BRPI1010761B1 - Semi-solid composition, kit and its use. - Google Patents

Abstract

SEMI-SOLID COMPOSITIONS AND PHARMACEUTICAL PRODUCTS. This invention relates to semi-solid compositions and semi-solid pharmaceutical products for use in photodynamic therapy (PDT) of cancer, precancerous conditions and non-cancerous conditions in the female reproductive system, anus and penis, preferably for use in PDT of endometrial, cervical, vulvar, vaginal, anal and penile dysplasia, and HPV infections of the uterus, cervix, vulva, vagina, anus and penis. The semi-solid compositions and pharmaceutical products comprise an active ingredient which is 5-aminolevulinic acid (5-ALA) or a pharmaceutically acceptable precursor or derivative of 5-ALA or salt thereof. The invention also refers to PDT methods for cancer, pre-cancerous conditions and non-cancerous conditions in the female reproductive system, anus and penis, in which said semi-solid compositions and pharmaceutical products are used.

Description

[001] This invention relates to semi-solid compositions and semi-solid pharmaceutical products for use in photodynamic therapy (PDT) of cancer, precancerous conditions and non-cancerous conditions in the female reproductive system, anus and penis, preferably for use in PDT of endometrial, cervical, vulvar, vaginal, anal and penile dysplasia and HPV infections of the uterus, cervix, vulva, vagina, anus and penis. The semi-solid compositions and pharmaceutical products comprise an active ingredient that is 5-aminolevulinic acid (5-ALA) or a precursor or derivative of 5-ALA or a pharmaceutically acceptable salt thereof. The invention further relates to PDT methods for cancer, precancerous conditions and non-cancerous conditions in the female reproductive system, anus and penis, in which said semi-solid compositions and pharmaceutical products are used.

[002] Photodynamic therapy (PDT) is a relatively new technique for treating precancerous lesions, cancer, and non-cancerous diseases. PDT involves administering a photosensitive substance or its precursor to an area of interest. The photosensitive substance or its precursor is absorbed into the cells, where a precursor of a photosensitive substance is converted into a photosensitive substance. Upon exposure of the area of interest to light, the photosensitive substance is excited, usually from a basic singlet state to an excited singlet state. It then undergoes a cross-intersystem to a longer-lived excited triplet state. One of the few chemical species present in tissue with a basic triplet state is molecular oxygen. When the photosensitive substance and an oxygen molecule are in close proximity, an energy transfer can occur that allows the photosensitive substance to relax to its basic singlet state and create an excited singlet state oxygen molecule. Singlet oxygen is a very aggressive chemical species and will very quickly react with any nearby biomolecules. Finally, these destructive reactions kill cells through apoptosis or necrosis, which is why, for example, cancer cells are selectively killed. The mechanisms are not yet fully understood, but studies suggest that the clinical outcome (i.e., selectivity for cancer cells) is not due to selective uptake by cancer cells. Rather, there are similar levels of uptake in all cell types, but the conversion and elimination processes are different in malignant cells and generally in metabolically active cells, such as inflamed or infected cells, leading to a concentration gradient between cancerous and normal tissue.

[003] Several photosensitive agents are known and described in the literature, including 5-aminolevulinic acid (5-ALA) and certain derivatives thereof, for example, 5-ALA esters, both of which are photosensitive precursors that are converted to protoporphyrins, such as protoporphyrin IX (PpIX). Currently, several pharmaceutical products comprising 5-ALA or an ester thereof are in clinical use for PDT. One of them is Metvix®, a dermal product in the form of a cream comprising 5-ALA methyl ester (developed by Photocure ASA, Norway and now sold by Galderma, Switzerland) for the photodynamic treatment of actinic keratosis and basal cell carcinoma. Another is Levulan Kerastick® developed by DUSA Pharmaceuticals (Canada), a product for the photodynamic treatment of actinic keratosis that contains 5-ALA.

[004] One of the most serious infections of the cervix is human papillomavirus (HPV), which can develop into cervical cancer. HPV infections are a common factor in the development of almost all cases of cervical cancer. Estimates for the prevalence of HPV infections vary, but are typically around 30% of all women. Recently, HPV vaccines have been developed, such as Gardasil® and Cervarix®. However, cancer remains a life-threatening disease. Unfortunately, cancer is often diagnosed late, as symptoms may be absent until the cancer has developed to an advanced stage. A possible early sign of cervical cancer is vaginal bleeding. Cervical cancer is diagnosed based on biopsy procedures. The main treatment is surgery; however, radiation and chemotherapy may be used in later stages of the disease. The prognosis for patients with cervical cancer depends on the stage of the disease at the time of diagnosis. HPV infections can also affect the uterus, vulva, vagina, anus, and penis, and these infections can develop into uterine cancer, vulvar cancer, vaginal cancer, anal cancer, and penile cancer. Multiple infection sites, such as the vagina and cervix, are possible.

