Solid compositions containing 5-aminolevulinic acid

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutics and concerns a solid pharmaceutical product, a solid composition applicable in methods for photodynamic diagnosing of cancer, pre-cancer and non-cancer conditions of the lower gastrointestinal system. The solid pharmaceutical composition and pharmaceutical product contain an active ingredient representing 5-aminolevulinic acid (5-ALA), or 5-ALA ester, or their pharmaceutically acceptable salts, as well as one or more triglycerides and one or more non-ionic emulsifiers and additionally one or more enteric coating. Further, the invention refers to a method for photodynamic diagnosing of cancer, pre-cancer and non-cancer conditions of the lower gastrointestinal tract, wherein the above solid pharmaceutical compositions and pharmaceutical products are applicable.

EFFECT: group of inventions provides the effective concentration of 5-ALA in the lower gastrointestinal tract, the homogenous distribution of 5-ALA, ease of use.

17 cl, 3 ex, 9 dwg

 

This invention relates to solid compositions and solid pharmaceutical products for use in the methods of photodynamic diagnosis of cancer, pre-cancerous and non-cancerous conditions in the lower part of the gastrointestinal system. Solid pharmaceutical compositions and pharmaceutical products contain the active ingredient, which is a 5-aminolevulinic acid (5-ALA), or a precursor or derivative of 5-ALA, or their pharmaceutically acceptable salts. In addition, this invention relates to a method of photodynamic diagnosis of cancer, pre-cancerous and non-cancerous conditions of the lower part of the gastrointestinal tract, employ solid pharmaceutical compositions and pharmaceutical products.

Photodynamic diagnosis (PDD) is a relatively new method of diagnosis of precancerous lesions, cancer and non-cancer diseases. PDD includes the introduction of a photosensitizer or his predecessor in the area of interest. The photosensitizer or precursor enters the cells, where the precursor of the photosensitizer into photosensitizer. When exposed to light on the area of interest, the photosensitizer is excited and demonstrates in response fluorescence, which is detected. The photosensitizer accumulates mainly is substantial in metabolically active tissue, such as diseased or neoplastic tissue; therefore, this tissue can be distinguished from healthy tissue. The mechanisms are not yet fully understood, but studies suggest that accumulation occurs not as a result of selective uptake by cancer cells. Rather, the levels of absorption is similar in all cell types, but the processes of transformation and removal from the body differ in metabolically active cells, such as neoplastic tissue, which leads to the concentration gradient between, for example, inflammatory/neoplastic and normal tissue.

Some photosensitizers and predecessors of photosensitizers known and described in the literature. 5-Aminolevulinic acid (5-ALA) and some of its derivatives, for example esters of 5-ALA, are precursors of photosensitizers and after exposure of the cells become fetoprotein, such as fetoprotein IX (PpIX). Currently, one pharmaceutical product, Hexvix®, developed by Photocure ASA (Oslo, Norway), which contains hexyl ester of 5-ALA, clinically used for PDD bladder cancer and precancerous lesions. In the way PDD Hexvix is placed into the bladder in the form of an aqueous solution, which is freshly prepared on the spot of dried powder hexyl ester of 5-ALA and environment for dissolution. This is due to ogran the Chennai stability of 5-ALA and esters of 5-ALA in the aquatic environment, that limits the shelf life of aqueous pharmaceutical products in which they are present.

They have adopted several different strategies in an attempt to overcome this problem. For example, Metvix® by Galderma S. And emulsion oil-in-water (cream) for photodynamic treatment of actinic keratosis and basal cell carcinoma stored in cold conditions. Levulan Kerastick developed DUSA Pharmaceuticals, product for photodynamic treatment of skin diseases, which contains 5-ALA, sold in a 2-chamber system with a single camera with dried 5-ALA, and a solution of 5-ALA is prepared from 2-chamber system immediately before use.

Such approaches, however, have drawbacks. For example, it is not always convenient to carry and store medicines in cold conditions. Moreover, usually it is also preferable to obtain the pharmaceutical composition in a ready-to-use form that is most convenient for clinicians and staff. Getting ready to use forms also makes it possible to obtain compositions with reliable and exact concentration. This is especially important in the treatment and diagnosis of many diseases, including cancer, where it may be necessary to enter the correct and effective dosage of a therapeutic or diagnostic tools.

In the US 2003/125388 described an alternative approach is to obtain stable compositions of 5-ALA, where is 5-ALA or its derivative is dissolved or dispersed in non-aqueous liquid having a dielectric constant of less than 80 at 25°C., and where the said liquid stabilized 5-ALA or its derivative. It is hypothesized that the use of non-aqueous liquid facilitates the formation of enol forms of 5-ALA, which then prevents its destruction. However, the stability data not shown. Examples of suitable non-aqueous liquids, referred to in the US 2003/125388 include glycerin and its complex of mono-, di - and treatery with C1-C20carboxylic acids, propylene glycol, alcohols, ethers, esters, poly(alkalophile), phospholipids, DMSO (dimethylsulfoxide), N-vinyl pyrrolidone and N,N-dimethylacetamide. This composition may be part of the set for therapeutic or diagnostic applications. Another part of the set is a composition containing water. In this case, the two parts of set mixed before use. Therefore, the approach in the US 2003/125388 has the same drawback, that Levulan Kerastick®, which consists in the fact that, as a rule, it is undesirable to receive pharmaceutical agents in a form that requires cooking physician pharmaceutical product, which is injected in fact.

The lower part of the gastrointestinal tract, particularly the colon and rectum, can be associated with a number of serious is life-threatening diseases, such as colitis, colorectal cancer, Crohn's disease, irritable bowel syndrome and a variety of local infection. Potentially the most serious of these is colorectal cancer. Modern diagnostic methods for colorectal cancer include monitoring of clinical symptoms such as blood in the stool, abdominal pain or weight loss, colonoscopy and visualization techniques based on x-rays. The prognosis for patients with colorectal cancer depends, as with most other forms of cancer, stage of disease at diagnosis and especially from developed if the patient has distant metastasis. In clinical use today, there are several therapeutic drugs for the treatment of colorectal cancer, however, modern medicines have their clinical limitations and remains a medical need for additional therapeutic regimes and alternative methods for early diagnosis.

In B. Mayinger et al. Endoscopy 40, 106-109, 2008 described a clinical study on the detection of pre-malignant conditions of the colon using fluorescence endoscopy using enemas containing hexyl ester of 5-ALA dissolved in sterile phosphate-saline buffer solution. The authors have shown that when using PDD detected in 28% more polyps than using endoscopic visualization through the white light.

In E. Endlicher et al. Gastrointestinal Endoscopy 60 (3), 449-454, 2004 used 5-ALA and various esters of 5-ALA, namely methyl ether, benzyl ether and hexyl ether, to detect dysplastic pathological changes using fluorescence in models of chronic colitis in rats. 5-ALA and ester derivatives of 5-ALA was a sterile solution, which was introduced in the form of local probes. The sensitivity and specificity in these experiments depended on the choice of ether. For example, hexyl ester, 5-ALA, the sensitivity was 60% with a specificity of 51%.

The above enema and injected locally probes have some drawbacks when used to diagnose conditions in the lower part of the gastrointestinal system. They relate to their stability during storage and form of administration. As local introduction of probes and the introduction of enemas requires the presence of medical personnel, such as nurses and/or doctors, during the introduction, and in the case of enema during incubation. In addition, the use of 5-ALA and complex ester of 5-ALA as precursors in the PDD requires their conversion into photosensitizer, that is, photoprotein that is not an instant process. Therefore, there is a delay in the form of the incubation period between the introduction of such predecessor and the excitation light and the investigator is about, diagnosis. To obtain the best diagnostic results enema or locally injected probe should be brought into contact with the walls of the colon during the incubation period, and for some patients may not be able to hold the enema inside of the colon during such period.

Therefore, there is a need for alternative compositions of 5-ALA and esters of 5-ALA and, therefore, pharmaceutical products containing 5-ALA and an ester of 5-ALA for use in PDD lower part of the gastrointestinal tract, particularly the colon and rectum.

In WO 2009/074811 the authors of the invention described solid pharmaceutical products for use in the PDD the lower part of the gastrointestinal tract, particularly the colon and rectum. These solid pharmaceutical products may be intended for oral administration or may be in the form of a suppository. Oral solid pharmaceutical products can be in the form of capsules, pellets, powders, tablets, granules, pills or minitablets where these minitablets, powders, granules or pellets can also be presented in a capsule or compressed into a tablet.

At present, the inventors have unexpectedly discovered new and alternative solid compositions containing 5-ALA or its derivative (e.g. the measures ether ALA), for use in the PDD the lower part of the gastrointestinal tract, particularly the colon and rectum.

New solid compositions are stable at room temperature, are compared with the enema and local probes is more convenient for the medical staff and provide more convenience patients. In addition, they can easily be delivered to the lower part of the gastrointestinal system, especially to the lower part of the small intestine, the entire colon and rectum. Therefore, they overcome the aforementioned disadvantages of the known prior art and is capable of providing an effective concentration of 5-ALA or its derivatives at the proposed location, i.e. in the lower part of the gastrointestinal tract, and, importantly, can also provide an essentially homogeneous (i.e. uniform) distribution of 5-ALA or its derivative (for example, ether ALA) in the intended location.

Thus, as seen from a first aspect, the invention features a solid pharmaceutical product for use in photodynamic diagnosis of cancer, pre-cancerous and non-cancerous conditions in the lower part of the gastrointestinal tract, containing

a) an active ingredient selected from 5-ALA, the precursor of 5-ALA or a derivative of 5-ALA and their pharmaceutically acceptable salts;

b) one or more than one triglyce the ID and

C) one or more than one emulsifier.

The term "solid" refers to the physical condition of the pharmaceutical product in the form of solids, not liquids or gas. Consequently, fluids, dispersions and solutions not covered by this term. In addition, none of the semi-solid substances such as gels, ointments, pastes and creams, are not covered by this term. Typical examples of solid pharmaceutical products which are covered by the invention include capsules, tablets, pellets, granules, powders and suppositories.

The term "pharmaceutical product" refers to the object that is actually administered to a subject such as a person or an animal, not a person.

The term "precancerous condition" means a disease, syndrome or indicator, which, if left untreated, can lead to cancer. It is a generalized state associated with a significantly increased risk of cancer. A precancerous condition may, for example, manifest itself in the form of extensive/abnormal cell proliferation, such as hyperplasia and neoplasia.

The term "non-cancerous condition" includes painful conditions such as colitis, Crohn's disease, irritable bowel syndrome and other viral, bacterial or fungal infection or inflammation, localized in the lower part of Zheludok what about the intestinal tract.

The term "active ingredient" means 5-ALA and its pharmaceutically acceptable salts, precursors of 5-ALA and their pharmaceutically acceptable salts, and derivatives of 5-ALA and their pharmaceutically acceptable salts.

The term "5-ALA" means 5-aminolevulinic acid, 5-amino-4-oxo-pentane acid.

The term "precursor of 5-ALA" means compounds that are metabolically converted into 5-ALA and thus are essentially equivalent. Thus, the term "precursor of 5-ALA" covers the precursors of biological fetoprotein in the metabolic pathway of heme biosynthesis.

The term "derivative of 5-ALA" includes chemically modified 5-ALA, for example esters.

The term "pharmaceutically acceptable salt" means a salt that is suitable for use in solid pharmaceutical product and which satisfies the requirements relating to, for example, to safety, bioavailability and tolerability (see, for example, P. N. Stahl et al. (eds.) Handbook of Pharmaceutical Salts, Publisher, Helvetica Chimica Acta, Zurich, 2002).

