatic saturated or unsaturated hydrocarbon group with a long or short chain. Unsaturated alkyl groups may be mono - and polyunsaturated and include as alkeneamine and alkyline group. Unless otherwise noted, these groups can contain up to 40 atoms. However, the preferred alkyl groups containing up to 30 carbon atoms, preferably containing up to 10 carbon atoms, particularly preferably up to 8, and most preferably up to 6, for example up to 4 carbon atoms.

Substituted alkyl group, R¹and R²can be mono - and polyamideimide. Suitable substituents can be selected from the groups hydroxy, alkoxy, acyloxy, alkoxycarbonyl, amino, aryl, nitro, oxo, fluorescent, -SR³,andand each alkyl group may be interrupted by one or more groups-O-, -NR³-, -S - or-PR³-, in which R³is a hydrogen or C_1-6alkyl group).

Preferred substituted alkyl groups of R¹include groups bearing one or more oxoprop, preferably unbranched_4-12alkyl (for example, C_8-10alkyl) groups, substituted one, two or three (preferably two or three) exography. Examples of such groups include groups of 3,6-dioxa-1-octyl and 3,6,9-trioxa-1-decyl.

Especially preferred for use according to the invention are those compounds of formula I in which at least one R²represents a hydrogen atom. In the most preferred compounds, each R²represents a hydrogen atom.

The compounds of formula I in which R¹represents an unsubstituted alkyl group (preferably with C_1-8alkyl, for example With_1-6alkyl) or, more preferably, alkyl group (for example, C_1-2alkyl, especially C₁alkyl), substituted as defined above substituent (for example, such an aryl group as a phenyl, or such alkoxygroup as a methoxy group) are also preferred.

Unsubstituted alkyl groups, which can be used according to the invention include both branched and unbranched hydrocarbon group. The compounds of formula I in which R¹represents a C_4-8preferably Cs-e, an unbranched alkyl group which is branched by one or more C_1-6alkylene (for example With_1-2alkyl) groups are preferred. Typical examples of suitable unsubstituted branched alkyl groups include 2-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 3,3-dimethyl-1-butyl. 4-methylpentyl is especially preferred.

Connect the Oia formula I, in which R¹represents a C_1-10unbranched alkyl group, are preferred. Typical examples of suitable unsubstituted alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl and octyl (for example n-propyl, n-butyl, n-pentyl, n-hexyl and n-octyl). Hexyl, especially n-hexyl, is especially preferred group. Methyl is particularly preferred group.

Particularly preferred for use according to the invention are those compounds of formula I in which R¹represents a C_1-2alkyl group (preferably₁alkyl group, possibly substituted aryl group.

Also preferred for use according to the invention are those compounds of formula I in which R¹represents an alkyl group (for example With_1-2especially With₁alkyl group), substituted aryl group (e.g. phenyl). Preferred substituted alkyl, R¹groups that may be present in the compounds of formula I include With_1-6alkylene group, preferably_1-4alkyl group, particularly preferably₁or₂alkyl (for example With₁alkyl) groups, substituted (preferably at the ends) maybe substituted aryl group.

By "aryl gr is ppoi" refers to the group which is aromatic. Preferred aryl groups contain up to 20 carbon atoms, more preferably up to 12 carbon atoms, for example 10 or 6 carbon atoms.

Aryl groups that may be present in the compounds according to the invention may be heteroaromatic (e.g. 5-7-membered heteroaromatic groups), but preferred negatioations group. Under "negatioations" refers to aryl group having an aromatic system containing electrons exclusively from carbon atoms. Preferred aryl groups include phenyl and naphthyl, especially phenyl. In a preferred use according to the invention the compounds may be present one or two aryl groups, preferably one.

A preferred aspect of the invention involves the application of a photosensitizer, which is a compound of formula I, where R¹represents a substituted aryl group With_1-4alkyl group (preferably_1-2for example , With₁), preferably where the specified aryl group contains up to 20 carbon atoms (for example up to 12 carbon atoms, especially 6 carbon atoms), and she possibly substituted, and each R²is as defined above (for example, each R^{2 is hydrogen), or its pharmaceutically acceptable salt, in the manufacture of a medicinal product for use in the prevention or treatment of acne.}

^{Aryl groups that may be present in the compounds according to the invention can be substituted by one or more (e.g. 1 to 5) groups, more preferably one or two groups (for example one group). Preferably aryl group substituted in the meta - or para-position, most preferably in the para-position. Suitable group substituents may include halogenoalkane (for example triptoreline) group, alkoxygroup (for example-OR group, where R preferably is a C_1-6alkiline group), halogen (for example iodine, bromine, and especially chlorine and fluorine), nitro and C_1-6alkylene group (preferably_1-4alkyl group). Preferred_1-6alkylene groups include methyl, isopropyl and tert-butyl, especially methyl. A particularly preferred group of substituents include chloro and nitro. Even more preferably, if the aryl group is unsubstituted.}

^{Preferred for use according to the invention compounds include methyl ALA ester, ethyl ester of ALA, propyl ALA ester, butyl ester of ALA, pentalogy the ALA ester, hexyl ester of ALA, oktilovom the ALA ester, 2-methoxyethylamine the ALA ester, 2-METI pentalogy ester of ALA, 4-methylpentanoic the ALA ester, 1-ethylbutylamine the ALA ester, 3,3-dimethyl-1-butyl ALA ester, benzyl ALA ester, 4-isopropylbenzylamine the ALA ester, 4-methylbenzylamine the ALA ester, 2-methylbenzylamine the ALA ester, 3-methylbenzylamine the ALA ester, 4-[tert-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl ALA ester, 4-methoxybenzyloxy the ALA ester, 3,4-[dichloro]benzyl ALA ester, 4-chlorbenzoyl the ALA ester, 4-tormentingly the ALA ester, 2-tormentingly the ALA ester, 3-tormentingly the ALA ester, 2,3,4,5,6-pentafluorobenzoyl the ALA ester, 3-nitrobenzyloxy the ALA ester, 4-nitrobenzyloxy the ALA ester, 2-phenethyl ester of ALA, 4-privately the ALA ester, 3-pyridinyl-methyl ALA ester, 4-diphenyl-methyl ALA ester and benzyl-5-[(1-acetylacetone)-carbonyl]aminolevulinat.}

^{More preferred for use according to the invention compounds include methyl ALA ester, ethyl ester of ALA, 2-methoxyethylamine the ALA ester, benzyl ALA ester, 4-isopropylbenzylamine the ALA ester, 4-methylbenzylamine the ALA ester, 2-methylbenzylamine the ALA ester, 3-methylbenzylamine the ALA ester, 4-[tert-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl ALA ester, 4-methoxybenzyloxy the ALA ester, 3,4-[dichloro]benzyl ALA ester, 4-chlorbenzoyl the ALA ester, 4-tormentingly the ALA ester, 2-tormentingly the ALA ester, 3-tormentingly the ALA ester, 2,3,4,5,6-pentafluorobenzoyl the ALA ester, 3-nitrobenzyloxy the ALA ester, 4-nitrobenzyloxy the ALA ester, 2-phenethyl ester of ALA, 4-privately the ALA ester, 3-pyridinyl-IU the sludge ALA ester, 4-diphenyl-methyl ALA ester and benzyl-5-[(1-acetylacetone)-carbonyl]aminolevulinat.}