[005] Cervical intraepithelial neoplasia (CIN), also known as cervical dysplasia, is the potentially pre-malignant transformation and abnormal growth of squamous cells on the surface of the cervix. Corresponding to this, endometrial intraepithelial neoplasia of the uterine lining (EIN), vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VAIN), anal intraepithelial neoplasia (AIN), and penile intraepithelial neoplasia (PelN), also known as endometrial, vulvar, vaginal, anal, and penile dysplasia, are the potentially pre-malignant transformations and abnormal growth of squamous cells of the uterine lining, in the vulva, vagina (usually in the upper 1/3 of the vagina, may be confluent with cervical lesions), anus (in the perineal skin or anal canal of the flat mucosa), and on the surface of the penis. Most cases of such dysplasias remain stable or are cleared by the immune system without intervention. However, a small percentage of cases progress to cancer, usually squamous cell carcinoma (SCC), if left untreated. The main cause of CIN, EIN, VIN, VAIN, AIN, and PelN is chronic infection of the affected organs or tissues with HPV, especially high-risk HPV types 16 or 18.

[006] More than 100 types of HPV have been identified. About a dozen of these HPV types appear to cause cervical dysplasia and can lead to the development of cervical cancer. The earliest microscopic change corresponding to CIN is dysplasia of the epithelial lining or surface of the cervix, which is essentially undetectable by the woman. Cellular changes associated with HPV infection, such as coleocleates, are also commonly seen in CIN. CIN is usually discovered by a screening test, the Papanicolaou test or "Pap" smear, through which VIN and VAIN can also be diagnosed. Anal Pap smears exist to detect AIN. The purpose of these tests is to detect changes early, while they have not yet progressed to invasive carcinoma, and are easier to cure. An abnormal Pap smear may lead to a recommendation for colposcopy of the cervix, vulva, and vagina, during which these organs and tissues are examined under magnification. Acetic acid or iodine solution may be applied to the surface to improve visualization of abnormal areas. Colposcopy may also be performed on the penis. A biopsy is taken from any areas appearing abnormal, and endometrial, cervical, vulvar, vaginal, anal, and penile dysplasia may be diagnosed by histological examination of the biopsy specimens.

[007] Methods used to treat the aforementioned intraepithelial neoplasia require removal or destruction of cells on the surface of the cervix, vulva, vagina, anus, and penis. These methods include excision, cryocautery, electrocautery, laser cautery, LEEP (cervix), and cervical conization. All of these methods can have side effects, such as stenosis (cervical) with resulting severe endometriosis, cervical insufficiency with premature delivery, or birth of low birth weight babies and pressure sores, and may include infections and hemorrhage. Therefore, a medical need remains for treatment methods for such intraepithelial neoplasia and PDT that have proven to be an alternative for treated patients, showing good response rates.

[008] In CIN PDT, both 5-ALA and 5-ALA esters have been used. K. Bodner et al., Anticancer Res 2003;23(2C): 1785-1788 used a 5-ALA solution (12% w/v) in 0.9% aqueous NaCl solution containing 1% EDTA (w/v). The 5-ALA solution was prepared just before conducting the PDT. A. Barnett et al., Int. J. Cancer: 103, 829832 (2003) used a 3% or 5% (w/w) 5-ALA solution in Intrasite Gel® that was prepared immediately before use. Intrasite Gel is a hydrogel comprising 2.3% of a modified carboxymethylcellulose (CMC) polymer along with propylene glycol (20%) as a humectant and preservative. P. Hillemanns et al., Int. J. Cancer:81, 34-38 (1999) used 5-ALA hydrochloride that had been freshly dissolved in 0.9% sterile aqueous NaCl solution to a final concentration of 20% (w/w) containing propylene glycol and adjusted to pH 5.5 using NaHCO3. P. Soergel et al., Lasers in Surgery and Medicine 40:611-615, 2008 used 5-ALA hexyl ester which was applied in a thermogel formulation. As a thermogel base, Lutrol F-127, a bioadhesive poloxamer, was used, provided as a powder, and the thermogel had to be prepared on-site by adding sterile water. The 5-ALA hexyl ester-containing thermogel had to be freshly prepared before application.

[009] As seen above, newly prepared formulations of 5-ALA and 5-ALA esters were used for CIN PDT, which is due to the limited stability of these compounds which in turn limits the shelf life of the pharmaceutical products in which they are present.

[0010] Several different strategies have been adopted to try to overcome this problem. For example, Metvix containing 5-ALA methyl ester is stored under refrigerated conditions. Levulan Kerastick containing 5-ALA is sold as a 2-compartment formulation that is used to prepare a solution immediately before application. Hexvix® developed by Photocure ASA (Oslo, Norway), which comprises 5-ALA hexyl ester, is in clinical use for photodynamic diagnosis (PDD) of bladder cancer and precancerous lesions. In the PDD procedure, Hexvix is installed inside the bladder in the form of an aqueous solution that is freshly prepared on-site from a lyophilized powder of 5-ALA hexyl ester and a dissolution medium.