The pharmaceutical products according to the invention are solid when administered to a subject such as a person or an animal, not a person. Preferred solid pharmaceutical product according to the invention are solid at a temperature of at least 18°C, more preferably at a temperature in m is Nisha least 25°C, even more preferably at a temperature at least 30°C.

If solid pharmaceutical product is not in the form of a suppository, such solid pharmaceutical products are most preferably solid at a temperature at least 40°C.

If solid pharmaceutical product is in the form of a suppository, such solid pharmaceutical product according to the invention are most preferably solid at room temperature and melt/dissolve at body temperature of the subject, i.e. a person or animal, not a person whom it is administered.

In the preferred embodiment of the solid pharmaceutical product according to the invention are intended for use in photodynamic diagnosis of cancer and precancerous lesions in the lower part of the gastrointestinal tract, preferably in the colon and rectum.

The use of 5-ALA and its derivatives, for example esters of 5-ALA in PDT and PDD is well known in the scientific and patent literature, see, for example, WO 96/28412, WO 2006/051269, WO 2005/092838, WO 03/011265, WO 02/09690, WO 02/10120, WO 2003/041673 and US 6034267, the contents of which are incorporated in this description by reference. All such derivatives of 5-ALA and their pharmaceutically acceptable salts are suitable for use in the methods described in this specification.

inches 5-ALA is known in the art. In addition, 5-ALA and its pharmaceutically acceptable salts are commercially available, for example from Sigma Aidrich.

Derivatives of 5-ALA, useful in accordance with the invention, can be any derivative of 5-ALA, capable of forming fetoprotein, for example PpIX or derived PpIX in vivo. Typically, these derivatives are the precursor of PpIX or derived PpIX, for example a complex ester of PpIX in the heme biosynthesis pathway, and who as a result is able to induce the accumulation of PpIX after administration in vivo. Suitable precursors of PpIX or derived PpIX include prodrugs of 5-ALA, which may be capable of forming 5-ALA in vivo as an intermediate in the biosynthesis of PpIX or which can be transformed, for example, enzymatic, porphyrins without the formation of 5-ALA as intermediate compounds. Esters of 5-ALA and its pharmaceutically acceptable salt described in this description of the invention, are among the preferred compounds for use in the invention described in this specification.

Esters of 5-ALA, which may be N-substituted, are preferred for use in the invention. Those compounds in which the 5-amino group is unsubstituted, i.e. esters of 5-ALA, are particularly preferred. Such compounds are generally known and described in the literature; see, n is the sample, WO 96/28412 and WO 02/10120, Photocure ASA, the contents of which are included in this description by reference.

Esters of 5-ALA with substituted or unsubstituted alkanols, i.e. esters of Akilov and esters substituted Akilov, and their pharmaceutical acceptable salts are especially preferred derivatives of 5-ALA for use in the invention. Examples of such compounds include compounds of General formula I and their pharmaceutically acceptable salts:

where

R1represents a substituted or unsubstituted alkyl group, and

R2each independently represents a hydrogen atom or a group R1.

When used in this description, the term "alkyl", unless otherwise indicated, includes any long - or short-chain, cyclic, straight or branched, saturated or unsaturated aliphatic hydrocarbon group. Unsaturated alkyl groups may be mono - or polyunsaturated and include as alkeneamine and alkyline group. Unless otherwise noted, these alkyl groups may contain up to 40 carbon atoms. However, preferred are alkyl groups containing up to 30 carbon atoms, preferably up to 10, particularly preferably up to 8, particularly preferably EAP is ot to 6 carbon atoms.

In the compounds of formula I group R1represent a substituted or unsubstituted alkyl group. If R1represents a substituted alkyl group, one or more than one Deputy or attached to the alkyl group and/or interrupted alkyl group. Suitable substituents that are attached to the alkyl group selected from hydroxy, alkoxy, acyloxy, alkoxycarbonyl, amino, aryl, nitro, oxo, fluorine, -SR3,andwhere R3represents a hydrogen atom or a C1-6alkyl group. Suitable substituents, which interrupted alkyl group selected from-O-, -NR3-, -S - or-PR3.

In the preferred embodiment R1represents an alkyl group, substituted by one or more aryl substituents, i.e. aryl groups, preferably substituted with one aryl group.

When used in this description, the term "aryl group" means an aromatic group which may contain or may not contain heteroatoms such as nitrogen, oxygen or sulfur. Aryl groups which do not contain heteroatoms are preferred. Preferred aryl groups contain up to 20 carbon atoms, more preferably up to 12 carbon atoms, for example the EP 10 or 6 carbon atoms. The preferred embodiments of aryl groups are phenyl and naphthyl, especially phenyl. In addition, the aryl group may be substituted by one or more, more preferably one or two substituents. Preferably aryl group substituted in the meta - or para-position, most preferably in the para-position.

Suitable substituents include halogenated, for example trifluoromethyl, alkoxy, preferably alkoxygroup containing from 1 to 6 carbon atoms, halogen, for example iodine, bromo, chloro or fluorescent, preferably chloro, fluorescent, nitro and C1-6alkyl, preferably1-4alkyl. Preferred1-6alkyl groups include methyl, isopropyl and tert-butyl, especially methyl. Particularly preferred aryl substituents are chloro and nitro. However, even more preferably the aryl group is unsubstituted.

Preferably such aryl-substituted groups R1represents benzyl, 4-isopropylbenzyl, 4-methylbenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-[tert-butyl]benzyl, 4-[trifluoromethyl]benzyl, 4-methoxybenzyl, 3,4-[di-chloro]benzyl, 4-Chlorobenzyl, 4-tormentil, 2-tormentil, 3-tormentil, 2,3,4,5,6-pentafluorobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-phenylethyl, 4-phenylbutyl, 3-pyridinyl-methyl, 4-diphenyl-methyl and benzyl-5-[(1-acetylacetone)-carbonyl]. More preference is sustained fashion such groups R 1represents benzyl, 4-isopropylbenzyl, 4-methylbenzyl-4-nitrobenzyl and 4-chlorbenzyl. Most preferred is benzyl.

If R1represents a substituted alkyl group, one or more oxo-substituents are preferred. Preferably such groups are remotemachine4-12alkyl groups that are substituted by one or more exography, preferably one to five exography. The carbonyl group is preferably present in the substituted alkyl group in an alternating, which leads to short polietilenglikoli deputies. Preferred examples of such groups include a 3.6-dioxa-1-octyl and 3,6,9-trioxa-1-decyl.

If R1represents an unsubstituted alkyl group, R1groups, which are saturated remotemachine or branched alkyl groups, are preferred. If R1represents a saturated remotemachine alkyl group, preferred is pravarasena1-10an alkyl group. Typical examples of suitable remotemachine alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and n-octyl. Especially preferred is pravarasena1-6alkyl group, most preferred are met the l and n-hexyl. If R1is a saturated branched alkyl group, such branched alkyl groups preferably consist of a main chain of 4-8, preferably 5-8 located on a straight chain of carbon atoms of the main chain of the branched one or more C1-6alkyl groups, preferably With1-2alkyl groups. Examples of such saturated branched alkyl groups include 2-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 3,3-dimethyl-1-butyl.

In the compounds of formula I, each R2independently represents a hydrogen atom or a group R1. Especially preferred for use in the invention are those compounds of formula I in which at least one R2represents a hydrogen atom. In especially preferred compounds, each R2represents a hydrogen atom.

Preferably the compounds of formula I and their pharmaceutically acceptable salts are used in solid pharmaceutical product according to the invention, where R1represents methyl or hexyl, more preferably n-hexyl, and both R2represent hydrogen, i.e. the methyl ester of 5-ALA, hexyl ester of 5-ALA and their pharmaceutically acceptable salts, preferably its HCl salt. The preferred compound for use in solid pharmaceutical products is those according to the invention is hexyl ester of 5-ALA and its pharmaceutically acceptable salts, preferably HCl salt or salts of sulfonic acid or salt sulfonatocalix derived.

Esters of 5-ALA and their pharmaceutically acceptable salts for use in the invention can be obtained by any conventional method available in the art, for example as described in WO 96/28412 and WO 02/10120. Briefly, esters of 5-ALA can be obtained by reaction of 5-ALA with a suitable alcohol in the presence of a catalyst, such as acid. Pharmaceutically acceptable salts of esters of 5-ALA can be obtained, as described above, through the interaction of a pharmaceutically acceptable salt of 5-ALA, for example chloride 5-ALA, with a suitable alcohol. Alternatively, the compounds for use in the invention, such as the methyl ester of 5-ALA or hexyl ester of 5-ALA may be commercially available, for example from Photocure ASA, Norway.

Esters of 5-ALA for use in the invention may be in the form of a free amine, for example-NH2-The other2or-NR2R2or preferably in the form of pharmaceutically acceptable salts. Such salts preferably are salt accession acids with pharmaceutically acceptable organic or inorganic acids. Suitable acids include, for example, hydrochloric, nitric, Hydrobromic, phosphoric, sulfuric, sulfonic acid and sulfonic acid derivatives, p is the recent described in WO2005/092838, Photocure ASA, the full contents of which are incorporated in this description by reference. The preferred acid is a hydrochloric acid, HCl, sulfonic acid and sulfonic acid derivatives. Methods of obtaining salts are conventional in the art.

Thus, the preferred embodiment of the invention is a solid pharmaceutical product for use in photodynamic diagnosis of cancer, pre-cancerous and non-cancerous conditions in the lower part of the gastrointestinal tract, containing

a) derivative of 5-ALA or its pharmaceutically acceptable salt, preferably an ester of 5-ALA or its pharmaceutically acceptable salt;

b) one or more than one triglyceride and

C) one or more than one emulsifier.

In the preferred embodiment of the specified ester of 5-ALA is a compound of formula (I) or its pharmaceutically acceptable salt, where R1represents an unsubstituted alkyl group, preferably unsubstituted saturated remotemachine or branched alkyl group, more preferably unsubstituted saturated remotemachine1-10alkyl group. More preferably the specified ester of 5-ALA is a hexyl ester of 5-ALA in one preferred embodiment, the decree is fair pharmaceutically acceptable salt hexyl ester of 5-ALA is a HCl salt or salt of sulfonic acid or salt derived sulfonic acid, such as mesilate, toilet or napsylat.

The compounds described above in this description of the invention, can be used for the manufacture of solid pharmaceutical product according to the invention any conventional way. The desirable concentration of 5-ALA or a derivative of 5-ALA or a precursor of 5-ALA in the pharmaceutical products according to the invention varies depending on several factors, including the nature of the connection, the nature of the product form in which it is present, the intended route of administration and the subject, i.e. a person or animal, not a person subject to treatment. However, as a rule, the concentration of 5-ALA or a derivative of 5-ALA or a precursor of 5-ALA or their pharmaceutically acceptable salts are conveniently is in the range from 1 to 50%, preferably from 1 to 40%, for example from 2 to 35%, more preferably from 5 to 30 wt%, by weight of the total amount of ingredients (a) plus (b) plus (C).

Solid pharmaceutical product according to the invention contain one or more than one triglyceride, i.e. triacylglycerol. A triglyceride consists of one molecule of glycerol and 3 molecules of fatty acids. 3 fatty acids may represent the same or different fatty acids.