^{More preferred for use according to the invention compounds include benzyl ALA ester, 4-isopropylbenzylamine the ALA ester, 4-methylbenzylamine the ALA ester, 2-methylbenzylamine the ALA ester, 3-methylbenzylamine the ALA ester, 4-[tert-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl ALA ester, 4-methoxybenzyloxy the ALA ester, 3,4-[dichloro]benzyl ALA ester, 4-chlorbenzoyl the ALA ester, 4-tormentingly the ALA ester, 2-tormentingly the ALA ester, 3-tormentingly the ALA ester, 2,3,4,5,6-pentafluorobenzoyl ether ALA, 3-nitrobenzyloxy the ALA ester, 4-nitrobenzyloxy the ALA ester, 2-phenethyl ester of ALA, 4-privately the ALA ester, 3-pyridinyl-methyl ALA ester, 4-diphenyl-methyl ALA ester and benzyl-5-[(1-acetylacetone)-carbonyl]aminolevulinat.}

^{Especially preferred for use in the ways described here compounds include benzyl ALA ester, 4-isopropylbenzylamine the ALA ester and 4-methylbenzylamine ester of ALA, in particular benzyl ALA ester. 4-Nitrobenzyloxy the ALA ester, 4-chlorbenzoyl the ALA ester and benzyl ALA ester is particularly preferred.}

^{Even more preferred compounds for use according to the invention are 5-ALA, methyl ester of 5-ALA, hexyl ester of 5-ALA, benzyl ether of 5-ALA and their physiologically acceptable salts. Among them hexyl ester of 5-ALA and its fiziologicheskii salt is particularly preferred, for example hexyl ester of 5-ALA in the form of the HCl salt.}

^{Compounds for use according to the invention can be obtained by any conventional method available at the present level of technology (e.g., as described in WO 02/10120 from Photocure ASA). For example, the esters of 5-ALA can be obtained by the interaction of 5-ALA with a suitable alcohol in the presence of a base. Alternative compounds for use according to the invention may be in the sale (for example from Photocure ASA, Norway).}

^{Compounds for use according to the method according to the invention can be in the form of a free amine (e.g.- NH₂-The other2or-NR2R2or preferably in the form of physiologically acceptable salts. Such salts preferably are salt accession physiologically acceptable organic and inorganic acids. Suitable acids include, for example, hydrochloric, nitric, Brestovitsa, phosphoric, sulfuric, sulfonic acid and sulfonic acid derivatives. Especially preferred are salts attaching sulfonic acid and its derivatives as described in WO 2005/092838 from PhotoCure ASA, the full text of which is incorporated herein by reference. Methods of obtaining salts generally accepted at the present level of technology.}

The above compounds may be used for the manufacture of terdag the pharmaceutical product in any conventional manner. The necessary concentration of the photosensitizer in the pharmaceutical products according to the invention will vary depending on a number of factors, including the nature of the connection, the nature and form of the product in which it is contained, intended route of administration, the nature of the cancer to be treated or diagnosed, and the subject to be treated. In General, however, the concentration of the photosensitizer is usually in the range from 1% to 50%, preferably from 1% to 40%, for example from 2% to 25%, preferably from 5% to 20% by weight of the total weight of the pharmaceutical product.

Preferred pharmaceutical products for use according to the invention contain at least one pharmaceutically acceptable carrier and/or excipient. The expert is able to select a suitable carrier or excipient based, for example, on the selected route of administration, and cancer, which is subject to treatment or diagnosis. Typical examples of excipients and carriers that can be used in pharmaceutical products include agar, alginic acid, ascorbic acid, amino acids, calcium salts (e.g. calcium phosphate), ammonium salts (e.g. ammonium acetate), carbomer, carbopol, the compounds and derivatives of cellulose (e.g. microcrystalline cellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose is, hydroxypropylcellulose), citric acid, compounds and derivatives of starch (e.g. corn starch, croscarmelose, crosspovidone, cyclodextrin, such as beta-cyclodextrin, lactose, such as anhydrous lactose or hydrated lactose, maltodextrin, mannitol, menthol, synthetic polymers (for example, methacrylic acid), derivatives of polyethylene glycol (such as Polysorbate), potassium salts (such as potassium phosphate), sodium salt (for example sodium carbonate), povidone, derivatives sorbitan, talc, wax, polyethylene glycol, poloxamer, medium chain triglycerides, glycerides C_8-18fatty acids (for example tallow and mixtures thereof. Oil Miglyol® (Miglitol), which are esters of saturated Caprylic and capric fatty acids derived from coconut and palm oil, and glycerin or propylene glycol are especially preferred for use according to the invention. For example, they can be used in obtaining capsules with liquid filling containing a photosensitizing agent.

In addition, pharmaceutical excipients and carriers that may be used is described here pharmaceutical products listed in different directories (for example, D.E.Bugay and W.P.Findlay (Eds) Pharmaceutical excipients (Marcel Dekker, New York, 1999), E-M Hoepfner, A.Reng and P.C.Schmidt (Eds) Fiedler Encyclopedia o Excipients for Pharmaceuticals, Cosmetics and Related Areas (Editio Cantor, Munich, 2002) and ..Fielder (Ed) Lexikon der Hilfsstffe fur Pharmazie, Kosmetik und angrenzende Gebiete (Editio Cantor Aulendorf, 1989)).

Promoters intake can have a positive impact, increasing the photosensitizing effect of the photosensitizer contained in the pharmaceutical products according to the invention. Thus, products can be included agents that promote surface penetration, especially diallylsulfide, such as dimethylsulfoxide (DMSO). The agent that promotes surface infiltration, can be any described in the pharmaceutical literature, the agent that promotes absorption through the skin, such as chelators (for example ethylenediaminetetraacetic acid (EDTA)), surfactants (e.g. sodium dodecyl sulphate), surface-inactive substances, bile salts (e.g. sodium deoxycholate) and fatty acids (e.g. oleic acid). Examples of suitable agents, contributing to surface penetration include isopropanol, NRE-101 (available from Hisamitsu), DMSO and other diallylsulfide, in particular n-decylmethacrylate (NDMS), dimethylacetamide, dimethylformamide (DMFA), dimethylacetamide, glycols, various derivatives of pyrrolidone (Woodford et al., J.Toxicol. Cut. & Ocular Toxicology, 1986, 5: 167-177) and Azone® (Stoughton et al., Drug Dpv. Ind. Pharm. 1983, 9: 725-744) or mixtures thereof. Prepact the sory for use in the compositions described herein are those agents, promotes surface infiltration, which are solids at ambient temperature.

The agent that promotes surface infiltration, may conveniently be present in the concentration range from 0.2% to 50% by weight of the total weight of the pharmaceutical product in which it is present, for example about 10% by weight of the total weight of the pharmaceutical product in which it is present.

Halirous agents can also have a beneficial impact on improving photosensitizing effect of photosensitizer present in the pharmaceutical products according to the invention. For example, chelating agents can be included to improve the accumulation of Pp, because the chelation of iron chelating agent prevents its inclusion in the Pp with the formation of heme under the influence of the enzyme ferrochelatase, thereby causing accumulation of Pp. As a result of this photosensitizing effect increases.

Suitable chelating agents that may be included in pharmaceutical products according to the invention include aminopolycarboxylate acid, such as any hepatoblastoma agents described in the literature for detoxification of metals or by chelation of paramagnetic ions of metals in magnetic resonance contrast agents. The company is and, can be marked EDTA, CDTA (cyclohexanedicarboxylate acid), DTPA (diethylenetriaminepentaacetic acid), DOTA (1,4,7,10-Tetra-azacyclopentadecan-1,4,7,10-tetraoxa acid) and their well-known derivatives and analogues. EDTA and DTPA are particularly preferred. Also to achieve the effect of iron chelation can be used desferrioxamine and the other siderophore, for example, together with chelating agents based on aminoalkanoic acids, such as EDTA.