[0011] These approaches, however, have disadvantages. For example, it is not always convenient to transport and store medicines under refrigerated conditions. Furthermore, it is also generally preferable to provide pharmaceutical compositions in a ready-to-use form, as these are more convenient for medical practitioners. The provision of ready-to-use forms also allows compositions to be prepared with a reliable and accurate concentration. This is particularly important in the treatment of most diseases, including cancer, where it can be critical that the correct and effective dosage of the therapeutic product is administered.

[0012] US 2003/125388 describes an alternative approach to provide stable 5-ALA formulations, wherein 5-ALA or a derivative thereof is dissolved or dispersed in a non-aqueous liquid having a dielectric constant of less than 80 at 25°C, and wherein said liquid stabilizes the 5-ALA or a derivative thereof. It is hypothesized that the use of a non-aqueous liquid facilitates the formation of the enol form of 5-ALA which then prevents its degradation. Without stability, the data are nevertheless shown. Examples of suitable non-aqueous liquids mentioned in US 2003/125388 include glycerol and its mono-, di-, and triesters with C1-C20 carboxylic acids, propylene glycol, alcohols, ethers, esters, poly(alkylene glycols), phospholipids, DMSO, N-vinylpyrrolidone, and N,N-dimethylacetamide. This composition may form part of a kit for therapeutic or diagnostic use. The other part of the kit is a composition comprising water. In this case, the two parts of the kit are mixed before use. The approach in US 2003/125388 in this manner suffers from the same disadvantage as Levulan Kerastick® in that it is generally undesirable to provide pharmaceutical products in a form that requires the practicing physician to formulate the pharmaceutical product that is actually administered.

[0013] Therefore there is a need for alternative formulations of 5-ALA and 5-ALA esters and, in this way, pharmaceutical products comprising 5-ALA and 5-ALA ester for use in PDT in order to treat HPV infections of the cervix, vulva, vagina, anus and penis, cellular abnormalities in said organs or tissues, in particular cervical, vulvar, vaginal, anal and penile dysplasia.

[0014] WO 2009/074811 describes solid pharmaceutical products for use in PDT of cancer and non-cancerous conditions such as HPV infections in the female reproductive system, i.e., uterus, cervix, and vagina. Said solid pharmaceutical products may be for administration in the form of a suppository or pessary. The term "solid," as defined in the application, refers to the physical state of the entity being described, i.e., the pharmaceutical product, as being a solid rather than a liquid or gas. Liquids, solutions, gels, and creams are not covered by said term. Said solid pharmaceutical products may be in the form of capsules, pellets, powders, tablets, granules, pills, suppositories, pessaries, or mini-tablets; said mini-tablets, powders, granules, or pellets may further be provided within a capsule or packed within a tablet.

[0015] Surprisingly, new alternative semi-solid formulations comprising 5-ALA or a derivative thereof (e.g., an ALA ester) have now been discovered for use in photodynamic therapy of cancer, precancerous conditions and non-cancerous conditions in the female reproductive system, anus and penis, preferably for use in PDT of cervical, vulvar, vaginal, anal and penile dysplasia, and HPV infections of the cervix, vulva, vagina, anus and penis.

[0016] The new solid formulations are stable at room temperature, are easy for healthcare personnel to handle, and provide greater convenience for patients. They can also be readily applied to the cervix, vulva, vagina, anus, and penis. Therefore, they overcome the disadvantages of the previous technique mentioned above, and are able to provide an effective concentration of 5-ALA or its derivatives at the intended site, and can also provide a substantially homogeneous (i.e., uniform) distribution of 5-ALA or a derivative thereof (e.g., an ALA ester) at said intended site.

[0017] In this way, viewed from the first aspect of the invention, it provides a semi-solid pharmaceutical product for use in the photodynamic treatment of cancer, pre-cancerous conditions and non-cancerous conditions in the reproductive system of the male, the anus and the penis comprising: a) an active ingredient selected from 5-ALA, a precursor of 5-ALA or a derivative of 5-ALA and pharmaceutically acceptable salts thereof; b) one or more triglycerides; and c) optionally, one or more viscosity enhancers.

[0018] The term "semi-solid" denotes a physical state that is neither solid nor liquid. Semi-solids (or near-solids) are similar to a solid in some respects, for example a semi-solid can support its own weight and maintain its shape, but also shares some properties of liquids, such as conforming to the shape of something by applying pressure to it, or the ability to flow under pressure. Semi-solids are characterized by a three-dimensional structure that is sufficient to impart solid-like character to the undisturbed system, but which is easily broken and realigned under an applied force. Semi-solids have a stiffness and viscosities intermediate between a solid and a liquid.