Triglycerides can be solid or liquid at room temperature, i.e. at temperatures of from about 18°C to p is IMEMO 25°C. Solid triglycerides are commonly called fats, while liquid triglycerides usually called oil. If you use solid triglycerides, the solid triglycerides preferably have a melting point below or equal to the body temperature of a human or animal, not a person to enter the solid pharmaceutical product. In the preferred embodiment of the solid pharmaceutical product is administered to the person, and the melting point of the solid triglyceride contained in the specified pharmaceutical product, is approximately 26-37°C.

Triglycerides can be synthetic, semi-synthetic or animal and/or vegetable origin. Triglycerides can be clean/dedicated triglycerides or part of a mixture, such as a mixture of triglycerides, monoglycerides and/or diglycerides and/or free fatty acids and/or unsaponifiable lipids. Such mixtures usually comprise edible oils of animal and/or vegetable origin. If triglycerides are part of the mix, they preferably comprise a large portion of this mixture. Such mixtures are also called "triglycerides".

Because triglycerides are used in the pharmaceutical product according to the invention, which is used for a person or animal, not a person, they must be farm is cautiously qualifications and meet the requirements and standards for such products in relation to physiological acceptability, tolerability and safety.

In addition, triglycerides should be inert compounds, i.e. compounds that do not interact with the active ingredient (a) or which do not contribute to the destruction of the active ingredient.

The term "one or more triglycerides" means that the solid pharmaceutical product according to the invention contains one or triglyceride several different triglycerides. As an example, a solid pharmaceutical product may contain tricaprylin (triglyceride Caprylic acid) or tricaprylin and Caprylic/capric triglyceride. In addition, as an example, a solid pharmaceutical product may contain soybean oil, which is a mixture of triglycerides of alpha-linolenic acid, linoleic acid, oleic acid, stearic acid and palmitic acid.

Preferred triglycerides are selected from edible oils of animal and/or vegetable origin and/or their fractions, such as soybean oil, palm oil, palm kernel oil, corn oil, olive oil, almond oil, safflower oil, peanut oil, coconut oil, sunflower oil, castor oil, pine oil, jojoba oil, cocoa butter and palm olein. Additional examples of preferred triglycerides are the oil illipe oil oil tree, cocoa butter, oils of kokum, oil, sawn or chipped lengthwise, and other natural oils or their fractions. Other examples of preferred triglycerides include hydrogenated or partially hydrogenated triglycerides selected from partially or fully hydrogenerating soybean oil, rapeseed oil, cottonseed oil, sunflower oil, coconut oil and their fractions. Triglycerides can also be synthetic or semi-synthetic triglycerides, such as medium chain triglycerides (MCT).

In the preferred embodiment, the triglyceride is a triglyceride glycerol and 3 identical or different fatty2-C22acid, more preferably 3 identical or different fatty4-C18acids, even more preferably 3 identical or different fatty6-C18acid and most preferably 3 identical or different fatty6-C12acids. In a more preferred embodiment, the triglyceride is a triglyceride glycerol and 3 of the same fatty2-C22acid, more preferably 3 identical fatty4-C18acids, even more preferably 3 identical fatty6-C18acid and most preferably 3 identical fatty6-C12the acid.

The most preferred solid triglycer the s are cocoa butter, lard, tallow, hydrogenated Coco glycerides, hydrogenated palm oil, tristearin, tripalmitin and trimyristin. Such solid triglycerides are especially preferred, if the solid pharmaceutical product is a suppository. For suppositories are preferred hydrogenated Coco glycerides, possibly mixed with glyceryltrinitrate, for example sold under the name "Witepsol®" and "Massa Estarinum®", the preferred hydrogenated Coco glycerides with low hydroxyl number and melting point of 31°C to 38°C, that is, Witepsol H 32, Witepsol H 35, Witepsol H 37 and Massa Estarinum® 299.

The most preferred liquid triglycerides are tricaprylin, takepron, tripeptinon, Caprylic/capric triglyceride, Caprylic/capric/linoleic triglyceride, and Caprylic/capric/succinic triglyceride, some of these liquid triglycerides sold under the name "Miglyol®", for example Miglyol 812, representing Caprylic/capric triglyceride, Miglyol 818 representing Caprylic/capric/linoleic triglyceride, and Miglyol 808 representing tricaprylin. The manufacturer of such triglycerides is, for example, Sasol, Witten, Germany.

In General, the amount of triglycerides in the pharmaceutical product according to the invention SOS the defaults from 50 to 90%, more preferably from 60 to 80% of the mass. by weight of the total amount of ingredients (a) plus (b) plus (C).

Triglycerides, and in the invention, can be obtained using standard processes and techniques well known in the art, and, as a rule, they are commercially available from various manufacturers such as Sasol, Croda, Cognis, Gattefosse, and others.

Solid pharmaceutical product according to the invention contain one or more than one emulsifier.

Emulsifier, also known as the surfactant, a surfactant or emulsifying substance is a substance which stabilizes an emulsion. To obtain emulsions which can be used in the pharmaceutical product, use a wide range of emulsifiers.

The term "one or more than one emulsifier" means that the solid pharmaceutical product according to the invention contains one emulsifier or more different emulsifiers.

The emulsifier used in solid pharmaceutical product according to the invention can be solid or liquid at room temperature, i.e. at temperatures of from about 18°to about 25°C.

In the preferred embodiment, the emulsifiers are nonionic emulsifiers.

Preferred nonionic emulsifiers are selected from the group of short-chain partial glycerides, i.e. the false esters of glycerol and short chain fatty acids, where only part of the available hydroxyl groups is esterified, that is mono - or diglycerides or mixtures of mono - and diglycerides. Preferred partial glycerides are mono - or diglycerides or mixtures of mono - and diglycerides of fatty6-C10acids.

Other preferred nonionic emulsifiers are esters of glycerol with fatty acids and alpha-hydroxy acids, such as glyceraldehyde citrate, glycerinated/lactate/oleate/linoleate, literallayout/citrate/lactate and glycerylmonostearate.

Other preferred nonionic emulsifiers are fatty alcohols and/or ethoxylated fatty alcohols, such as cetosteatil alcohol or cetomacrogol.

Other preferred nonionic emulsifiers are ethoxylated fatty acids such as ethoxylated castor oil.

Other preferred nonionic emulsifiers are methoxylamine and ethoxylated esters sorbitan and fatty acids, sold under the name "Span" and "Tween", i.e. Polysorbate, preferably (polyoxyethylene)sorbitanoleat, (polyoxyethylene)servicemanagement, (polyoxyethylene)servicemonitor, (polyoxyethylene)servicemanual, (polyoxyethylene)corbettreport or (polyoxyethyl is)sarbatorile.

Other preferred nonionic emulsifiers are lecithins such as egg yolk lecithin or soybean lecithin or phospholipids derived from lecithin, preferably phosphatidylcholine.

Other preferred nonionic emulsifiers are compounds based on polyethylene glycol, such as polyethylene glycol-400 monostearate.

Other preferred nonionic emulsifiers are ethoxylated glycerides, such as ethoxylated caprianavillage or products obtained by the reaction of polyethylene glycol and natural or hydrogenated oils such as palm kernel oil, hydrogenated palm kernel oil, castor oil, hydrogenated castor oil, almond oil, oil of apricot pits and the like.

These last nonionic emulsifiers are preferred, and preferred examples are lauroyl-macrogol-32 glycerides, Gelucire® 44/14 (Gattefosse); stearoylbenzoylmethane, Gelucire® 50/13 (Gattefosse); PEG-50 castor oil Emalex C-50 (Nihon Emulsion); Eumulgin® HRE 40 (Cognis); PEG-45 hydrogenated castor oil, PEG-8 Caprylic/capric glycerides, Labrasol® (Gattefosse); either by themselves or in mixture with other emulsifiers. In the preferred embodiment some Gelucires are mixed, for example, Gelucire® 44/14, mesilat with Gelucire® 50/02 (saturated poliglecaprone glycerides), or Gelucire® 33/01 (glycerol esters of saturated fatty8-C18acids).

Another preferred nonionic emulsifiers are poloxamer, i.e. triblock copolymers composed of a Central hydrophobic chain of polyoxypropylene located on either side by two hydrophilic chains of polyoxyethylene. Poloxamer also known under the trademark Pluronics®. The most preferred poloxamers are those which are liquid and have a pH below 7, preferably below 6, such as Pluronic® L43, HLB 7-12 and Pluronic® L44, HLB 12-18, either by themselves or in mixture with other emulsifiers, preferably other poloxamers, such as Pluronic® F68.

If the active ingredient (a) is a C1-C10alkilany ester of 5-ALA or its pharmaceutically acceptable salt, preferably using non-ionic emulsifiers with high hydrophilic-lipophilic balance (HLB value), even more preferably with an HLB value of at least 7, preferably with an HLB value of at least 12, more preferably with an HLB value of about 12-18. If you use more than one emulsifier, it is also possible to use an emulsifier with an HLB value below 7 or above 18, provided that the mixture of emulsifier has a HLB value of at least 7 and preferably the value is their HLB of about 12 to 18.

Typically, the emulsifier is present in the solid pharmaceutical product in the quantity necessary to facilitate uniform distribution of the pharmaceutical product at the site of application, for example in the colon and rectum. Appropriate amount of the emulsifier is chosen, taking into account the amount of triglycerides. Preferably the emulsifier is present in the pharmaceutical product according to the invention in quantities of from about 0.5 to 50%, preferably from 1 to 35%, more preferably from 2 to 30 wt.%. of the total weight of the solid pharmaceutical product.

The emulsifiers used in the invention can be obtained using standard methods and techniques well known in the art, although many are commercially available from various manufacturers such as Sasol, Croda, Cognis, Gattefosse, American Lecitin Company, BASF, Cytec, and others.

Solid pharmaceutical product also contains

d) possibly one or more of mucoadhesive

d) possibly one or more pharmaceutically acceptable excipients, different from b) and C);

e) possibly one or more penetrating the surface agents, and

f) possibly one or more chelating agents.

Solid pharmaceutical product according to the invention may contain one or more of mucoadhesives, i.e. one mucoadhesive or more RA is ing of mucoadhesives.

The term "mucoadhesive" means a compound that exhibits an affinity to the surface of the mucous membrane, that is, adheres to such surface due to the formation of relationships that are, as a rule, are non-covalent in nature, or binding, no matter interact with mucous and/or downstream cells. In the context of the invention, the mucosal surface is a surface of the mucous membrane of the lower part of the gastrointestinal tract, in particular the mucous membrane of the colon and rectum.

Mucoadhesive, which may be present in the solid pharmaceutical product according to the invention is preferably mucoadhesive, which does not dissolve or is not metabolized by bacterial and non-bacterial enzymes present in the lower part of the gastrointestinal tract, particularly the colon and rectum.

Mucoadhesive that can be used in solid pharmaceutical products according to the invention can be a natural or synthetic compounds, polyanionic, poly -, or neutral, water-soluble or nevadacalifornia, but preferably are large, for example having a molecular weight of from 500 to 3000 kDa kDa, for example from 1000 kDa to 2000 kDa, not soluble in water, made the, for example containing from 0.05% to 2% wt. cross-linking agent of the total polymer, prior to any hydration, swelling in water of the polymers capable of forming hydrogen bonds. Preferably such mucoadhesive compounds have mucoadhesive force of more than 100, particularly preferably more than 120, more particularly 150, expressed as a percentage relative to the standard in vitro, in the evaluation method of Smart et al., 1984, J. Pharm. Pharmacol., 36, pp. 295-299.