When the pharmaceutical product chelating agent typically may be used in concentrations of from 0.05% to 20%, for example from 0.1% to 10%, by weight of the total weight of the pharmaceutical product in which it is present.

The pharmaceutical products according to the invention can additionally contain protivorakovye agent. Thus, another aspect of the invention provides the use of a photosensitiser which is 5-ALA or a precursor or derivative (for example an ester of 5-ALA) along with the anti-cancer agent in the manufacture of a pharmaceutical product for use in the treatment of cancer or infection associated with cancer, where specified pharmaceutical product is in the form of solids.

A further aspect of the invention provides a kit or package containing the above-defined pharmaceutical is pool cue product and a separate anti-cancer agent for simultaneous, separate or sequential use in the treatment of cancer or infection associated with cancer.

Preferred anti-cancer agents present in the pharmaceutical product and set according to the invention? are antitumor agents. Typical examples of anticancer agents include alkaloids (e.g. vincristine, vinblastine, vinorelbine, topotecan, teniposide, paclitaxel, and docetaxel etoposide), alkylating agents (e.g. alkyl sulphonates such as busulfan), aziridine (e.g. carboquone, ethylenimine and methylmelamine), nitrogen mustards (such as chlorambucil, cyclophosphamide, estramustine, ifosfamide, and melphalan), derived nitrosamine (for example, carmustine and lomustin), antibiotics (such as mitomycin, doxorubicin, daunorubicin, epirubicin and bleomycin), antimetabolites (e.g analogues of folic acid antagonists such as methotrexate and raltitrexed)the purine analogues (e.g. 6-mercaptopurine), pyrimidine analogues (for example, tegafur, gemcitabine, fluorouracil, and cytarabine), cytokines, enzymes (for example, L-asparaginase, ranpirnase), immunomodulators (e.g., interferons, immunotoxins, monoclonal antibodies), taxanes, inhibitors of topoisomerases, platinum complexes (e.g., carboplatin, oxaliplatin and cisplatin) and hormonal agents (such as androgens, estrogens, antiestrogens and aromatase inhibitors. Other antineoplastic agents for use in the invention include imiquimod, irinotecan, leucovorin, levamisole, etoposide and hydroxyurea.

Particularly preferred anti-cancer agents for use in the invention include 5-fluorouracil, imiquimod, cytokines, mitomycin C, epirubicin, irinotecan, oxaliplatin, leucovorin, levamisole, doxorubicin, cisplatin, etoposide, doxorubicin, methotrexate, taxanes, topoisomerase inhibitors, hydroxyurea and vinorelbine. Even more preferred for use as anti-cancer agents, antibiotics such as mitomycin analogues, and pyrimidine, for example, 5-fluorouracil.

Pharmaceutical products can additionally include lubricating agents, moisturizing agents, preservatives, corrigentov and/or flavorings. Pharmaceutical products for use in the method according to the invention can be designed to provide quick, sustained or delayed release of the photosensitizer after administration to the patient by means well known in the prior art procedures. When they are intended for oral administration in the treatment of conditions in the lower part of the gastrointestinal tract, preferably slow release.

However, suppose the equipment pharmaceutical products according to the invention do not include non-aqueous liquid with a dielectric constant of less than 80 at 25°C. Especially preferred pharmaceutical products do not include non-aqueous liquid selected from alcohols, esters and ethers, poly(alkalophile), phospholipids, DMSO, N-vinylpyrrolidone, N,N-dimethylacetamide and mixtures thereof.

Solid pharmaceutical products used in the method according to the invention, can be any conventional solid form, for example the form of powder, granules, pills, tablets, pessaries, suppositories or capsules.

Particularly preferred solid pharmaceutical products for use in the invention include the above-defined photosensitizer in the form of solid compositions. Thus, the preferred solid pharmaceutical products for use in the invention are tablets, powders, granules, pills, suppositories and pessaries. Capsules containing powder, beads or pellets of the composition are preferred pharmaceutical products. Capsules containing semi-solid substance or liquid (preferably non-aqueous liquid), also suitable for use according to the invention. Capsules can be coated. The preferred coating of the capsules described below.

Preferred solid pharmaceutical product according to the invention are in the form of tablets, suppositories, pills, capsules or pessary. These products prefer is Ino contain at least one above-defined photosensitizer in the form of solid compositions. Such products themselves are novel and are the next aspect of the invention.

If the product is delivered in the form of beads (for example, the very small pellets), it can be entered as such. Alternatively, the beads can be incorporated in a tablet or capsule. Tablets or capsules containing many balls are particularly preferred for use in the ways described here and represent another aspect of the invention. Similarly, if the drug is supplied in tablet form, it can be administered as such, or, alternatively, may be placed in the capsule to provide a single dose in the capsule that contains many mini-tablets.

Preferably, the described preparations, especially those intended for oral administration, provided delay the release of the photosensitizer, especially when they are intended for use in the treatment or diagnosis of conditions of the lower section of the gastrointestinal tract. Delayed (such as slow) release can be achieved using any conventional method known and described in the prior art, such as, for example, depending on the pH of the system developed for the release of the photosensitizer in response to a change in pH, and time-dependent (or Visu bodywise time) system, designed to release the drug after a predetermined time.

Preferably described here, solid preparations such as tablets, capsules and pills) may include one or more additional components that increase the release of the active photosensitizing agent. Such slow release agents are well known in the prior art and can include, for example, resins such as guar gum. The required contents of such components (such as resins) in the solid preparation can be easily determined by the person skilled in the art and, for example, may be in the range from 10% to 70% by weight, typically about 50% by weight.

In particular, suitable slow release agents for use in the compositions described herein are compositions Gelucire. This inert semi-solid waxy substance having amphiphilic properties and is available in versions with different physical characteristics. They are identified by their melting point and HLB value. The melting temperature is expressed in degrees Celsius, a HLB (hydrophilic-lipophilic balance) is a numerical scale from 0 to about 20. Lower HLB values characterize more lipophilic and hydrophobic substances, large values are more hydrophilic and lipophobia prophetic is TBA. Composition Gelucire generally considered to be esters of fatty acids and glycerol and esters of PEG (polyethylene glycol) or poliglecaprone the glycerides. The collection of songs Gelucire characterized by a wide range of melting points from about 33°to about 64°C., usually from about 35°to about 55°C, and different HLB values from about 1 to about 14, more often from about 7 to about 14. For example, Gelucire 44/14 denotes a melting temperature of about 44°C. and an HLB value of about 14. Suitable choice of the melting point and HLB values for Gelucire or mixture of compositions Gelucire can provide the required characteristics of delivery for delayed release. It was found that Gelucire 44/14 and Gelucire 50/02 particularly suitable for use according to the invention, both separately and together. It was determined that when sharing a mixture of Gelucire 44/14 and Gelucire 50/02 in the ratio 50:50 (wt./mass.) and 75:25 (wt./mass.) particularly effective to provide the required characteristics of the delayed release.

Other ways to control the parameters of the release photosensitizing agent include the use of additional excipients, which disintegrate in the area requiring treatment or diagnosis (for example in the lower part of the gastrointestinal tract). Thus, the photosensitizer sufficient which is directly to the desired site of treatment or diagnosis. For example, the photosensitizing agent may be prepared together with the matrix (for example enclosed in it), which falls in the lower part of the gastrointestinal tract. For example, can be developed drugs using intersolubility polymers which have a relatively high pH threshold of collapse. Examples of suitable agents for forming the matrix include carbohydrates such as disaccharides, oligosaccharides and polysaccharides. Other suitable matrix substances include alginates, amylase, cellulose, xanthan gum, tragacanth gum, starch, pectin, dextran, cyclodextrin, lactose, maltose and chitosan.