[0019] The term "pharmaceutical product" refers to the entity that is actually administered to the individual, for example, a human being or a non-human animal, preferably a human being.

[0020] Semi-semi-solid pharmaceutical products, according to the inventions, are creams, ointments, pastes and gels for topical application to the skin and mucous membranes.

[0021] Creams are semi-solid emulsion systems with an opaque appearance. Their consistency and rheological properties are based on whether the emulsion is o/w or w/o, and on the nature of the solid in the internal phase. Ointments are composed primarily of fluid hydrocarbons embedded in a matrix of higher-melting-point solid hydrocarbons. Pastes are basically ointments to which a high percentage of insoluble solids has been added. Gels are semi-solid systems in which the liquid phase is compressed within a three-dimensional polymeric matrix in which a high degree of physical crosslinking has been introduced.

[0022] The term "precancerous condition" denotes a disease, syndrome, or finding that, if left untreated, may lead to cancer, for example dysplasia and neoplasia.

[0023] The term "non-cancerous conditions" includes comoviral, bacterial or fungal infections, preferably HPV infection, or inflammation.

[0024] The term "female reproductive system" means the uterus, cervix, vagina and vulva, preferably the cervix, vagina and vulva.

[0025] The term "active ingredient" denotes pharmaceutically acceptable 5-ALA and salts thereof, pharmaceutically acceptable precursors of 5-ALA and salts thereof, and pharmaceutically acceptable derivatives of 5-ALA and salts thereof.

[0026] The term "5-ALA" denotes 5-aminolevulinic acid, that is, 5-amino-4-oxo-pentanoic acid.

[0027] The term "5-ALA precursor" denotes compounds that are metabolically converted to 5-ALA and are, in this way, essentially equivalent to it. In this way, the term "5-ALA precursor" covers biological precursors for protoporphyrin in the metabolic pathway for haem biosynthesis.

[0028] The term "5-ALA derivative" includes chemically modified 5-ALA, for example, esters.

[0029] The term "pharmaceutically acceptable salt" denotes a salt that is appropriate for use in the semi-solid pharmaceutical product and that meets the requirements relating to, for example, safety, bioavailability and tolerability (see, for example, P. H. Stahl et al. (eds.) Handbook of Pharmaceutical Salts, Publisher Helvetica Chimica Acta, Zurich, 2002)

[0030] In a preferred embodiment, the semi-solid pharmaceutical products according to the invention are for use in photodynamic therapy of cervical, vaginal, vulvar, anal and penile dysplasia, and HPV infections of the cervix, vagina, vulva, anus and penis.

[0031] The use of 5-ALA and derivatives thereof, for example, 5-ALA esters, in PDT and PDD is well known in the scientific and patent literature, see, for example, WO 15 2006/051269, WO 2005/092838, WO 03/011265, WO 02/09690, WO 02/10120, WO 2003/041673 and US 6,034,267, the contents of which are incorporated herein by reference. All such 5-ALA derivatives and their pharmaceutically acceptable salts are suitable for use in the methods described herein.

[0032] The synthesis of 5-ALA is known in the art. Additionally, pharmaceutically acceptable 5-ALA and salts thereof are commercially available, for example, from Sigma Aldrich.

[0033] Useful 5-ALA derivatives according to the invention may be any 5-ALA derivatives capable of forming protoporphyrins, for example, PpIX or a PpIX derivative in vivo. Typically, such derivatives will be a PpIX precursor or a PpIX derivative, for example, a PpIX ester in the blood biosynthetic pathway, and which are thus capable of inducing an accumulation of PpIX following in vivo administration. Suitable PpIX precursors, or PpIX derivatives, include 5-ALA prodrugs that may be capable of forming 5-ALA in vivo as an intermediate in PpIX biosynthesis, or that may be converted, for example, enzymatically, to porphyrins without forming 5-ALA as an intermediate. Pharmaceutically acceptable 5-ALA esters and salts thereof are among the preferred compounds for use in the invention described herein.

[0034] 5-ALA esters that are optionally N-substituted are preferred for use in the invention. Those compounds in which the 5-amino group is unsubstituted, i.e., 5-ALA esters, are particularly preferred. Such compounds are generally known and described in the literature, see, for example, WO 96/28412 and WO 02/10120 for Photocure ASA, the contents of which are incorporated herein by reference.

[0035] Esters of 5-ALA with substituted or unsubstituted alkanols, that is, alkyl esters and substituted alkyl esters, and pharmaceutically acceptable salts thereof, are particularly preferred 5-ALA derivatives for use in the invention. Examples of such compounds include those of general formula I and pharmaceutically acceptable salts thereof: R22N-CH2COCH2-CH2CO-OR1 (I) wherein R1 represents a substituted or unsubstituted alkyl group; and R2 each independently represents a hydrogen atom or an R1 group.