Preferred mucoadhesive selected from polysaccharides, preferably dextran, pectin, amylopectin or agar; gums, preferably the guar gum or gum carob; salts of alginic acid, preferably the sodium alginate or magnesium alginate; poly (acrylic acid) and stitched or unstitched copolymers of poly (acrylic acid) and derivatives of poly (acrylic acid), such as salts and esters, such as, for example, carbomer (carbopol).

If available, mucoadhesive can be conveniently represented in the concentration range from 0.05 to 50%, preferably from 0.1 to 25%, for example from 0.2 to 10% by weight. of the total weight of the solid pharmaceutical product according to the invention.

Solid pharmaceutical product according to the invention may contain one or more pharmaceutically acceptable excipients other than the excipients (b), (C) and vozmojnos is excipient (g). Such one or more pharmaceutically acceptable excipients may be selected from the group of antiadhesive, fillers, binders, flavorings, dyes, amplifiers, smell, moving substances, lubricants, disintegrating agents, solvents or preservatives. The expert can select suitable excipients, based on, for example, the selected route of administration. Excipients that can be used in pharmaceutical products described in this description of the invention, are listed in various guides (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 of Excipients for Pharmaceuticals, Cosmetics and Related Areas (Edition Cantor, Munich, 2002) and H.P.Fielder (Ed) Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete (Edition Cantor Aulendorf, 1989)).

If solid pharmaceutical product according to the invention may contain one or more pharmaceutically acceptable solvents, such solvents can be a free fatty acid, free fatty alcohol, an aqueous solution such as a buffer or water. However, preferably, the solid pharmaceutical product according to the invention contained no water, then there was nesteriak water. Under "nesteriak water" is meant that the solid pharmaceutical product not add water and that any measurable water content in which the product due to water, may be contained in any of the ingredients (a)-f).

Solid pharmaceutical product according to the invention may contain one or more agents that promote penetration through the surface. A useful effect of such agents may be increased photosensitizing effect of 5-ALA, a derivative of 5-ALA or a precursor of 5-ALA present in pharmaceutical products according to the invention.

Therefore, agents that promote penetration through the surface, especially diallylsulfide, such as dimethylsulfoxide (DMSO), can be included in products. The agent that promotes penetration through the surface, can be any of the agents promoting skin penetration, are described in the pharmaceutical literature, such as chelating agents (such as EDTA (ethylenediaminetetraacetic acid)), surfactants (e.g. sodium dodecyl sulphate), substances which are not surfactants, bile salts (sodium dezoksiholatom) and fatty acids (e.g. oleic acid). Examples of suitable agents promoting penetration through the surface, include isopropanol, 1-[2-(decillia)ethyl]-azacyclopenta-2-he (NRE-101 commercially available from Hisamitsu), DMSO and other diallylsulfide, in particular n-decylmethacrylate (NDMS), dimethylsulfate, DIMET formamide (DMFA), dimethylacetamide, isopropylmyristate, alerby alcohol and oleic acid, and 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.

The use of glycols, such as propylene glycol, as penetrating the surface of the auxiliary agents is not recommended, as this may contribute to the destruction of the active ingredient (a) in the solid pharmaceutical product according to the invention.

The agent that promotes penetration through the surface, can be conveniently represented in the concentration range from 0.2 to 50% by weight. from the total mass of the pharmaceutical product in which it is present, for example from about 0.5 to 5% wt. of the total weight of the solid pharmaceutical product in which it is present.

Solid pharmaceutical product according to the invention may contain one or more chelating agents. Such agents can also have a beneficial effect in enhancing photosensitizing effect of 5-ALA, a derivative of 5-ALA or a precursor of 5-ALA present in pharmaceutical products according to the invention.

Chelating agents can, for example, enable to enhance the accumulation of PpIX, as the chelation of iron chelating agent prevents its inclusion in PpIX with the formation of the subject action is armenta ferrochelatase, which leads to the accumulation of PpIX. Photosensitizing effect is therefore enhanced.

Suitable chelating agents that can be included in the solid pharmaceutical product, are aminopolycarboxylate acid, such as any of the chelating agents described in the literature for detoxification of metals or ions chelation of paramagnetic metals in contrasting agents for magnetic resonance imaging. I can specifically be mentioned EDTA, CDTA (cyclohexanedicarboxylate acid), DTPA and DOTA and their well-known derivatives and analogues. EDTA and DTPA are particularly preferred. Other suitable chelating agents are desferrioxamine and siderophore, and can be used by themselves or in combination with aminopolycarboxylate chelating agents such as EDTA.

Some of the above chelating agents also exhibit properties of agents promoting penetration through the surface, for example EDTA.

If present, the chelating agent can be conveniently used in a concentration of from 0.01 to 12%, for example from 0.1 to 10 wt.%, of the total weight of the solid pharmaceutical product.

Solid pharmaceutical product according to the invention are intended, or for oral or rectal administration, preferably for pergaminowane.

For rectal administration (rectal introduction) solid pharmaceutical product according to the invention is preferably presented in the form of a suppository.

Preferably, the solid pharmaceutical product according to the invention, which is represented in the form of a suppository (hereinafter called "the suppository according to the invention")contains one or more triglycerides b) one or more solid triglycerides having a melting point below or equal to the body temperature of a human or animal, not a person to enter a suppository. In the preferred embodiment, the suppository is administered to the person, and the melting point of the specified one or more solid triglyceride is from about 26°C and 37°C. Such preferred solid triglycerides are cocoa butter, lard, tallow, hydrogenated Coco glycerides, more preferably hydrogenated Coco glycerides, for example sold under the name "Witepsol®" and "Massa Estarinum®" (for example from Sasol), even more preferably hydrogenated Coco glycerides with low hydroxyl number and melting point of 31°C and 38°C, that is, Witepsol® H 32, Witepsol® H 35, Witepsol® H 37 and Massa Estarinum® 299. Solid triglycerides, which have a melting point above body temperature, for example hydrogenated palm wt is about, tristearin, tripalmitin or trimyristin, can be used in a mixture with a solid or liquid triglycerides, as long as the melting point of this mixture will comprise from about 26°C and 37°C.

Preferably, the solid pharmaceutical product according to the invention, which is represented in the form of a suppository (hereinafter called "the suppository according to the invention")contains one or more emulsifiers lecithin, phosphatidylcholine, poloxamer, ethoxylated fatty alcohols, or the products obtained by the reaction of polyethylene glycol and natural or hydrogenated oils.

The suppository can be prepared by any conventional method, for example by direct compression of the compounds a)to C) and possibly g)-(h), by pressing after granulation, or by molding, for example by melting one or more solid triglycerides, mixing with the active ingredient, one or more emulsifiers and possibly other compounds and pouring the mixture into molds, where it cools and solidifies.

If solid pharmaceutical product is in the form of a suppository for rectal administration, it is necessary that the active ingredient was released from the suppository at body temperature of the subject, such as human or animal, not the human susegana man, which impose a suppository, or a slightly lower temperature. Thus, the preferred solid pharmaceutical products, which are in the form of suppositories are solid at a temperature below the body temperature of the subject, which they are, plus they are solid at a temperature at least 30°C and melt at higher temperatures, for example in the range of from 31°C. to about 42°C. If the subject is a person, they are preferably melt in the range of approximately 31°C to about 37°C.

For oral administration of the solid pharmaceutical product according to the invention is represented in the usual solid form, such as powder, granule, pellet, tablet or capsule, where these capsules contain ingredients (a)-(C) and possibly the ingredients (d)to(g) in the form of powder, granules, pellets, minitablets or semi-solid substance or liquid.

In one preferred embodiment of the solid pharmaceutical product according to the invention, which is represented in the form of a capsule, contains as one or more triglycerides b) one or more liquid triglycerides, preferably selected from triglycerides, glycerol and 3 identical or different fatty2-C22acids, more preferably 3 identical or different fatty4-C18acids,even more preferably 3 identical or different fatty 6-C18acids and most preferably 3 identical or different fatty6-C12acids, more preferably tricaprylin, TRICORONA, tripeptinon, Caprylic/capric triglyceride, Caprylic/capric/linoleic triglyceride, and most preferably Caprylic/capric triglyceride. For the manufacture of solid pharmaceutical product, i.e. for filling capsules, one or more than one liquid triglyceride can be mixed with the active ingredient together with one or more emulsifiers and possibly other compounds (C)-(g). Preferred emulsifiers are lecithin, phosphatidylcholine, ethoxylated glycerides, polyoxyethylene sorbitan monooleate, dioctyl sodium sulfosuccinate, sodium lauryl sulfate, poloxamer and products obtained by the reaction of polyethylene glycol and natural or hydrogenated oils.

In another preferred embodiment of the solid pharmaceutical product according to the invention, which is represented in the form of a capsule, contains as one or more triglycerides b) one or more solid triglycerides having a melting point below or equal to the body temperature of a human or animal, not a person to enter the capsule. In the preferred embodiment the capsule is injected man, and the melting point of the specified one or more solid triglyceride is between approximately 26°C and 37°C. Preferably, such solid triglycerides are cocoa butter, lard, tallow, hydrogenated Coco glycerides, hydrogenated palm oil, tristearin, tripalmitin or trimyristin, more preferably hydrogenated Coco glycerides, possibly mixed with glyceryltrinitrate, for example sold under the name "Witepsol®" and "Massa Estarinum®", even more preferably hydrogenated Coco glycerides with low hydroxyl number and a melting point of between 31°C and 38°C, that is, Witepsol® H 32, Witepsol® H 35, Witepsol® H 37 and Massa Estarinum® 299. For the manufacture of solid pharmaceutical product, i.e. for filling capsules, can be fused one or more solid triglycerides and mix the active ingredient with a molten triglycerides, together with one or more emulsifiers and possibly other compounds (C)-(g). Preferred emulsifiers are selected from lecithins, phosphatidylcholine, of ethoxylated glycerides, polyoxyethylene sorbitan monooleate, dioctylsulfosuccinate sodium, sodium lauryl sulphate, poloxamers and products obtained by the reaction of polyethylene glycol and natural or hydrogenated oils.

In yet another preferred in which the polishing solid pharmaceutical product according to the invention, which is represented in the form of a capsule, contains a number of triglycerides (b), which are liquid and solid substances, for example one solid triglyceride and one liquid triglyceride. Solid triglycerides have a melting point below or equal to the body temperature of a human or animal, not a person to enter the capsule. In the preferred embodiment the capsule is administered to the person, and the melting point of these solid triglyceride is between approximately 26°C and 37°C. the Preferred liquid triglycerides are selected from triglycerides, glycerol and 3 identical or different fatty2-C22acids, more preferably 3 identical or different fatty4-C18acids, even more preferably 3 identical or different fatty6-C18acids and most preferably 3 identical or different fatty6-C12acids, more preferably tricaprylin, TRICORONA, tripeptinon, Caprylic/capric triglyceride, Caprylic/capric/linoleic triglyceride, and most preferably Caprylic/capric triglyceride. Preferred solid triglycerides are cocoa butter, lard, tallow, hydrogenated Coco glycerides, hydrogenated palm oil, tristearin, tripalmitin or trimyristin, bol is e preferably hydrogenated Coco glycerides, possibly mixed with glyceryltrinitrate, for example sold under the name "Witepsol®" and "Massa Estarinum®", even more preferably hydrogenated Coco glycerides with low hydroxyl number and a melting point of between 31°C and 38°C, that is, Witepsol® H 32, Witepsol® H 35, Witepsol® H 37 and Massa Estarinum® 299. For the manufacture of solid pharmaceutical product, i.e. for filling capsules, one or more solid triglycerides can be melted and mixed with one or more liquid triglycerides, the active ingredient, one or more emulsifiers and possible other compounds (g)-(g). Preferred emulsifiers are selected from lecithins, phosphatidylcholine, of ethoxylated glycerides, polyoxyethylene sorbitan monooleate, dioctylsulfosuccinate sodium lauryl sodium, poloxamer, products obtained by the reaction of polyethylene glycol and natural or hydrogenated oils and ethoxylated fatty alcohols.