Solid preparations of coating can also provide the required characteristics of delayed release of the destruction of the coating in the body after a predetermined time or when the pH desired area of the gastrointestinal tract. Typical materials for coatings for use in the invention include synthetic and semi-synthetic polymers. The preferred polymers are acetated cellulose, acetate-trimellitate cellulose, polyvinylacetate, copolymers of methacrylic acid, for example, Eudragit®, phthalate of hydroxypropylmethylcellulose, pectin and salt of pectin and cross-linked polymers and copolymers, such as 2-hydroxyethylmethacrylate transversely crosslinked with divinylbenzene and N',N'-bis(beta-styrene-sulfonyl)-4,4'-diaminobenzene.

Other drugs and methods of administration can be used to achieve not only the desired prolonged or delayed release of the photosensitizing agent, but also a high and essentially homogeneous (i.e. uniform) concentration of 5-ALA or its derivatives is in the lower part of the gastrointestinal tract. When conducting PDT or PDD preferably to cover the entire large intestine photosensitizing agent. The desired uniform coating can be achieved by regulating the time and place of the release agent in the colon. Appropriate forms and dosing regimens, which include a number of individual doses (for example, tablets, capsules or a mixture of pills)that are capable of after the introduction of release of the active component with different speeds and/or in different time intervals. Individual doses may be contained in a single dosage form, for example a lot of balls, small tablets, pellets or mini-tablets may be enclosed in a single tablet or capsule, in which individual beads, pills, pellets or mini-tablets are able to provide different release profiles of the active photosensitizing agent. This is commonly called "systems in the form of a set of particles". Alternative dosage may include one or more (preferably several who) single dosage forms (such as one or more tablets or capsules), intended for separate or simultaneous administration, where individual single dosage forms differ in their release profiles. In the treatment of the patient are expected to be introduced by two or more different dosage forms such as capsules or tablets), containing a photosensitizing agent and having different release profiles. For example, using three different capsules, it is possible to aim the beginning, middle and end of the colon. Due to the peristaltic movements of the colon, different doses before the release of their contents will be moved to different depths of the colon, thereby providing a better (i.e. more uniform) coating the walls of the colon. When clinical dose includes more than a single dose, various single dose can be administered simultaneously or over different periods of time.

Different release profiles (as individual particles, such as beads contained in a single dosage form or multiple dosage forms)can be achieved by any of the methods described above, such as changing the nature and/or concentration of any agent that helps to release, by applying a suitable coating, etc. When using coverage, the nature of the coating material, t is Lina and/or concentration of components in the coating can vary so as it is necessary to obtain the desired delayed release. If to cover a variety of pills, tablets or capsules uses the same coating material, delayed release can be achieved consistent increase in the concentration of the agent used for coating individual doses. If the beads or granules coated are placed in a capsule or pressed together with a common excipients for the formation of tablets, the drug dosage form is in the form of a set of particles. In the forms of tablets or capsules containing beads or granules coated, can be additionally covered with suitable intersolubility coating, which may be the same as the coating of pellets or granules, or it may differ.

Alternatively, to provide the desired release profile can be used a combination of agents that promote rapid and slow release. Suitable dosing regime may, for example, include the introduction of a variety of capsules or tablets that contain various agents, contributing to the release. In this regard, it was found that the capsules containing Miglyol, suitable for relatively quick release of the photosensitizing agent, then as capsules containing Gelucire provide NANOG is slower (delayed) release. Therefore, the introduction of a combination of such capsules may be used to provide improved coverage of the mucous membrane of the colon.

Thus, a preferred aspect of the present invention relates to oral therapeutic or diagnostic dose of 5-ALA or its derivative (for example ester of 5-ALA), which contains a number of tablets or capsules, or a mixture of beads containing components, disintegrating in the lower part of the gastrointestinal tract, and in which the individual tablets, capsules or pellets disintegrate with kinetic profiles, providing an intense and homogeneous distribution of 5-ALA or a derivative of 5-ALA in the lower part of the gastrointestinal tract. The total dose can contain different types of balls, for example, in one capsule, where these balls break up with different kinetic profiles, which prolongs the release of 5-ALA or a derivative of 5-ALA. Another option is that therapeutic or diagnostic dose includes several separate dosage forms (more than one tablet or capsule), which have different kinetic profiles of decay.

Oral doses of these drugs may, for example, be supplied in the form of packages, which include a number of individual doses with different release profiles. For convenience, the COI is whether individual doses (e.g. capsules) can be marked by a color code. Such packages are also part of the invention.

Tablets, capsules and pills for use in the present invention can be manufactured by any conventional method. However, preferably the tablets are produced by direct extrusion of the composition, as described above, or by pressing after granulation.

As described in this document, tablets for use in the method according to the present invention may have a coating. Particularly preferred coatings for tablets and capsules are soluble in the intestine and resistant to the action of gastric juice coating. These coatings provide stability of tablets or capsules when the pH of the stomach, and tablet/capsule, thus, begins to release the contained photosensitizer only after logging in the intestinal system, such as the colon. Typical examples of substances suitable for use as such coatings include cellulose acetate, hypromellose, methacrylic acid and methacrylic esters and polivinilatsetatftalat. Other suitable coatings include acetated cellulose (CAP), ethylcellulose, dibutyl phthalate and diethylphthalate. Grade polymers Eudragit®, which is capable of slow release, are also especially preferred for use in the image quality is as the coating materials. They are based on copolymers of acrylate and methacrylates with Quaternary ammonium groups as functional groups, as well as copolymers of ethyl acrylate with methyl methacrylate and neutral ester groups. Such polymers are insoluble and permeable and their release profiles can be modified by changing the ratios of the components of the mixture and/or the thickness of the coating. Preferably, such coating is not dissolved in the stomach (low pH), but was destroyed in the large intestine, where the pH is usually equal to approximately 6.5. Suitable polymers Eudragit® include Eudragit® types S and L.

Suppositories and pessaries for use in the present invention can be manufactured in any conventional manner, for example by direct extrusion of a composition containing a photosensitizer as described above, pressing after granulation or by casting. Preferably suppositories are adapted for insertion into the uterus, vagina or cervix.

In the formulation of suppositories and pessaries may include any of the above-mentioned excipients and carriers such as lactose, microcrystalline cellulose or crosspovidone. Water-soluble suppositories and pessaries can be made of microhollow, propylene glycols, glycerol, gelatin or mixtures thereof. Made so suppositories and pessaries preferably square is become and dissolve after introduction into the body and thereby release the photosensitizer. Described here suppositories and pessaries may also contain agents that promote bioadhesive, for example, agents that increase the adhesion to the mucous membrane, to improve adhesion and thereby prolonging contact of the composition with mucosal membranes, such as the epithelium of the vagina.

Alternative suppositories and pessaries can be manufactured using fat and fat-like compounds, such as solid fat (i.e. glycerides C_8-18fatty acids), a mixture of solid fat and additives, grease, paraffin, glycerol and synthetic polymers. The preferred substance is a solid fat, which mainly consists of mixtures of triglycerides of higher fatty acids with mono - and diglyceride in different proportions. Examples of suitable solid fats include a number of products that are sold under the brand name Witepsol (e.g. Witepsol S55, Witepsol S58, Witepsol H32, Witepsol N35 and Witepsol H37). Made so suppositories and pessaries preferably melt after introduction into the body and thereby release the photosensitizer. Thus, the preferred suppositories and pessaries of this species have a melting point in the range of 30°C-37°C.