[0036] As used herein, the term "alkyl," unless otherwise stated, includes any long or short chain, saturated or unsaturated aliphatic hydrocarbon group, branched cyclic or linear. Unsaturated alkyl groups may be mono- or polyunsaturated and include both alkenyl and alkynyl groups. Unless otherwise stated, such alkyl groups may contain up to 40 carbon atoms. However, alkyl groups containing up to 30 carbon atoms, preferably up to 10, particularly preferably up to 8, especially preferably up to 6 carbon atoms are preferred.

[0037] In compounds of formula I, the R1 groups are substituted or unsubstituted alkyl groups. If R1 is a substituted alkyl group, one or more substituents are coupled to the alkyl group and/or interrupt the alkyl group. Suitable substituents that are coupled to the alkyl group are those selected from hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo, fluorine, -SR3, -NR32 and -PR32, wherein R3 is a hydrogen atom or an alkyl group. Suitable substituents that interrupt the alkyl group are those selected from -O-, -NR3-, -S- or -PR3-.

[0038] In a preferred embodiment, R1 is an alkyl group substituted with one or more aryl substituents, that is, aryl groups, preferably substituted with an aryl group.

[0039] As used herein, the term "aryl group" denotes an aromatic group that may or may not contain heteroatoms such as nitrogen, oxygen, or sulfur. Aryl groups that do not contain heteroatoms are preferred. Preferred aryl groups comprise up to 20 carbon atoms, more preferably up to 12 carbon atoms, for example, 10 or 6 carbon atoms. Preferred embodiments of aryl groups are phenyl and naphthyl, especially phenyl. Furthermore, the aryl group may optionally be substituted by one or more, more preferably one or two, substituents. Preferably, the aryl group is substituted in the meta or para position, more preferably in the para position. Suitable substituents include halo alkyl, for example, trifluoromethyl, alkoxy, preferably alkoxy groups containing 1 to 6 carbon atoms, halo, for example iodine, bromine, chlorine or fluorine, preferably chlorine and fluorine, nitro and C1-6 alkyl, preferably C1-4 alkyl. Preferred C1-6 alkyl groups include methyl, isopropyl and t-butyl, particularly methyl. Particularly preferred aryl substituents are chlorine and nitro. However, even more preferably the aryl group is unsubstituted.

[0040] Preferred R1 groups as substituted aryl groups are benzyl, 4-isopropylbenzyl, 4-methylbenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-[t-butyl]benzyl, 4-[trifluoromethyl]benzyl, 4-methoxybenzyl, 3,4-[dichloro]benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 2,3,4,5,6-pentafluorobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-phenylethyl, 4-phenylbutyl, 3-pyridinyl-methyl, 4-diphenyl-methyl and benzyl-5-[(1-acetylooxyethoxy)-carbonyl]. The most preferred groups as R1 groups are benzyl, 4-isopropylbenzyl, 4-methylbenzyl, 4-nitrobenzyl, and 4-chlorobenzyl. Benzyl is the most preferred.

[0041] If R1 is a substituted alkyl group, one or more oxo substituents are preferred. Preferably, such groups are linear chain C4-12 alkyl groups that are substituted by one or more oxo groups, preferably by one to five oxo groups. The oxo groups are preferably present in the substituted alkyl group in an alternating order, i.e., resulting in small polyethylene glycol substituents. Preferred examples of such groups include 3,6-dioxa-1-octyl and 3,6,9-trioxa-1-decyl.

[0042] If R1 is an unsubstituted alkyl group, R1 groups that are saturated linear or branched chain alkyl groups are preferred. If R1 is a saturated linear chain alkyl group, C1-10 linear chain alkyl groups are preferred. Representative examples of suitable linear chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and n-octyl. Particularly preferred are linear chain C1-6 alkyl groups, more particularly preferred are methyl and n-hexyl. If the alkyl group R1 is a saturated branched alkyl group, such branched alkyl groups preferably consist of a 4 to 8, preferably 5 to 8 carbon atom linear chain trunk, and said trunk is branched by one or more C1-6 alkyl groups, preferably C1-2 alkyl groups. Examples of such saturated alkyl groups include 2-methylpentyl, 4-methylpentyl, 1-ethylbutyl, and 3,3-dimethyl-1-butyl.

[0043] In compounds of formula I, each R2 independently represents a hydrogen atom or an R1 group. Particularly preferred for use in the invention are those compounds of formula I in which at least one R2 represents a hydrogen atom. In especially preferred compounds, each R2 represents a hydrogen atom.

[0044] Preferably, the compounds of formula I and the pharmaceutically acceptable salts thereof used in the semi-solid pharmaceutical product of the invention, wherein R1 is methyl or hexyl, more preferably n-hexyl, and both R2 represent hydrogen, i.e., 5-ALA methyl ester, 5-ALA hexyl ester and pharmaceutically acceptable salts thereof, preferably HCl salts. The preferred product for use in the semi-solid pharmaceutical product of the invention is 5-ALA hexyl ester and pharmaceutically acceptable salts thereof, preferably the HCl salt or sulfonic acid salts or sulfonic acid derivatives.