In a more preferred embodiment of the solid pharmaceutical product according to the invention, which is represented in the form of a capsule, contains liquid triglycerides (b), selected from triglycerides, glycerol and 3 identical or different fatty2-C22acids, more preferably 3 identical or different fatty4-C18acids, even more preferably 3 Odin is new or different fatty 6-C18acids and most preferably 3 identical or different fatty6-C12acids, more preferably tricaprylin, TRICORONA, tripeptinon, Caprylic/capric triglyceride, Caprylic/capric/linoleic triglyceride, and most preferably Caprylic/capric triglyceride and non-ionic emulsifier, where the emulsifier preferably is poloxamer or a product obtained by the reaction of polyethylene glycol and natural or hydrogenated oils, more preferably Pluronic® L43, Pluronic® L44, lauroyl-macrogol-32 glycerides, Gelucire® 44/14 (Gattefosse); or stearoylbenzoylmethane, Gelucire® 50/13 (Gattefosse). For the manufacture of solid pharmaceutical product, i.e. for filling capsules, one or more solid triglycerides can be melted and mixed with one or more liquid triglycerides, the active ingredient, one or more emulsifiers and possibly other compounds (g)-(g). Alternatively, a liquid triglyceride, emulsifier and possible other compounds (g)-(g) can be given the form of pellets, minitablets or granules, and you can add excipients known in the art for the formation of such pellets, minitablets or granules, such as amplifiers viscosity or fillers. Then, the thus formed pellets is, minitablets or granules fill the capsule.

If oral administration of the solid pharmaceutical product according to the invention are presented in the form of powder, granules, tablets, pellets, capsules or minitablets, these products contain one or more triglycerides of solid and/or liquid triglycerides. Tablets, powder, granules, pellets or minitablets can be prepared by any conventional method. Preferably tablets and minitablets prepared by direct compression of the compounds (a)-(C) possibly (d)-(f) or by pressing after granulation.

As oral solid pharmaceutical product is intended for use in photodynamic treatment or diagnosis of cancer, pre-cancerous and non-cancerous conditions in the lower part of the gastro-intestinal system, this pharmaceutical product must be delivered into the lower part of the digestive system intact, i.e. without premature release of the active ingredient. To make a successful delivery in the lower part of the gastrointestinal tract, the active ingredient must be protected from absorption and/or environment of the upper part of the gastrointestinal tract, such as stomach, and upper small intestine, and then to release in the lower part of the gastrointestinal tract, i.e. in igna part of the small intestine and the cecum. The advantage is that the active ingredient is essentially homogeneous (i.e. uniformly) distributed over the entire lower part of the gastrointestinal tract. This requires the release of the active ingredient in the lower part of the gastrointestinal tract, i.e. in the lower end of the small intestine and the caecum, and the allocation/distribution of the active ingredient from the release in more distant parts of the colon and rectum. This can be achieved through delayed release, i.e. the release of the active ingredient begins at the lower end of the small intestine and the caecum and is deferred and not abrupt, so that the pharmaceutical product could move within the colon with the gradual release of the active ingredient. In another embodiment this may be accomplished by applying two or more oral solid pharmaceutical product according to the invention with different release profiles or one oral solid pharmaceutical product, such as a capsule containing, for example, minitablets, pellets or pellets with different release profiles.

There are various methods and systems for oral delivery to the colon pharmaceutical active ingredients, which is based on the fact that oral FA the pharmaceutical product contains one or more pharmaceutical excipients, providing modified release of the active ingredient, and/or by coating the oral pharmaceutical product shell that provides such a timed release.

Managed medium pressure systems use pressure increase luminale content to effect the release of the active ingredient. In one embodiment the active ingredient is dispersed in the molten solid triglyceride (base of the suppository), which melts at body temperature, together with one or more emulsifiers, and the mixture is cooled to obtain a solid pharmaceutical product according to the invention. Solid pharmaceutical product covered by ethylcellulose. After the product has been swallowed, the body temperature is responsible for melting the basis of the suppository, which increases the volume inside the shell so as to form a cylinder of ethyl cellulose, liquid filled. Such a balloon can remain intact in the small intestine, but will break under the impact of more intense contractions and luminating content with a higher viscosity, with whom he will meet in the large intestine.

Adjustable time systems (pulsed release) is based on the principle of trapping time release medicines, parasitemia passes from the mouth to the colon. System pulsed release is prepared in the form of drugs so that they had suffered a delay time predetermined duration with no release, with subsequent rapid and complete release, or delayed release downloaded(s) of drug(s) means (). The delay time of 5 hours is usually considered sufficient, since the passage of the small intestine is about 3-4 hours, which is relatively constant and is almost unaffected by the nature of the introduced composition. In one embodiment of the oral solid pharmaceutical product covered lipid barriers, such as Carnauba wax and/or beeswax, along with surfactants such as polyoxyethylene sorbitan monooleate. When the product is in contact with water, the shell emulsify or destroyed after the time delay that depends on the shell thickness. The delay time of such a system is not dependent on gastrointestinal motility, pH, enzyme and residence time in the stomach. In another embodiment of the pharmaceutical product (liquid or solid) download insoluble in the body of the capsule, which is tightly closed with a stopper swelling of the hydrogel. Upon contact with gastrointestinal fluid tube swells, vitalitas from the capsules after the time delay and, which regulate the position and size of the tube. The tube material may be made of (1) swelling of the substances covered insoluble but permeable polymer, such as polymethacrylates; (2) erosion compressible polymer, such as a receiver array (hydroxypropylmethylcellulose), polyvinyl alcohol, polyethylene oxide; (3) frozen molten polymer, such as glycerylmonostearate or enzymatic adjustable erodirovannogo polymer, such as pectin. In the preferred embodiment and to account for variable residence time in the stomach capsule cover enteric shell.

Shipping reacting to the bacteria, based on the enzymatic activity of bacteria in the lower gastrointestinal tract, especially the colon, where bacteria approximately 10 million times higher than in the proximal gastrointestinal tract. The drug, which is delivered to the colon, is prepared in the form of compounds or matrix, which is destroyed by enzymes produced and secreted by the bacteria of the colon. In one embodiment of the solid pharmaceutical product according to the invention cover a natural polysaccharide, preferably aminosol. In the glassy state, amylose has good film-forming properties and is resistant to degradation pankreaticski and enzymes in the small intestine. In combination with water-insoluble polymers, which reduce the swelling and the release of the active ingredient hydrophilic amylose, for example ethyl cellulose film membrane can be easily applied to a solid pharmaceutical product manufactured in the form of tablets or pellets, or in liquid form, or pellets, or granules, and loaded into capsules.

For controlled release of the active ingredient oral solid pharmaceutical product according to the invention are preferred system, depending on pH. the pH of the small intestine increases the aboral, and sensitive to pH pharmaceutically acceptable excipients and a shell with a threshold of dissolution in the range from pH 6.5 to pH 7.5 (distal part of the small intestine, i.e. the end of the ileum) are suitable for pH-controlled release of drugs that are subject to shipping in the lower part of the intestinal tract such as the colon. pH at the end of the ileum approximately 1-2 pH units higher than in the caecum, and is sensitive to pH pharmaceutically acceptable excipients and shell start destabilized and destroyed at the end of the ileum/cecum. In the preferred embodiment of the oral solid pharmaceutical product according to the invention is probalility pharmaceutical product, which provides a pH-controlled release of the active ingredient (a) in the range from pH 6.5 to pH 7.5. To achieve this, the solid pharmaceutical product is preferably covered with one or more enteric membranes. Typical examples of substances suitable for use as such membranes include cellulose acetate, hypromellose, methacrylic acid and esters of methacrylic acid and polyvinylacetate. Other suitable membranes include cellulose acetate phthalate (cap), ethylcellulose, dibutyl phthalate and diethylphthalate. In the preferred embodiment the enteric shell is an enteric membrane containing anionic polymers of methacrylic acid and methacrylate (Eudragit®). The type of the polymer Eudragit®, which is able to provide slow release, are also particularly suitable for use as coating substances. They are based on copolymers of acrylate and methacrylates with Quaternary ammonium groups as functional groups, and acrylate/methyl methacrylate copolymers with a neutral ester group. Such polymers are insoluble and permeable and their release profiles can be changed by varying the ratio when mixing and/or thickness of the shell. Suitable for emery Eudragit® include Eudragit® S - and L-types. In a more preferred embodiment of the solid pharmaceutical product cover the first and second enteric shell, where the specified first enteric shell using substances selected from acetate, hydroxypropylmethylcellulose, polyvinylacetate, cellulose acetate phthalate (cap), ethyl cellulose, dibutyl phthalate and diethylphthalate, and where specified the second shell consists of anionic polymers of methacrylic acid and methacrylate.

As mentioned earlier, it is desirable to achieve high and essentially homogeneous (i.e. uniform) concentration of active ingredient in the lower part of the gastrointestinal system. The desired uniform coating can be achieved by adjusting the time and place of release of the active ingredient in the colon and choosing the appropriate combination of triglyceride/emulsifier.

Suitable for use in the dosage form or regimens that include a large number of individual doses, for example a pharmaceutical product according to the invention in the form of tablets, capsules or a mixture of pellets, which is capable of releasing the active ingredient at different speeds and/or at different time intervals after injection. Individual doses may be contained in a single dosage form, for example a large number of nanoparticles, micro is astiz, pellets, tiny pills, granules or minitablets can be represented in a single tablet or capsule, where individual particles, pellets, pills, granules or minitablets able to provide different release profiles of the active ingredient. They usually are called "many-particle systems". Alternatively, the dosage may contain one or more, preferably several, dose forms, such as one or more tablets or capsules, intended for separate or simultaneous administration, where a separate dose forms differ in their release profiles. When examining a patient can be provided that will put two or more different doses (e.g., capsules or tablets), containing the active ingredient, which have different release profiles. For example, when using three different capsules can target a beginning, middle and end of the colon. Due to the peristaltic movement of the colon different doses move further down the colon, thereby providing a better and more uniform distribution of the active ingredient. When the batch contains more than one single standard doses, different standard dose can be entered at the same time or over different time intervals.

Desired profile the release may be a slow release profile, and so different release profiles or from individual particles, such as pellets, in a single dosage form or from a large number of disposable dosage forms - can be obtained by any of the methods previously described, for example, by changing the nature, composition and/or concentration of triglycerides, emulsifiers and possibly pharmaceutically acceptable excipients, or by providing a suitable shell. When using the shell, the nature of the covering substance, its thickness and/or concentration of components in the shell can be varied if necessary to obtain the desired delayed release profile. When use the same covering material for covering a large number of pellets, tablets or capsules, change the release profile can be achieved by a gradual increase in the concentration of the covering agent, used to cover individual doses, which leads to changes in shell thickness and, thus, change the release profile. When coated pellets or granules filled capsule or pressed together with the formation of tablets, the composition is many-particle dosage form. Thus tablets or capsules containing coated pellets or granules, may optionally be coated, for example, a suitable enteric, bolocco is, which may be the same or different from that used for coating the pellets and granules.