Advantage of pharmaceutical products according to the invention is that they are stable. In particular, photosensitizers, codereading pharmaceutical products according to the invention, not prone to degradation and/or decomposition. As a consequence, pharmaceutical products can be stored, for example, at room temperature and humidity for at least 6 months, more preferably for at least 12 months, more preferably for at least 24 months or more (for example, up to 36 months).

Solid pharmaceutical product according to the present invention is preferably administered orally or topically (e.g., vagina or rectum). The preferred route of administration will depend on a number of factors, including the severity and nature of cancer is subject to treatment or diagnosis, localization of cancer and the nature of the photosensitizer. If you want oral administration, the preferred form of the pharmaceutical product is a tablet or a powder, granules or pellets contained in the capsule (e.g., tablet). If you want local introduction, the preferred form of the pharmaceutical product is a suppository or pessary.

After the introduction of pharmaceutical product containing the photosensitizer(s), the area subject to treatment or diagnosis, is subjected to the action of light to achieve the desired photosensitizing effect. Period of time after the introduction to the exposure to light will depend on the nature of pharmace the political product, state, subject to treatment or diagnosis, and forms the introduction. In General, before the photo-activation requires that the photosensitizer is reaching effective concentrations in the tissue in the area of cancer. This usually requires from 0.5 to 24 hours (for example, from 1 to 3 hours).

In a preferred procedure, treatment or diagnosis of a photosensitizer(s) apply to the affected area followed by radiation (for example through a period of time about 3 hours). If necessary (for example in the course of treatment), this procedure can be repeated, for example, before 3 times, at intervals of up to 30 days (for example, 7-30 days). In that case, if the procedure does not produce satisfactory reduction of tumors or full recovery, additional therapy may be carried out in a few months.

Methods of exposure to various areas of the body for therapeutic purposes, for example lamps or lasers, are well known from the prior art (see, for example, Van den Bergh, Chemistry in Britain, May 1986 p.430-439). The wavelength of light used for irradiation may be selected to achieve efficient photosensitizing effect. The most effective is light with a wavelength in the range 300-800 nm, typically 400-700 nm, it was discovered, that in this case, the light penetrates relatively deeply. Typically, the irradiation will be used and what tensionally from 10 to 100 j/cm ²and with a capacity from 20 to 200 mW/cm²when using laser or with an intensity of 10 to 100 j/cm²and with a capacity from 50 to 150 mW/cm²when using lamps. The irradiation is preferably performed for 5 to 30 minutes, preferably 15 minutes. The irradiation can be conducted in a single session, or, alternatively, it may be fractional radiation sessions, which are held in several stages, for example, with intervals between them of from several minutes to several hours. Can also be used multiple exposure.

Diagnostic use of the area is preferably first examined with white light. After this suspicious areas exhibited under blue light (usually in the region of 400-450 nm). Then the emitted fluorescence (635 nm) selectively determined cancerous tissues. Causes of selectivity is unknown, but is likely due to higher metabolic activity in cancer cells compared with normal cells.

Methods and applications according to the invention can be used for the treatment and/or diagnosis of any cancer or any infection associated with cancer. In this document, the term "infection associated with cancer" refers to any infection that positively correlates with the development of cancer. An example of this in which eccii can serve as the human papilloma virus (HPV).

Can be used for treatment or diagnosis of cancer and infections associated with cancer located in any part of the body (e.g. skin, mouth, throat, esophagus, stomach, intestines, rectum, anal canal, the nasopharynx, trachea, bronchi, bronchioles, the urethra, bladder, ovary, vagina, cervix, uterus, and so on).

However, methods and applications according to the invention is particularly useful in the treatment and diagnosis of cancer of the uterus, cervix, vagina, rectum and colon. Particularly preferred methods and applications according to the invention in the treatment or diagnosis of cervical cancer and colon cancer. It was found that in the treatment or diagnosis of diseases of the colon (e.g., colon cancer) are particularly effective enteric capsule containing a photosensitizing agent (for example, hexyl ester of 5-ALA). Treatment for cancer of the cervix preferably use suppository, containing the photosensitizer (e.g., hexyl ester of 5-ALA).

Hereinafter the invention will be described in more detail with further non-limiting examples and references to the accompanying drawings.

Example 1. Suppository containing hexyl ester of 5-ALA

Each suppository (2 g) contains:

Hydrochloride hexyl ester 5-aminolevulinic acid (HAL HCl) -

100 mg, 10 m is or 0.8 mg

The disodium salt of EDTA - 40 mg

Witepsol S 55 S 58 - as required

Suppositories made suspendirovanie HAL HCl and dissolve disodium EDTA salt in the liquid Witepsol. The mixture was poured in the form of a suppository and cooled.

Example 2. Stability hexyl ester 5-aminolevulinic acid suppositories on the basis of Witepsol S55

Suppositories containing hydrochloride hexyl ester 5-aminolevulinic acid (HAL HCl), produced as described in Example 1. Stability HAL HCl rectal suppositories on the basis of Witepsol S55 was investigated using HPLC (high performance liquid chromatography) analysis. Tested stability at room (25°C) temperature, and the temperature of the refrigerator (2-8°C). The results are shown below in Table 1.

The results in Table 1 show that the suppositories on the basis of Witepsol S55 containing HAL HCl, remained stable at least for 3 months at room temperature, and the temperature of the refrigerator.

Example 3. Stability hexyl ester 5-aminolevulinic acid suppositories on the basis of Witepsol S58

Suppositories containing hydrochloride hexyl ester 5-aminolevulinic acid (HAL HCl), produced as described in Example 1. Stability HAL HCl rectal suppositories on the basis of Witepsol S58 was investigated using HPLC analysis. Tested stability at room (25°C) temperature, the AK and the temperature of the refrigerator (2-8°C). The results are shown below in Table 2.

The results are shown in Table 2, show that the suppositories on the basis of Witepsol S58 containing HAL HCI, remained stable at least for 3 months at room temperature, and the temperature of the refrigerator.

Control example

4 party aqueous creams containing 160 mg/g of methyl ester of 5-aminolevulinic acid (MAL), kept at room temperature (25°C) for three months and through different time periods analyzed the content MAL. Three months was observed loss of 27±7% (mean ± STD. error).

Although experiments with cream served with MAL, and not with HAL, the results demonstrate the advantage of the preparation of the ester of ALA in the form of a solid pharmaceutical product.

Example 4. Tablets with intersolubility coating for oral administration containing hexyl ester of 5-ALA

Core tablets containing HAL HCl, were made by mixing the following components, with subsequent direct pressing of the mixture.

Each tablet core contains:

HAL HCl 100 mg

Microcrystalline cellulose - 230 mg

The hypromellose - 130 mg

Povidone - 60 mg

Silicon dioxide - 14 mg

Magnesium stearate 6 mg

The total weight of the core tablet - 530 mg

Core tablets were coated with several layers of acetamidoacrylate (CAP)process using the CAP in acetone. The final weight of the tablets was from 540 mg to 700 mg

Example 5. The pessary

Core tablets were made as described in Example 4. On kernel deposited the following solution:

Ethylcellulose (2%)

Dibutyl phthalate (1%)

Alcohols (ethyl and isopropyl alcohols) (97%)

Example 6. Preparation for aerosol delivery, containing the esters of 5-ALA

HAL HCl was mixed with lactose and ekranizirovali. The particle size is about 2-10 microns. The amount of active substance is about 4% by weight (HAL HCl). The composition was filled in capsules for use in the inhalation device. Each capsule contains 10 mg HAL HCl. One dose contains from 1 to 10 capsules.