[0045] Pharmaceutically acceptable 5-ALA esters and salts thereof for use in the invention can be prepared by any conventional procedure available in the art, for example, as described in WO 96/28412 and WO 02/10120. Briefly, 5-ALA esters can be prepared by reacting 5-ALA with the appropriate alcohol in the presence of a catalyst, for example, an acid. Pharmaceutically acceptable salts of 5-ALA esters can be prepared, as described above, by reacting a pharmaceutically acceptable 5-ALA salt, for example, 5-ALA hydrochloride, with the appropriate alcohol. Alternatively, compounds for use in the invention, such as 5-ALA methyl ester or 5-ALA hexyl ester, may be commercially available, for example, from Photocure ASA, Norway.

[0046] The 5-ALA esters for use in the invention may be in the form of a free amine, for example -NH2-, -NHR2 or -NR2R2 or preferably in the form of a pharmaceutically acceptable salt. Such salts are preferably acid addition salts with pharmaceutically acceptable organic or inorganic acids. Suitable acids include, for example, hydrochloric, nitric, hydrobromic, phosphoric, sulfuric, sulfonic, and sulfonic acid derivatives, the latter being described in WO2005/092838 for Photocure ASA, the entire contents of which are incorporated herein by reference. A preferred acid is hydrochloric acid, HCl, sulfonic acid and sulfonic acid derivatives. Procedures for salt formation are described in conventional art.

[0047] Thus, in a preferred embodiment, the invention provides a semi-semi-solid pharmaceutical product for use in the photodynamic treatment of cancer, precancerous conditions and non-cancerous conditions in the female reproductive system, anus and penis comprising a) a 5-ALA derivative or a pharmaceutically acceptable salt thereof, preferably a 5-ALA ester or a pharmaceutically acceptable salt thereof; b) one or more triglycerides; and c) optionally one or more viscosity enhancers.

[0048] In a preferred embodiment, said 5-ALA ester is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 represents an unsubstituted alkyl group, preferably a saturated linear or branched unsubstituted alkyl group, more preferably an unsubstituted saturated linear C1-10 alkyl group. More preferably, said 5-ALA ester is a 5-ALA hexyl ester and in a further preferred embodiment, said pharmaceutically acceptable salt of 5-ALA hexyl ester is the HCl salt or a sulfonic acid or sulfonic acid derivative salt, such as mesylate, tosylate or napsylate.

[0049] The compounds a) described above herein may be used for the manufacture of the semi-solid pharmaceutical product according to the invention in any conventional manner. The desired concentration of 5-ALA or 5-ALA derivative or 5-ALA precursor in the pharmaceutical products of the invention will vary depending on several factors including the nature of the compound, the nature and form of the product in which it is presented, and the intended site and mode of administration. Generally, however, the pharmaceutically acceptable concentration of 5-ALA or 5-ALA derivative or 5-ALA precursor or salts thereof is conveniently in the range of 0.25 to 50%, preferably 0.5 to 30%, for example 0.5 to 15%, preferably 1 to 10% and more preferably 1 to 7% by weight of the total weight of the semi-solid pharmaceutical product.

[0050] The semi-solid pharmaceutical products according to the invention comprise one or more compounds (b), one or more triglycerides (triacylglycerols). A triglyceride comprises one molecule of glycerol and 3 molecules of fatty acid. The 3 fatty acids may be identical or different fatty acids. Compounds (b) are vehicles and/or carriers.

[0051] The triglycerides used in the invention are liquid or semi-solid at room temperature, that is, at temperatures of about 18 °C to about 25 °C. If the triglycerides are liquid at room temperature, it is preferred to add one or more viscosity enhancers c) to obtain a semi-solid product. If the triglycerides are semi-solid at room temperature, one or more viscosity enhancers c) may or may not be added.

[0052] In addition, triglycerides must be inert compounds, that is, compounds that do not react with the active ingredient a) or that promote the degradation of the active ingredient.

[0053] Triglycerides can be synthetic, semi-synthetic, or of animal and/or vegetable origin. Triglycerides can be pure/isolated 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 are typically found in edible oils of animal and/or vegetable origin. If triglycerides are part of a mixture, they preferably constitute the main part of said mixture. Hereinafter, such mixtures are also denoted "triglycerides".

[0054] Since triglycerides are used in the pharmaceutical product according to the invention, which is for use in a human or non-human animal, they need to be of pharmaceutical grade and meet the requirements and standards for such products, with regard to physiological acceptance, tolerability and safety.

[0055] The term "one or more triglycerides" means that the semi-solid pharmaceutical product, according to the invention, contains one or more different triglycerides. For example, the semi-solid pharmaceutical product may contain tricaprilin (caprylic acid triglyceride) or tricaprilin and caprylic/capric triglyceride. Also, for example, the semi-solid pharmaceutical product may contain soybean oil, which is a mixture of alpha-linolenic acid, linoleic acid, oleic acid, stearic acid, and palmitic acid triglycerides.