Alternatively, a combination of songs fast and slow release can be used to obtain the desired release profile. A suitable regimen may, for example, include the introduction of a large number of capsules or tablets containing agents with different release.

Oral dosage compositions described in this description of the invention, can, for example, be presented in a package that contains a large number of individual doses, having different release profiles. To facilitate the application of individual dose (e.g. capsules) can be marked by painting in different colors. Such packaging also form part of the invention.

The advantage of solid pharmaceutical products according to the invention is that they are stable. In particular, the active ingredient present in the pharmaceutical products according to the invention, not prone to destruction and/or degradation. In the pharmaceutical products can be stored, for example, at room temperature and humidity for at least 6 months, more preferably at least 12 months, even more preferably at least 24 months or more, for example up to 36 months.

Solid pharmaceutically the products of the present invention is administered orally or by injection into the rectum. The preferred route of administration will depend on a number of factors, including the seriousness and the nature of cancer, precancerous lesions or cancer status, subject to diagnosis, localization and nature of the active ingredient.

Photodynamic diagnosis of cancer, pre-cancerous and non-cancerous conditions in the lower part of the gastrointestinal system is usually performed by endoscopic examination of the lower part of the gastrointestinal tract, i.e. the colon and the distal part of the small intestine, with the camera on a flexible tube inserted through the anus of a person or animal, not a person undergoing endoscopy. In addition to diagnostics, it also provides the opportunity for biopsy or removal of suspicious pathological changes or polyps.

The colon must not contain solid matter during the PDD for its correct execution. From one to three days may be required subject, recorded on PDD, namely animal, not a person, or the person, i.e. the patient, the diet is low in dietary fiber or totally liquid diet. The day before PDD intestine needs cleaning, the procedure commonly referred to as bowel preparation for surgery or bowel preparation. the hypoxia agents for bowel preparation are commercially available in the form of a solution or tablets. Tablet for bowel preparation contain compounds, such as Bisacodyl, and solutions for bowel preparation containing compounds such as sodium phosphate or polyethylene glycol and electrolytes. In standard mode for colonoscopy amount of solution to be drinking for bowel preparation is about 4 liters.

On the day of the PDD and preferably for 4-12 hours before endoscopy take oral solid pharmaceutical product according to the invention according to a prescribed regimen, for example in a single dose of one unit or a single dose of multiple units or multiple reception. Patients can afford to drink the liquid. If solid pharmaceutical product is a suppository, the suppository is placed on the area of study. In case studies throughout the lower part of the gastrointestinal tract suppository is placed in the distal part of the large intestine, for example in a blind gut.

The period of time between introduction and endoscopic study, including photo-activation, i.e. the effect of light on the area of study will depend on the nature of the pharmaceutical product, its form and nature of the active ingredient. As a rule, it is necessary that the active ingredient in the specified pharmaceutical product was transformed into f is desensibilization and reach effective concentrations in the tissue at the site of the study prior to photoactivation.

In the preferred embodiment, and to facilitate the distribution of the active ingredient in a pharmaceutical product in the entire lower part of the gastrointestinal tract, the patient is prescribed a "booster" of a liquid, preferably a solution for bowel preparation. The magnitude of the booster is usually from 250 to 750 ml, preferably about 500 ml, and the booster drink for about 15 min to 90 min, preferably for from about 30 to 60 min after administration of the pharmaceutical product according to the invention. In another embodiment of the second booster liquid, preferably a solution for bowel preparation may be administered to the patient approximately 120-150 min after administration of the pharmaceutical product. Homogeneous distribution of the active ingredient may also contribute to patient movement or turning from one side to the other, for example, after 10 min on the right side, roll over on its back and, after 10 min on the back, to turn over on the left side and soak for 10 min on the left side.

During endoscopic studies field of study, effect light, which is suitable for photoactivation, that is, to achieve the desired photodynamic effect. The area under study, impact blue light is usually in the range of the e 380 to 450 nm. In the General case using irradiation with doses from 10 to 100 Joules/cm2with the intensity of 20-200 MW/cm2when using a laser or with a dose of 10-100 j/cm2with the intensity of 50-150 MW/cm2when using the lamp. The emitted fluorescence (635 nm) is then used to selectively detect the affected cancerous tissue or precancerous lesions or other non-cancer conditions such as inflammation. Suitable endoscopes, i.e. colonoscopy, represent the colonoscope from the prior art that are adapted to make possible the emission of such light blue in addition to white light, for example by providing an internal filter, which passes mostly blue light. Foot pedal makes it possible to easily switch between white light and blue light. The light source may be a laser or a lamp. To visualize the fluorescence of the colonoscope can be equipped with built-in filter that blocks most of the reflected blue light. The camera is similar to the modified camera device color conversion in electric charge (CCD), can be used to record images of the lower part of the gastrointestinal tract, and the standard color monitor can be used to display images bottom is part of the gastrointestinal tract. The irradiation is preferably performed for 5 to 30 minutes. You can use a single exposure or, alternatively, a fractional dose of light, when the light dose delivered in several fractions, for example you can use from several minutes to several hours between exposures. You can also apply multiple exposure. The research area can also be examined using white light, for example before, during or after irradiation with blue light. Polyps cancerous tissue or pre-cancerous lesions, identified by their fluorescence, can be removed during irradiation or with white light.

In the second aspect of the invention features use:

a) an active ingredient selected from 5-ALA, the precursor of 5-ALA or a derivative of 5-ALA and their pharmaceutically acceptable salts;

b) one or more triglycerides and

C) one or more emulsifiers

in the manufacture of a solid composition or a solid pharmaceutical product for use in photodynamic diagnosis of cancer, pre-cancerous and non-cancerous conditions in the lower part of the gastrointestinal tract.

In the preferred embodiment of the invention proposes the application:

a) an active ingredient selected from 5-ALA, the precursor of 5-ALA or a derivative of 5-ALA and their pharmaceutically acceptable salts;

b) one who does more triglycerides and

C) one or more emulsifiers

in the manufacture of a solid composition or a solid pharmaceutical product for use in photodynamic diagnosis of cancer and precancerous lesions in the lower part of the gastrointestinal tract, preferably in the colon and rectum.

In addition, in another aspect of the invention proposes a method of photodynamic diagnosis of cancer, pre-cancerous and non-cancerous conditions in the lower part of the gastrointestinal tract, where the method includes the following stages:

(a) introduction to the subject, such as a person or an animal, not a man, a solid pharmaceutical product or a solid composition as defined in this description;

(b) wait for a period of time required for the conversion of the active ingredient specified in the pharmaceutical product in the photosensitizer and achieve an effective concentration in the tissue at the desired site in the lower part of the gastrointestinal tract;

(C) photoactivatable photosensitizer and

(d) detecting fluorescence of the specified photosensitizer indicating cancerous, pre-cancerous and non-cancerous state.

Solid pharmaceutical are new, and therefore in another aspect the invention features a solid composition containing:

a) active in radiant, selected from 5-ALA, the precursor of 5-ALA or a derivative of 5-ALA and their pharmaceutically acceptable salts;

b) one or more triglycerides and

C) one or more emulsifiers.

The preferred embodiment of the solid compositions identical to the preferred embodiments of the solid pharmaceutical products for use in photodynamic diagnosis of cancer, pre-cancerous and non-cancerous conditions in the lower part of the gastrointestinal tract, described above, that is, the preferred compounds (a), (b) and (C) and their preferred combinations, also described above.

In yet another preferred embodiment of the solid composition consists of:

a) an active ingredient selected from 5-ALA, the precursor of 5-ALA or a derivative of 5-ALA and their pharmaceutically acceptable salts;

b) one or more triglycerides and

C) one or more emulsifiers.

In the preferred embodiment of the specified solid composition is in the form of a suppository.

Preferably, the solid compositions according to the invention is a composition where the active ingredient is a derivative of 5-ALA, preferably a complex ester of 5-ALA or its pharmaceutically acceptable salt and one or more triglycerides are solid triglyceride selected from cocoa butter, fat, solid fat, hydrogenated coconut is x glycerides, hydrogenated palm oil, tristearin, tripalmitin and trimyristin, or liquid triglyceride selected from triglycerides, glycerol and 3 identical or different fatty2-C22acids, more preferably 3 identical or different fatty4-C18acids, even more preferably 3 identical or different fatty6-C18acids and most preferably 3 identical or different fatty6-C12acids, in particular tricaprylin, TRICORONA, tripeptinon, Caprylic/capric triglyceride, Caprylic/capric/linoleic triglyceride, and Caprylic/capric/succinic triglyceride, and one or more emulsifiers are non-ionic emulsifier, obtained by the reaction of polyethylene glycol and natural or hydrogenated oils.

Preferred solid composition does not contain water.

In one preferred embodiment of the solid compositions contain a liquid, semi-solid or solid mixture of compounds (a)-(b)loaded in a hard capsule, preferably in a capsule, which cover one or more enteric membranes, and more preferably covered by one or more enteric membranes, which provide a pH-controlled release of the active ingredient (a) in diapazonom pH 6.5 to pH 7.5.

In another aspect of the invention proposes a capsule containing a liquid, semi-solid or solid mixture of compounds (a)-(C). Preferably the specified capsule cover one or more enteric shells, and more preferably cover one or more enteric membranes, which provide a pH-controlled release of the active ingredient (a) in the range from pH 6.5 to pH 7.5. In the preferred embodiment of the invention proposes a capsule containing a liquid, semi-solid or solid mixture consisting of compounds (a)-(C). Preferably the specified capsule cover one or more enteric shells, and more preferably cover one or more enteric membranes, which provide a pH-controlled release of the active ingredient (a) in the range from pH 6.5 to pH 7.5.

In another aspect of the invention offers a solid composition or capsule, as described above, for use as a drug. In the preferred embodiment of the invention offers a solid composition, as described above, for use as pharmaceuticals.

In another aspect of the invention offers a solid composition, capsules or suppositories, as described above, for use in photodynamic diagnosis of cancer, precancer is o and non-cancerous conditions in the lower part of the gastrointestinal system. In the preferred embodiment of the invention offers a solid composition, as described above, for use in photodynamic diagnosis of cancer, pre-cancerous and non-cancerous conditions in the lower part of the gastrointestinal system.

Description of graphic materials

On Figa shows gamma scintigraphic image of the gastrointestinal tract of six subjects who were administered the capsule Enterion™containing labeled111In-isotope aqueous solution obtained 2 hours after activation. The capsule is activated to release its contents at the end of the ileum/cecum.

On Figb shows gamma scintigraphic image of the gastrointestinal tract six subjects described above, the obtained 6 hours after activation.

On FIGU shows gamma scintigraphic image of the gastrointestinal tract six subjects described above, obtained 12 hours after activation.

On Figa shows gamma scintigraphic image of the gastrointestinal tract of four subjects who were administered the capsule Enterion™containing labeled111In-radioisotope composition consisting of 100 mg HAL HCl 200 mg Miglyol® 812 and 100 mg Gelucire® 44/14 obtained 2 hours after activation. The capsule is activated to release its contents at the end of the ileum/cecum.

On Figb shows gamma scintigraphic image of the gastrointestinal tract of four subjects, the above obtained 6 hours after activation.

On FIGU shows gamma scintigraphic image of the gastrointestinal tract of four subjects described above, obtained 12 hours after activation.