Example 7. The pessary containing esters of 5-ALA

Core tablets are made of the following:

HAL HCl 50 mg

Lactose 100 mg

Starch 40 mg

PVP (polyvinylpyrrolidone), 50 mg

Magnesium stearate 10 mg

HAL HCl, lactose and starch were mixed for 20 minutes. Was added an aqueous solution of PVA and the resulting granulate was sieved and dried at 50°C for 24 hours. The material was mixed with magnesium stearate and produced tablets. The diameter of the tablets is 5 mm.

Core tablets were coated Eudragit S100 and diethylphthalate by spraying a solution of Eudragit S100 (10% wt./about.) and diethylphthalate (3% wt./about.) in ethanol.

Example 8. Coated tablets containing ester of 5-ALA

Tablets containing poison is about, semi-permeable layer and intersolubility floor, was prepared from substances listed below, using conventional methods of manufacture of tablets.

Each tablet contains:

The core tablets

Salt of the ester of 5-ALA - 100 mg

AvicelPH 102-80 mg

Croscarmellose 20 mg

Mannitol 40 mg

Polyvinylpyrrolidone 10 mg

Magnesium stearate 3 mg

Semi-permeable layer:

Ethylcellulose 30 mg

Dibutylsebacate 8 mg

Intersolubility floor:

Eudragit L100-50 mg

Triethylcitrate 6 mg

Examples 9-12. Capsules coated, containing 5-ALA and esters of 5-ALA

The following composition was mixed at a temperature above their melting point. Then the mixture was poured into capsules and sealed. After that, the capsule is covered with a mixture of two grades of Eudragit (S and N) to obtain a film which is sensitive to pH.

Example 13. The manufacture of beads containing hydrochloride hexyl ester of 5-ALA

Were prepared by two different drug in the form of beads as follows:

The composition of the drug in the form of beads And:

The carbopol - 1 mass%

Hydrochloride hexyl ester of 5-ALA - 1 mass%

Spherolac - 24 mass%

Microcrystalline cellulose (Avicel PH-102) - 74 mass%

The composition of the drug in the form of beads In:

The hypromellose (receiver array) - 1 mass%

Hydrochloride hexyl ester of 5-ALA - 1 mass%

Spherolac - 24 mass%

Microcrystalline cellulose (Avicel PH-102) - 74 mass%

The average diameter of the balls was 1 mm.

Example 14. The tablets are uncoated, containing hydrochloride hexyl ester of 5-ALA in the balls

The drug were is s (Example 13) - 800 mg

Microcrystalline cellulose (Avicel PH-102) - 140 mg

Magnesium stearate 10 mg

The components were mixed and then the tablets were made by direct compression. The tablet diameter: 13 mm

Example 15. Coated tablets (2% CAP)

Tablets made according to Example 14. Tablets were coated twice, and three times with a solution of acetated cellulose (CAP) (2 mass%) in acetone. Tablets were air-dried for 30 minutes and for 5 minutes at 80°C.

Example 16. NMRS beads coated (2% CAP)

Balls (composition In Example 13) was thoroughly washed with a solution of CAP (2% by weight) in acetone. Excess solvent was removed. The beads were dried for 30 minutes at room temperature and then for 5 minutes at 80°C.

Example 17. The balls on the basis of carbopol coated (2% CAP)

Beads (drug a, Example 13) was thoroughly washed with a solution of CAP (2% by weight) in acetone. Excess solvent was removed. The beads were dried for 30 minutes at room temperature and then for 5 minutes at 80°C.

Example 18. The balls on the basis of carbopol coated (4% CAP) Beads (drug a, Example 13) was thoroughly washed with a solution of CAP (4% by weight) in acetone. Excess solvent was removed. The pellets were dried for 30 minutes at room temperature and then for 5 minutes at 80°C.

Example 19. The balls on the basis of carbopol coated (6% CAP)

Beads (drug And PR which measures 13) thoroughly washed with a solution of CAP (6% by weight) in acetone. Excess solvent was removed. The beads were dried for 30 minutes at room temperature and then for 5 minutes at 80°C.

Example 20. The balls on the basis of carbopol with a coating (8% CAP)

Beads (drug a, Example 13) was thoroughly washed with a solution of CAP (8% by weight) in acetone. Excess solvent was removed. The beads were dried for 30 minutes at room temperature and then for 5 minutes at 80°C.

Example 21. The balls on the basis of carbopol coated (10% CAP)

Beads (drug a, Example 13) was thoroughly washed with a solution of CAP (10% by weight) in acetone. Excess solvent was removed. The pellets were dried for 30 minutes at room temperature and then for 5 minutes at 80°C.

Example 22. Coated tablets containing beads coated

Each tablet contains:

Balls without coating (product from Example 13A) - 200 mg

Beads coated with 2% CAP (from Example 17) - 220 mg

Beads coated with 4% CAP (from Example 18) - 240 mg

Beads coated with 6% CAP (from Example 19) and 133 mg

Beads coated with 8% CAP (from Example 20) - 122 mg

Beads coated with 10% CAP (from Example 21) - 104 mg

Microcrystalline cellulose (Avicel PH-102) - 183 mg

Croscarmellose sodium is 11 mg

Magnesium stearate 10 mg

The components were mixed and tablets produced by direct pressing. Tablets were coated CAP (6% by weight in acetone) and dried in air at t is within 30 minutes and for 5 minutes at 80°C. The tablet diameter: 13 mm

Example 23. Coated tablets containing beads uncoated and hydrochloride hexyl ester of 5-ALA

Each tablet contains:

Balls without coating (product from Example 13A) - 1000 mg

Hydrochloride hexyl ester of 5-ALA - 50 mg

Microcrystalline cellulose (Avicel PH-102) - 210 mg

Croscarmellose sodium is 23 mg

Magnesium stearate 25 mg

The components were mixed and tablets produced by direct pressing. Tablets were coated CAP (8% by weight in acetone) and dried in air for 30 minutes and for 5 minutes at 80°C. the tablet Diameter: 13 mm

Example 24. Gelatin capsules coated, containing balls without coating

Hard gelatin capsule filled balls without coating (product from Example 13A) (273 mg). Capsule size 17 mm, diameter 6 mm Gelatin capsule twice thoroughly covered CAP (4%solution in acetone). The resulting capsule was dried in air for 30 minutes and then for 5 minutes at 80°C.

Example 25. Gelatin capsule coated, containing hydrochloride hexyl ester of 5-ALA

Hard gelatin capsule filled hydrochloride hexyl ester of 5-ALA (273 mg). Capsule twice thoroughly covered CAP (10%solution in acetone) and dried as described in Example 24.

Example 26. Gelatin capsule without coating containing two types of balls is coated

Beads coated with 2% CAP (from Example 17) - 278 mg

Beads coated with 8% CAP (from Example 20) - 376 mg

The beads were mixed and filled hard gelatin capsule and dried as described in Example 24.

Example 27. Tablets based on chitosan containing hydrochloride hexyl ester of 5-ALA

Chitosan (medium molecular weight) 800 mg

Microcrystalline cellulose (Avicel PH-102) 300 mg

Hydrochloride hexyl ester of 5-ALA - 50 mg

Magnesium stearate - 17 mg

Colloidal silicon dioxide (anhydrous) 5 mg

The components were mixed and produced tablets by direct compression. The tablet diameter: 13 mm

Example 28. Tablets based on chitosan containing hydrochloride hexyl ester of 5-ALA

Chitosan (medium molecular weight) - 506 mg

Microcrystalline cellulose (Avicel PH-102) - 580 mg

Hydrochloride hexyl ester of 5-ALA - 103 mg

Croscarmellose sodium 10 mg

The components were mixed and produced tablets by direct compression. The tablet diameter: 13 mm

Example 29. Tablets based on chitosan coated with Eudragit®

Tablets made according to Example 27. Tablets twice covered by the dispersion of Eudragit® (Eudragit® RS30D). Tablets were air-dried for 30 minutes and then for 5 minutes at 80°C.