[0056] Preferred liquid triglycerides are selected from edible oils of animal and/or vegetable origin and/or fractions thereof, such as soybean oil, edible palm kernel oil, corn oil, olive oil, almond oil, sunflower oil, peanut oil, coconut oil, sunflower oil, castor oil or pine oil. Other examples of liquid triglycerides include hydrogenated or preferably partially hydrogenated triglycerides selected from partially or fully hydrogenated soybean oil, rapeseed oil, sunflower oil, peanut oil and fractions thereof. Liquid triglyceride oils may be synthetic or semi-synthetic, such as medium-chain triglycerides (MCTs).

[0057] Preferred semi-solid triglycerides are selected from edible semi-solid fats of animal and/or vegetable origin and/or fractions thereof, such as palm oil, cottonseed oil or lard. Other examples of semi-solid triglycerides include hydrogenated or partially hydrogenated triglycerides selected from soybean oil, rapeseed oil, sunflower oil, coconut oil and fractions thereof that are partially or fully hydrogenated.

[0058] In a preferred embodiment, the triglyceride is a triglyceride of glycerol and 3 identical or different C2-22 fatty acids, more preferably 3 identical or different C4-C18 fatty acids, even more preferably 3 identical or different C6-C18 fatty acids, and most preferably 3 identical or different C6-C12 fatty acids. In a more preferred embodiment, the triglyceride is a triglyceride of glycerol and 3 identical C2-22 fatty acids, more preferably 3 identical C4-C18 fatty acids, even more preferably 3 identical C6-C18 fatty acids, and most preferably 3 identical C6-C12 fatty acids.

[0059] The most preferred triglycerides are tricaprilin, tricaproin, triheptanoin, caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride, and caprylic/capric/succinic triglyceride. Some of these triglycerides are marketed under the name "Miglyol®", for example, with Miglyol 812 being caprylic/capric triglyceride, Miglyol 818 being caprylic/capric/linoleic triglyceride, and Miglyol 808 being tricaprilin. One manufacturer of such triglycerides is, for example, Sasol, Witten, Germany.

[0060] In a preferred embodiment, the semi-solid pharmaceutical product according to the invention comprises as a compound b) one or more triglycerides selected from tricaprilin, tricaproin, trie-hptanoin, caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride and caprylic/capric/succinic triglyceride.

[0061] The triglycerides used in the invention can be prepared using standard processes and procedures well known in the art, although many are commercially available from various manufacturers such as Sasol, Croda, Gattefossé and others.

[0062] Compounds b) are vehicles or carriers in the semi-solid pharmaceutical products of the invention and, in this way, are present in relatively high concentrations. The compounds of concentration b) are conveniently in the range of about 50 to 98%, preferably 60 to 96% and more preferably 65 to 94% by weight of the total weight of the semi-solid pharmaceutical product. If compound c) is not present, the concentration of compounds b) is conveniently in the range of about 50 to 99.75%, preferably 70 to 99.5%, for example 85 to 99.5%, more preferably 90 to 99% and most preferably 93 to 99%.

[0063] The semi-solid pharmaceutical products, according to the invention, optionally comprise one or more compounds c), that is, one or more viscosity enhancers.

[0064] The term "viscosity enhancer" denotes a compound that thickens or hardens a mixture of compounds b) and the active ingredient a). If a liquid compound b) is used, a mixture of compound b) and the active ingredient a) is a liquid, for example a solution or a suspension, and by adding one or more compounds c), the mixture will become semi-solid.

[0065] Generally, any viscosity enhancer that – when added to a mixture of compounds b) and the active ingredient a) – results in said mixture becoming a semi-solid can be used. Furthermore, the viscosity enhancer must be an inert compound, that is, a compound that does not react with the active ingredient or that does not promote degradation of the active ingredient. Usually, the viscosity enhancer will be chosen according to the nature of the active ingredient and the nature of compound b), that is, the triglyceride carrier or vehicle.

[0066] The term "one or more viscosity enhancers" means that the semi-solid pharmaceutical product according to the invention may contain one or more different viscosity enhancers. By way of example, the semi-solid pharmaceutical product may contain stearyl alcohol or stearic acid. Also by way of example, the semi-solid pharmaceutical product may contain cetostearyl alcohol, which is a mixture of fatty alcohols consisting predominantly of cetyl and stearyl alcohols, or it may contain stearyl alcohol and stearic acid.

[0067] Examples of viscosity enhancers are cellulose and derivatives thereof such as sodium carboxymethylcellulose, hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), synthetic polymers such as polyacrylic acid (carbomer), polyethylene glycols, vegetable gums such as guar gum, gum arabic or tragacanth, starch and starch derivatives, carrageenan, agar, gelatin, wax and waxy solids.