On Figa shows gamma scintigraphic image of the gastrointestinal tract of six subjects who were administered enteric-coated capsule shell containing labeled111In-radioisotope composition consisting of 100 mg HAL HCl 200 mg Miglyol® 812 and 100 mg Gelucire® 44/14 obtained 2 hours after activation. The capsule was dissolved at pH>6,5.

On Figb shows gamma scintigraphic image of the gastrointestinal tract of the subjects described above, the obtained 6 hours after activation.

On FIGU shows gamma scintigraphic image of the gastrointestinal tract of four subjects described above, obtained 12 hours after activation.

The invention is illustrated in the following examples.

Example 1: Solid composition according to the invention

Coated capsules containing n-hexyl ester hydrochloride aminolevulinic acid (HAL) (HAL HCl) (Photocure ASA, Norway) was obtained by mixing the compounds listed in the column "composition of the capsules at temperatures above their melting points. The mixture was poured in a white capsule of the receiver array (hydroxypropyl etilzelluloza) and put a strip of a mixture of a receiver array (3.1 mg), Gellan gum (0.015 mg) and trisodium citrate (0.05 mg) in water. The capsule was covered with moisture-resistant shell (6,3 mg/cm2), Opadry CA), then enteric shell (8 mg/cm2with a mixture of 80% Eudragit® L 30 D-55 and 20% Eudragit® FS 30 D, both dispersed in water) obtaining sensitive to the pH of the film that dissolves at a pH of 6.5 and above.

CapsuleABCDEFGH
Composition of the capsule (mg)
HAL HCl100100100100100100100100
Miglyol® 812300292 260200260200100
Sodium docusinate-8100-----
Pluronic® L44---40100---
Gelucire® 44/14-----40100200

All capsules contained Miglyol 812 as triglycerides, capsule And is a solid pharmaceutical product outside the scope of the invention as it does not contain an emulsifier. Capsules and may contain anionic emulsifier, capsules D-H contain non-ionic emulsifier.

Example 2: Dissolution HAL

Capsule A-H, manufactured with the according to Example 1, used in the study of dissolution in vitro. To simulate conditions in the human stomach, the capsule is first immersed in 500 ml of medium for dissolution (1) of 0.1 M HCl with a temperature of 37°C for 1 h and Then the capsules were removed from this environment and immersed in 500 ml of medium for dissolution (2) from aqueous phosphate buffer with a pH of 6.5 and a temperature of 37°C to simulate the condition at the end of the ileum, that is, the water environment and pH. During both dives apparatus used to perform the dissolution according to USP 711", equipped with blades and sinker. The capsule was placed on a sinker and immersed in the environment for dissolution. Chose the rotation speed of 75 rpm, 2 ml samples environment for dissolution were selected manually in 5, 15, 30, 60, 120 and 180 minutes, the Samples were filtered (40 µm HDPE filters) and HAL content was determined by HPLC. The HAL content in the samples was calculated by comparison with a standard curve. Analyzed the release of HAL from six capsules A-N and the following tables reflect the average release.

The results:

It was not observed the release of HAL in the environment for dissolution (1).

Observed release of HAL in the environment for dissolution (2) as follows:

99,2
Release HAL (% of nominal dose)
Time (min)AndInDEFGN
50,00,30,30,45,00,00,00,0
150,0the 5.714,51,786,450,282,434,8
304,814,630,516,498,596,4103,698,3
6038,635,041,953,799,2100,2104,8
12061,4of 45.749,866,499,3100,3100,298,8
18059,247,854,466,0the 98.9100,399,3of 99.1

The contents of all capsules were immediately released into the environment for dissolution (2).

After releasing the contents of the capsules And in the environment for dissolution was observed unstable release from HAL compositions with high levels of variability. Released the song floated environment for dissolution.

The composition of the capsules and did not show an improved profile release HAL compared to capsules composition A. As capsule And they showed a release profile comprising a uniform increase in the release of HAL within the first 120 min with a subsequent plateau concentration HAL for the remaining 60 minutes. After 180 min on the surface of the medium for dissolving attended the oil drops. Obviously, p is OUTSTA anionic emulsifier, of sodium docusinate, at a concentration of 2% and 25% did not contribute to the spread/dissolution HAL in the aquatic environment for dissolution.

The capsules composition D showed a slightly higher release of HAL from the drug. However, after 180 min on the surface of the medium for dissolving attended the oil drops. Obviously, the presence of non-ionic emulsifier Pluronic® L44 at a concentration of 10% to some extent contributed to the spread/dissolution HAL in the aquatic environment for dissolution.

The composition of capsules E showed clearly different release profile HAL with a full release in 30 minutes and about 80% release after 15 minutes On the surface environment for dissolution was not observed oil drops. Obviously, the presence of non-ionic emulsifier Pluronic® L44 at a concentration of 25% significantly contributed to the spread/dissolution HAL in the aquatic environment for dissolution.

The composition of all capsules from F to H showed complete release of HAL within 30 minutes of Visual observations suggest that upon release of the formed emulsion, which is then merged into an oil layer on the surface environment for dissolution. The test results confirmed that this effect is sufficient to allow dissolution of the HAL environment for dissolution. Obviously, the presence of einoo emulsifier Gelucire® 44/14 at a concentration of 10%, 25% and 50% significantly contributed to the spread/dissolution HAL in the aquatic environment for dissolution. In addition, the results show that at a concentration of Gelucire® 44/14 higher than 25% does not increase the dissolution HAL. Also, the increased number of HAL was released from the composition within 15 minutes in the presence of 25% Gelucire® 44/14, then in the presence of 10% Gelucire® 44/14 (82,4% vs. 50.2 per cent). This indicates that the amount of emulsifier not only affects the dissolution of HAL in the aqueous phase, but also affects the rate of release of HAL from the composition.

Example 3: the Release HAL HCl in vivo

Gamma scintigraphic study was performed in healthy male volunteers to assess gastrointestinal transit enteric-coated shell of the capsule, i.e. the solid pharmaceutical product according to the invention, to determine the site of release of the composition from the specified enteric-coated shell capsules and distribution HAL HCl in empty, i.e. cleared, the large intestine.

Gamma scintigraphic imaging makes it possible to evaluate the physical integrity of the solid pharmaceutical product according to the invention, as it passes through the gastrointestinal tract. You can get detailed information about the time and the anatomical localization of the destruction of the product. For gamma scintigraphies is the first study used a capsule for site-specific delivery Enterion™, which provides for the delivery of drugs within the target region of the gastrointestinal tract. The capsule has a length of 35 mm and a diameter of 10-12 mm and capable of delivering solutions, suspensions or powders in specific areas. Localization of the capsule in the gastrointestinal tract determined using gamma scintigraphy. The capsule contains a camera for medicines, which loads the measured composition. Capsules activate and composition is released with the use of electromagnetic fields of low intensity generated by the device for activation. Activation of the capsule is confirmed by a signal, which is emitted from the capsule when the activation, and transmitted back to the device to activate. Indium-111 is used as a marker in the capsule to provide tracking of the capsule throughout the gastrointestinal tract. Water-soluble radioactive marker, technetium-diethylenetriaminepentaacetic acid99mTc-DTPA, mixed with water, which is taken with the capsule to get a visual (scintigraphic) confirm gastrointestinal anatomy of the subject.

All subjects had undergone purgation: introduced MoviPrep® in the evening before dosing for bowel cleansing prior to dispensing the next morning.

Control group:

A group of 6 subject who received treatment And, the aqueous composition of radioisotope-labeled no more than 1 MBq111In-DTPA (composition A), delivered through the Enterion capsule™ at the end of the ileum/cecum, where he released the contents. The Enterion capsule™ delivered a total of 500 ml of water, radioisotope-labeled no more than 4 MBq99mTc-DTPA. Water labeled with99mTc, ingested 2 aliquot of 250 ml; the first aliquot during the introduction of the capsule and the second - after the release of the capsule from the stomach. Performed gamma scintigraphy and determined the degree distribution of the composition And around the thick intestine. Within 1 hour after activation distribution was limited and was lokalizovanog in the caecum and ascending colon. The maximum spread, i.e. the spread around the thick intestine was observed in approximately 7 hours after activation. On Figa-shows the distribution of 2, 6 and 12 hours after activation.

The distribution of the composition And took over the "best situation ", it represents the spread of relatively hydrophilic compounds (111In-DTPA), prepared in the form of the drug in aqueous solution, in the aquatic environment (the colon) and, thus, will be similar to the distribution in the aquatic environment (colon) relatively hydrophilic compounds HAL HCl prepared in the form of the drug in aqueous solution is.

Treatment group 1:

A group of 4 subjects were treated, composition, 100 mg HAL HCl 200 mg Miglyol® 812 and 100 mg Gelucire® 44/14, radioisotope-labeled no more than 1 MBq111In-DTPA (composition), delivered through the Enterion capsule™ at the end of the ileum/cecum, where he released the contents. The Enterion capsule™ is delivered with 500 ml of water, radioisotope-labeled no more than 4 MBq99mTc-DTPA. Water labeled with99mTc, ingested 2 aliquot of 250 ml; the first aliquot during the introduction of the capsule and the second after the release of the capsule from the stomach. Performed gamma scintigraphy and determined the degree distribution of the composition throughout a thick intestine. After 1 hour, after activating the flow of the composition in the colon occurred in only 1 subject. The maximum spread, i.e. the spread around the thick intestine was observed after an average of 10 hours after activation. Found that the distribution of the composition was similar to the distribution of the composition And, that is the same as the distribution of water, see Figa-in, which shows the distribution of 2, 6 and 12 hours after activation.

Treatment group 2:

A group of 6 subjects received treatment With a composition of 100 mg HAL HCl 200 mg Miglyol® 812 and 100 mg Gelucire® 44/14, radioisotope-labeled no more than 1 MBq111In-DTPA (composition C)delivered by means of the PTO enteric-coated shell capsules, as described in Example 1. Enteric-coated capsule shell delivered with 500 ml of water, radioisotope-labeled no more than 4 MBq99mTc-DTPA. Water labeled with99mTc, ingested 2 aliquot of 250 ml; the first aliquot during the introduction of the capsule and the second after the release of the capsule from the stomach. Performed gamma scintigraphy and determined the degree distribution of the composition throughout a thick intestine. Found that the distribution of the composition was similar to the distribution of the composition And, that is the same as the distribution of water, see Figa-in, which shows the distribution of 2, 6 and 12 hours after release.

1. Solid pharmaceutical product for oral use in photodynamic diagnosis of cancer, pre-cancerous or non-cancerous conditions in the lower part of the gastrointestinal tract, where these non-cancerous condition is selected from colitis, Crohn's disease, irritable bowel syndrome and other viral, bacterial or fungal infections or inflammation, and where specified product contains:
a) an active ingredient selected from 5-ALA (5-aminolevulinic acid), a complex ester of 5-ALA or its pharmaceutically acceptable salt;
b) one or more triglycerides and
C) one or more non-ionic emulsifiers;
where specified pharmaceutical product further comprises the bottom or more than one enteric coated and provides a pH-controlled release of the active ingredient (a) in the range from pH 6.5 to pH 7.5.

2. Solid pharmaceutical product according to claim 1, where the specified active ingredient is an ester of 5-ALA or its pharmaceutically acceptable salt.

3. Solid pharmaceutical product according to claim 1, where the specified active ingredient is a compound of formula I or its acceptable salt

where
R1represents a substituted or unsubstituted alkyl group, and
each R2represents a hydrogen atom.