Example 30. Tablets based on chitosan coated CAP

Tablets made according to Example 28. Tablets DV is GDI covered CAP (6% by weight in acetone). Tablets were air-dried for 30 minutes and for 5 minutes at 80°C.

Example 31. Beads containing hexyl ester of 5-ALA, coated with Eudragit®

Balls (from Example 13) was covered with Eudragit® dispersion of Eudragit® RS30D). The beads were air-dried for 30 minutes and then for 15 minutes at 80°C.

Example 32. Beads containing hexyl ester of 5-ALA, coated with Eudragit® (1,0%)

Balls (from Example 13) was covered with Eudragit® (Eudragit® S100, and 1.0% by weight in acetone). The beads were air-dried for 30 minutes and then for 15 minutes at 80°C.

Example 33. Beads containing hexyl ester of 5-ALA, coated with Eudragit® (2,5%)

Balls (from Example 13) was covered with Eudragit® (Eudragit® S100, a 2.5% by weight in acetone). The beads were air-dried for 30 minutes and then for 15 minutes at 80°C.

Example 34. Beads containing hexyl ester of 5-ALA, coated with Eudragit® (2,5%)

Balls (from Example 13) was covered with Eudragit® (Eudragit® S100, a 2.5% by weight in acetone). The beads were air-dried for 30 minutes and then for 15 minutes at 80°C.

Example 35. Tablets containing balls with different coating containing hydrochloride hexyl ester of 5-ALA

Each tablet contains:

Beads coated with 1% Eudragit® S-100 (Example 32) - 132 mg

Beads coated with 2.5% Eudragit® S-100 (from Example 33) - 190 mg

Beads coated with 5% Eudragit® S-100 (from Example 34) - 164 mg

Microcrystalline cellulose (Avicel PH-102) 130 mg

Magnesium stearate 10 mg

The components were mixed and then the tablets were made by direct compression. The tablet diameter: 13 mm

Example 36. Coated tablets containing balls with different coating containing hydrochloride hexyl ester of 5-ALA

Tablets made according to Example 35. Tablets were coated Eudragit® S-100 (3% by weight Eudragit® and 1% triethylcitrate in acetone). Tablets were air-dried for 30 minutes and then for 5 minutes at 80°C.

Example 37. Intersolubility capsules for release in the colon

A receiver array capsules size 1 was covered with Eudragit L30 D-55, Eudragit FS 30 D and triethylcitrate. The capsule contained 100 mg of the hydrochloride of hexyl-5-aminolevulinat (HAL-HCl) and 300 mg of excipient(s). Excipients include Poloxamer 188, Gelucire 44/14, a mixture of Gelucire (44/14:50/02=50:50 wt./mass.) and Miglyol 812 N. Excipients included to influence the release of the drug in the rectum after the dissolution of the capsule. The capsules were coated intersolubility the floor.

Example 38. Characteristics stability

To characterize the stability of HAL in the presence of various excipients, conducted stress research at a temperature of 80°C. to 100 mg HAL HCl+300 mg excipient (Poloxamer 188, Gelucire 44/14, a mixture of Gelucire (44/14:50/02=50:50 wt./mass.) and Miglyol 812 N) were mixed and the result after 20 hours was analyzed using HPLC. The level of each pollution Rasch Tivoli relatively pirazinamida standard. The results are presented in the table below. You can see that when using Miglyol virtually no contamination was not detected, whereas the use of other excipients has led to more pollution and higher levels of pollution. Sample containing Miglyol, had lower levels of contamination than the sample itself HAL HCl.

Example 39. The stability studies

Capsules containing 100 mg HAL HCl + 300 mg excipient (a mixture of Gelucire (44/14:50/02=50:50 wt./mass.) or Miglyol 812 N), produced as described in Example 37, and control stability at 25°C and 60% relative humidity. For stability control as an indicator of stability used the concentration of 5-aminolevulinic acid (5-ALA) (formed by hydrolysis HAL). The results are shown in figure 1, which shows the release of 5-ALA from HAL as a result of hydrolysis. You can see that Miglyol 812 N confirms its ability to provide the greatest stability of the product, almost without showing any increase in the content of 5-ALA. To a mixture of Gelucire the increase in the content of 5-ALA was observed after 3 months of aging at 25°C and 60% otnositelnoi humidity. The corresponding increase in the content of 5-ALA was also observed for Poloxamer 188 (not shown). This excipient also caused the formation of substantial quantities of two unknown pyrazinoic dirt.

Example 40. Investigation of the solubility

The capsules were coated as described in Example 37, was filled with 100 mg HAL HCI mixed with 00 mg excipient (or Miglyol, or a mixture of Gelucire (44/14:50/02=50:50 wt./mass.)) and sealed. The capsules used in the study of solubility in vitro using the apparatus for dissolving type 2 according to the US Pharmacopoeia (with blades) in accordance with the requirements of the European Pharmacopoeia 2.9.3. Capsules were first immersed in 0.1 M HCl for 1 hour (to play the acidic conditions of the stomach), and then moved in phosphate buffer (pH 6.5). Initial experiments showed that it required the addition of 2% sodium lauryl solvent in the environment as the basis of both drugs are fatty, hydrophobic substances. The samples were taken and analyzed for HAL at various time points.

Figure 2 shows the dissolution profiles for drugs on the basis of Miglyol and a mixture of Gelucire (44/14:50/02=50:50 wt./mass.). This suggests that HAL was not released in 0.1 M HCl. After moving in phosphate buffer (pH 6.5) HAL quickly released from the drug on the basis of Miglyol than drug based on a mixture of Gelucire, which provided a more prolonged release.

Example 41. Suppositories for cervical

Several parties suppositories on the basis of solid fat - Witepsol H32 (TPL 31-33°C), N (TPL 33,5-35,5°C) and N (TPL 36-38°C) is produced by dissolving 200 mg HAL-HCl 1.8 g melted fat with the subsequent filling in forms (see Example 1).

Testing stability at 5°C and 25°C) did not reveal nick is their significant stability issues - see Examples 2 and 3.

Investigation of the solubility performed (European Pharmacopoeia 2.9.3, the apparatus with basket) for suppositories made from Witepsol H32 and Witepsol N, each of which contained 100 mg HAL HCl. As the solvent medium used phosphate buffer (pH 4.0) at 37°C and the amount of released drug was determined using HPLC. The study revealed that suppositories on the basis of Witepsol H32 gave rapid and almost complete release of HAL within 1 hour, unlike suppositories on the basis of Witepsol N, which was released only 6% of HAL within 8 hours. The Witepsol bases with a higher melting temperature, for example, N, as the basis of suppositories proved to be defective in respect of release of the drug. Differences in dissolution rate, probably due to the different melting temperatures of solid fats.

Example 42. Tablets containing hydrochloride benzyl ester of 5-ALA

Microcrystalline cellulose (Avicel PH-102) - 380 mg

Monohydrate lactose - 340 mg

Hydrochloride benzyl ester of 5-ALA - 70 mg

Magnesium stearate 10 mg

The components were mixed and tablets produced by direct pressing. The tablet diameter: 13 mm

Example 43. Tablets containing benzyl ether of 5-ALA, coated with Eudragit®

Tablets made according to Example 42. Tablet and covered with a solution of Eudragit® S-100 (6%) and triethylcitrate (1%) in acetone and dried.