4. Solid pharmaceutical product according to claim 3, where R1represents remotemachine C1-C6alkyl group.

5. Solid pharmaceutical product according to claim 4, where R1represents n-hexyl.

6. Solid pharmaceutical product according to claim 1, where one or more triglycerides are triglycerides glycerol and 3 identical or different fatty2-C22acid, more preferably 3 identical or different fatty4-C18acids, even more preferably 3 identical or different fatty6-C18acid and most preferably 3 identical or different fatty6-C12the acid.

7. Solid pharmaceutical product according to claim 1, where one or more triglycerides are solid triglycerides selected from cocoa butter, fat, solid fat, hydrogencarbon the x glycerides of coconut oil, hydrogenated palm oil, tristearin, tripalmitin and trimyristin, or liquid triglycerides selected from tricaprylin, TRICORONA, tripeptinon, Caprylic/capric triglyceride, Caprylic/capric/lanolinovogo triglycerides.

8. Solid pharmaceutical product according to claim 1, where one or more non-ionic emulsifiers are non-ionic emulsifier, obtained by the reaction of polyethylene glycol and natural or hydrogenated oils.

9. Solid pharmaceutical product according to claim 1, additionally containing one or more of the following:
g) one or more of mucoadhesive;
d) one or more pharmaceutically acceptable excipients other than (b), (C) and (g);
e) one or more agents to penetrate through the surface and
g) one or more chelating agents.

10. Solid pharmaceutical product according to any one of claims 1 to 9, which does not contain water.

11. Solid composition suitable for oral use in photodynamic diagnosis of cancer or precancerous lesions or non-cancerous conditions in the lower part of the gastrointestinal tract, where these non-cancerous condition is selected from colitis, Crohn's disease, irritable bowel syndrome and other viral, bacterial or fungal infections or inflammation, comprising:
a) the active ingredient is selected from 5-ALA, complex ester of 5-ALA or its pharmaceutically acceptable salt;
b) one or more triglycerides and
C) one or more non-ionic emulsifiers;
and where the specified composition further comprises one or more than one enteric coated and provides a pH-controlled release of the active ingredient (a) in the range from pH 6.5 to pH 7.5.

12. The solid composition according to claim 11, where the active ingredient is an ester of 5-ALA or its pharmaceutically acceptable salt; one or more triglycerides are solid triglycerides selected from cocoa butter, fat, solid fat, hydrogenated glycerides of coconut oil, hydrogenated palm oil, tristearin, tripalmitin and trimyristin, or liquid triglycerides selected from triglycerides, glycerol and 3 identical or different fatty2-C22acids, more preferably 3 identical or different fatty4-C18acids, even more preferably 3 identical or different fatty6-C18acids and most preferably 3 identical or different fatty6-C12acids, and one or more emulsifiers are nonionic emulsifiers, obtained by the reaction of polyethylene glycol and natural or hydrogenated oils.

13. The solid composition according to claim 11, where the uke is p active ingredient is a compound of formula I or its pharmaceutically acceptable salt

where
R1represents a substituted or unsubstituted alkyl group, and
each R2represents a hydrogen atom.

14. The solid composition according to item 13, where R1represents remotemachine1-C6alkyl group.

15. The solid composition according to 14, where R1represents n-hexyl.

16. The solid composition according to any one of § § 11-15 for use as a medicine.

17. Method of photodynamic diagnosis of cancer, pre-cancerous or non-cancerous conditions in the lower part of the gastrointestinal tract, where these non-cancerous condition is selected from colitis, Crohn's disease, irritable bowel syndrome and other viral, bacterial or fungal infections or inflammation, and where the method includes the following stages:
(a) introducing to a subject, such as a person or an animal, not a man, a solid pharmaceutical product according to any one of claims 1 to 10 or a solid composition according to any one of § § 11-15;
(b) waiting for a period of time required for the active ingredient in the specified pharmaceutical product or a specified composition turned into a photosensitizer and reaching effective concentrations in the tissue at the desired site in the lower part of the gastrointestinal tract;
(C) photoact the growing photosensitizer and
(d) detecting fluorescence of the specified photosensitizer indicating cancerous, pre-cancerous or non-cancerous state.



 

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SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutics and medicine, and concerns a semi-solid composition and a semi-solid pharmaceutical product applicable in photodynamic therapy (PDT) of cancer, pre-cancer and non-cancer conditions of a female reproductive system, an anus and a penis, and contain an active ingredient which represent 5-aminolevulinic acid (5-ALA) ester or its pharmaceutically acceptable salts, one or more triglycerides, one or more viscosity enhancers specified in cellulose or its derivatives, synthetic polymers, polyethylene glycols, vegetable gums, starch and starch derivatives, carrageenan, agar, gelatine, wax and waxy solid substances. Further, the invention refers to a kit for photodynamic therapy.

EFFECT: group of inventions provides stability of the composition and product at room temperature, ease of use for a patient.

19 cl, 2 dwg, 10 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an herbal formulation of topical nanoemulsion for treating acne-related skin disorders. The above formulation contains an aqueous phase comprising a therapeutic agent, rose water and/or lemon juice, and an oil phase containing an essential oil, a non-ionic surfactant and an accessory surfactant. The aqueous and oil phases are related within the range of 1:1 to 1:2, while a particle size of the herbal formulation is less than 5 nm. The essential oil is presented by tea tree oil, basil oil, rosemary oil, lavender oil, jojoba oil, bergamot oil, clove oil and peppermint oil. The invention also refers to a method for preparing the herbal formulation which involves providing the aqueous and oil phases, mixing the above phases to produce a mixture to be emulsified with the non-ionic surfactant to prepare a macroemulsion. The prepared macroemulsion is mixed with ethanol to produce a nanoemulsion with a particle size less than 5 nm.

EFFECT: invention provides the herbal formulation with good penetration, prolonged effect causing no irritation.

8 cl, 4 dwg, 7 ex

Burn ointment // 2523551

FIELD: medicine.

SUBSTANCE: ointment contains biologically active substances which are Apis mellifera in an amount of 21-23 wt %, St. John's wort oil in an amount of 12-14 wt %, propolis in an amount of 10-12 wt % and wax in an amount of 7-9 wt %, as well as Vaselin and lanolin as the ointment base.

EFFECT: invention accelerates cell regeneration processes considerably due to a synergetic action of the ingredients.

7 ex

FIELD: medicine.

SUBSTANCE: invention refers to biochemistry. What is involved is a qualitative assessment of the efficacy of oleic acid as an RNA carrier through biological membranes. The biological membrane is presented by soft sac cells of ripe pulp of honey pomelo of the genus Citrus. The RNA carrier is presented by oleic acid from the preparation Vitalang-2 in an amount of 10.8% and forming a complex with RNA. The preparation Vitalang-1 containing pure RNA is used as a reference. The pomelo cells are poured separately with aqueous solutions of the preparations Vitalang-1, Vitalang-2 and distilled water in an amount of 4.8 ml in each flask. They are incubated for 22 hours at room temperature. A spectrophotometer is used to measure optical density of the solutions versus distilled water with determining the RNA content in the pomelo cells and surrounding solution. Comparing the derived optical densities of the solutions provides stating the fact that Vitalang-2 penetrates through the biological membranes by 4.7-4.9 times more effectively than the preparation Vitalang-1. It is stated that absorption spectra of RNA recovered from the soft sacs are identical to those for the initial compounds.

EFFECT: invention enables assessing the efficacy of oleic acid used as the RNA carrier through the biological membranes.

1 ex

FIELD: medicine.

SUBSTANCE: invention represents a drug preparation for treating diseases caused by type 1 herpes simplex and cytomegalovirus, containing recombinant human interferon 2α, lisocyme, Licopid, carnitine 20%, vitamin E and a fatty base.

EFFECT: higher clinical effectiveness and reduced length of treatment, prolonged intercurrent periods, lower recurrent rate by prophylactic administration, reduced manifestation of neurotoxic effects of herpes viruses, lower administration of antibiotics for preventing bacterial complications in infectious-inflammatory diseases caused by herpes simplex virus and cytomegalovirus in children.

2 cl, 3 tbl

FIELD: medicine.

SUBSTANCE: agent contains 0.2% Pyriton, an emulsifier, an emollient - isopropyl myristate, and a solvent. The emulsifier is presented by glycerol cocoate PEG-7; the emollient is presented by triglycerides of caprylic and capric acids; the solvent is water. Besides, the agent additionally contains glycerol, cyclomethicone, urea, allantoin and a flavouring agent. All the ingredients of the agent are taken in certain mass ratio.

EFFECT: invention enables eliminating side effects, recovering physiological properties of skin and providing high patient's satisfaction upon completion of the treatment.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention discloses a cream for external treatment of Graham-Little-Piccardi-Lasseur syndrome, which contains lanolin, peach oil and distilled water, and is characterised by that it further contains chloroquine, wherein components of the cream are in a defined ratio given in g%.

EFFECT: inhibiting progression of scarring without marked side effects.

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: using nalbuphine salt in the form of a hydrophilic emulsion suppository for treating moderate to severe pain syndrome, a pharmaceutical composition for the same application in the form of suppositories comprising nalbuphine hydrochloride as an active substance and a hydrophilic emulsion base in the following ratio, g/100 g of the composition: nalbuphine hydrochloride 0.0125-5.00, hydrophilic emulsion base up to 100 g, and a method for preparing the same.

EFFECT: effective and prolonged analgesic action with no laxative action has been shown.

7 cl, 3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely to a soft dosage form in the form of a topical oily gel used in treating purulent skin infections and containing sodium fusidine, methyluracil (dioxomethyl tetrahydropyrimidine), an oily gel base (mineral oil and polyethylene) and additionally hydroxymethyl quinoxaline dioxide.

EFFECT: developing the preparation for treating purulent wounds, degrees 3-4 burns, decubituses and ulcers, possessing the improved antibacterial effect and regenerative action.

2 cl, 8 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: declared products are presented in the form of suppositories and contain a mechanically active amorphous or amorphocrystalline calcium gluconate as an active substance and additives as a base. One of the declared agents contains hard fat, paraffin, cacao butter and Lutrol F68 as a base in specific proportions. The other agent contains Witepsol W35, Witepsol H15, kollidon CL and Cremophore RH-40 as a base in specific proportions.

EFFECT: invention provides the agents with uniformly released active substances, prolonged action and applicability for unassisted use by the patients; the declared agents provide a wide spectrum of therapeutic activity, particularly the regulation of Ca2+ and phosphate exchange, reduced resorption and higher bone tissue density, Ca2+ replacement, improved Ca2+ intestinal absorption, phosphate renal re-absorption, bone mineralisation, improved blood coagulation, maintained stable cardiac function, and enabled neurotransmission.

2 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutics and medicine, and concerns a semi-solid composition and a semi-solid pharmaceutical product applicable in photodynamic therapy (PDT) of cancer, pre-cancer and non-cancer conditions of a female reproductive system, an anus and a penis, and contain an active ingredient which represent 5-aminolevulinic acid (5-ALA) ester or its pharmaceutically acceptable salts, one or more triglycerides, one or more viscosity enhancers specified in cellulose or its derivatives, synthetic polymers, polyethylene glycols, vegetable gums, starch and starch derivatives, carrageenan, agar, gelatine, wax and waxy solid substances. Further, the invention refers to a kit for photodynamic therapy.

EFFECT: group of inventions provides stability of the composition and product at room temperature, ease of use for a patient.

19 cl, 2 dwg, 10 tbl, 5 ex

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