Example 44. Tablets containing the hydrochloride of the methyl ester of 5-ALA

Microcrystalline cellulose (Avicel PH-102) - 266 mg

Monohydrate lactose - 280 mg

The hydrochloride of the methyl ester of 5-ALA 200 mg

Magnesium stearate 10 mg

Croscarmellose sodium 15 mg

The components were mixed and tablets produced by direct pressing. The tablet diameter: 13 mm

Example 45. Tablets containing the methyl ester of 5-ALA, coated with Eudragit®

Tablets made according to Example 44. Tablets were coated with a solution of Eudragit® S-100 (6%) and triethylcitrate (1%) in acetone and dried.

Example 46. Tablets containing the hydrochloride of 5-ALA and pectin

Microcrystalline cellulose (Avicel PH-102) - 215 mg

Pectin citrus fruits - 210 mg

Monohydrate lactose - 116 mg

The hydrochloride of 5-ALA - 190 mg

Magnesium stearate 10 mg

Croscarmellose sodium 15 mg

The components were mixed and tablets produced by direct pressing. The tablet diameter: 13 mm

Example 47. Tablets containing 5-ALA and pectin coated with Eudragit®

Tablets made according to Example 46. Tablets were coated with a solution of Eudragit® S-100 (6%) and triethylcitrate (1%) in acetone and dried.

Example 48. Capsules coated, containing the methyl ester of 5-ALA

The hydrochloride of the methyl ester of 5-ALA (90 mg) was filled in hard gelatin capsule and a gelatin capsule coated with a solution of Eudragit® S-100 (6%) triethylcitrate (1%) in acetone and dried.

Capsule size: length 17 mm, diameter 6 mm

Example 49. Stability balls containing hexyl ester of 5-ALA

Beads containing hexyl ester of 5-ALA (from Example 13, the drug a and b), kept in an open container in a climatic chamber for about 3 weeks at 40°C and a relative humidity of 70%.

HPLC analysis did not show any increase of the collapse of the hexyl ester of 5-ALA as a result of high temperature and humidity.

Example 50. Slow release hydrochloride hexyl ester of 5-ALA balls

Beads containing hexyl ester of 5-ALA (from Example 13, the drug a and b), (1.0 g) suspended in water (10 ml) and kept for several hours at 37°C. after this time the aqueous solution was analyzed for content of the hexyl ester of 5-ALA. For several hours the release hexyl ester of 5-ALA was less than 10%.

Example 51. Tablets containing the methyl ester of 5-ALA and DMSO

DMSO (200 mg) was mixed with microcrystalline cellulose (500 mg) to obtain a powder (powder DMSO/MCC)

Powder DMSO/MCC - 700 mg

The hydrochloride of the methyl ester of 5-ALA - 25 mg

Magnesium stearate 10 mg

Croscarmellose sodium 15 mg

The components were mixed and tablets produced by direct pressing. The tablet diameter: 13 mm

Example 52. Coated tablets containing the methyl ester of 5-ALA and DMSO

Tablets were made according to the Example is 51. Tablets were coated with a solution of Eudragit® S-100 (6%) and triethylcitrate (1%) in acetone and dried.

Example 53. Capsules containing 5-ALA and DMSO

DMSO (19 mg) was mixed with microcrystalline cellulose (72 mg) and the hydrochloride of 5-ALA (9 mg) to obtain a powder. The powder was filled in gelatin capsules.

Example 54. Capsules coated, containing 5-ALA and DMSO

Capsules produced according to Example 53. The capsules were coated with a solution of Eudragit® S-100 (6%) and triethylcitrate (1%) in acetone and dried.

1. Solid pharmaceutical product for oral administration, containing the photosensitizer, which is a compound of the General formula I

where
R¹represents a substituted or unsubstituted unbranched, branched or cyclic alkyl group, and
each R²independently represents a hydrogen atom or a possibly substituted alkyl group, or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient,
where specified pharmaceutical product is presented in the form of tablets, pills or capsules having intersolubility and resistant to the action of gastric juice coating, or in the form of tablets or capsules containing many beads, pills, pellets or mini-tablets coated with intersolubility and resistant the m to the action of gastric juice coating
and where the said coating dissolves in the lower part of the gastrointestinal tract.

2. Solid pharmaceutical product according to claim 1 in the form of tablets or capsules containing many beads, pills, pellets or mini-tablets coated with intersolubility and resistant to the action of gastric juice coating.

3. Solid pharmaceutical product according to claim 2, where the specified set of beads, pellets, tablets or mini-tablets are able to provide different release profiles of the photosensitizer after injection.

4. Solid pharmaceutical product according to claim 2, containing one or more of these tablets or capsules, are able to provide different release profiles of the photosensitizer after injection.

5. Solid pharmaceutical product according to claim 1, capable of delayed release of the above photosensitizer.

6. Solid pharmaceutical product according to claim 1, where the specified at least one pharmaceutically acceptable carrier or excipient is an oil containing esters of saturated Caprylic and capric fatty acids derived from coconut and palm oil, and glycerin or propylene glycol.

7. Solid pharmaceutical product according to claim 1, additionally containing slow release of the agent that represents the esters of fatty acids or glycerol and ethers is of poliatilenglikola (PEG) or poliglecaprone glycerides, having a melting point from about 33°to about 64°C and the value of the hydrophilic-lipophilic balance (HLB) from about 1 to about 14.

8. Solid pharmaceutical product according to claim 1, where the coating is destroyed at a pH of approximately 6.5.

9. Solid pharmaceutical product according to claim 1, where in formula I, each R²represents a hydrogen atom.

10. Solid pharmaceutical product according to claim 1, where in formula I R¹represents an unsubstituted alkyl group.

11. Solid pharmaceutical product of claim 10, where R¹represents a C_1-6alkyl.

12. Solid pharmaceutical product according to claim 1, where the specified connection is selected from ALA methyl ester, ethyl ester of ALA, propyl ALA ester, butyl ester of ALA, pentalofos of ALA ester, hexyl ester ALA, oktilovom of ALA ester, 2-methylpentylamino of ALA ester, 4-methylpentylamino of ALA ester, 1-ethylbutanol of ALA ester and 3,3-dimethyl-1-butyl ether ALA.

13. Solid pharmaceutical product according to claim 1, where the specified connection is a hexyl ALA ester or its pharmaceutically acceptable salt.

14. Solid pharmaceutical product according to item 13, where the specified compound is a hydrochloride salt of hexyl ALA ester.

15. The use of a photosensitizer, which is a compound of the General formula I

DG is
R¹represents a substituted or unsubstituted unbranched, branched or cyclic alkyl group, and
each R²independently represents a hydrogen atom or a possibly substituted alkyl group, or its pharmaceutically acceptable salt, in the manufacture of solid pharmaceutical product according to any one of claims 1 to 14 for oral administration in photodynamic treatment or diagnosis of a cancerous condition in the lower part of the gastrointestinal tract.

16. The application indicated in paragraph 15, where the specified solid pharmaceutical product is intended for use in the photodynamic treatment or diagnosis of colorectal cancer.

17. The application indicated in paragraph 15, where the specified solid pharmaceutical product further comprises an anti-cancer agent.

18. Photodynamic treatment or diagnosis of a cancerous condition in the lower part of the gastrointestinal tract, which includes the following stages:
(a) oral administration of animal solid pharmaceutical product according to any one of claims 1 to 14;
(b) you can wait for a period of time necessary to achieve the effective concentration of the photosensitizer in the tissue of the desired area; and
(C) photo-activation of the photosensitizer.

19. Solid pharmaceutical product according to any one of claims 1 to 14 for use in the method chirurgeons the CSO intervention or medicine.

20. Solid pharmaceutical product according to claim 19 for use in the photodynamic treatment or diagnosis of a cancerous condition in the lower part of the gastrointestinal tract.