[0068] In a more preferred embodiment, the viscosity enhancer is a hydrophobic compound, more preferably a wax or a waxy solid, more preferably a solid fatty alcohol or solid fatty acid. In a more preferred embodiment, said wax or waxy solid has a melting point between about 45 °C and 75 °C. Preferred examples of such viscosity enhancers are beeswax, yellow wax, white beeswax, carnauba wax, castor wax, cetyl alcohol, stearyl alcohol, cetostearyl alcohol (cetearyl alcohol), arachidyl alcohol, behenyl alcohol, palmitic acid or stearic acid.

[0069] Some of the viscosity enhancers mentioned, such as some fatty alcohols, also exhibit emulsifying properties.

[0070] The viscosity enhancers mentioned above are commercially available compounds and are manufactured and supplied by various suppliers, for example Sasol (Witten, Germany) International Specialty Products (New Jersey, USA) BASF (Ludwigshafen, Germany), Croda (USA).

[0071] The viscosity enhancer is present in an amount that is necessary to obtain a semi-solid product. The actual amount will depend on the nature of the mixture of the active ingredient a), and one or more triglycerides b), for example, on its viscosity and also on the nature of the one or more viscosity enhancers. If one or more semi-solid triglycerides are used in the manufacture of the semi-solid pharmaceutical product according to the invention, the addition of a viscosity enhancer may not be necessary at all. The amount and nature of the one or more viscosity enhancers impact the dropping point of the semi-solid pharmaceutical product according to the invention; a dropping point well above body temperature will be the limit for spreading the product on the surface of the tissue or organ to be treated, thus negatively impacting the bioavailability of the active ingredient. If the semi-solid pharmaceutical product is for use in humans, the dropping point of the product is preferably in the range of 28 to 43 °C, more preferably in the range of 41 to 32 °C. The dropping point is defined and determined as described in European Pharmacopoeia 6.0 section 2.2.17: the dropping point is the temperature at which the first drop of the melting substance to be examined falls from a cavity under defined conditions.

[0072] In a preferred embodiment, the semi-solid pharmaceutical product according to the invention comprises one or more liquid triglycerides, and one or more viscosity enhancers are present. In a more preferred embodiment, said one or more liquid triglycerides are triglycerides of glycerol and 3 identical or different C2-C22 fatty acids, more preferably 3 identical or different C4-C18 fatty acids, even more preferably 3 identical or different C6-C18 fatty acids, and even more preferably 3 identical or different C6-C12 fatty acids. In a more preferred embodiment, the triglyceride is a triglyceride of glycerol and 3 identical C2-C22 fatty acids, more preferably 3 identical C4-C18 fatty acids, even more preferably 3 identical C6-C18 fatty acids, and even more preferably 3 identical C6-C12 fatty acids. In another, more preferred embodiment, the semi-solid pharmaceutical product according to the invention comprises, as mentioned above, one or more liquid triglycerides and one or more viscosity enhancers selected from a wax or waxy solid, more preferably selected from a solid fatty alcohol or solid fatty acid.

[0073] Generally, if one or more viscosity enhancers are present in the semi-solid pharmaceutical product according to the invention, they are present in an amount of about 0.5 to 40%, preferably 1 to 30% by weight of the total weight of the semi-solid pharmaceutical product.

[0074] The semi-solid pharmaceutical product further comprises: d) optionally, one or more emulsifiers; e) optionally, one or more mucoadhesives; f) optionally, one or more pharmaceutically acceptable excipients instead of b) and c); g) optionally, one or more surface penetration agents; and h) optionally, one or more chelating agents.

[0075] The semi-solid pharmaceutical product according to the invention optionally comprises one or more emulsifiers.

[0076] An emulsifier, also known as a surfactant, surface-active material, or emulsifier, is a substance that stabilizes an emulsion. A wide variety of emulsifiers are used in pharmacy to prepare emulsions.

[0077] The term "one or more emulsifiers" means that the semi-solid pharmaceutical product according to the invention contains one or more different emulsifiers.

[0078] In a preferred embodiment, emulsifiers are non-ionic emulsifiers.

[0079] Preferred nonionic emulsifiers are selected from the group of short-chain partial glycerides, i.e., glycerol esters with short-chain fatty acids, whereby only a portion of the existing hydroxyl groups is esterified, i.e., mono- or diglycerides or mixtures of mono- and diglycerides. Preferred partial glycerides are mono- or diglycerides or mixtures of mono- and diglycerides of C6-C10 fatty acids.

[0080] Still other preferred non-ionic emulsifiers are glycerol esters with fatty acids and alpha-hydroxy acids, for example, glyceryl stearate citrate, glyceryl citrate/lactate/oleate/linoleate, glyceryl cocoate/citrate/lactate and glyceryl isostearate.

[0081] Other preferred non-ionic emulsifiers are fatty alcohols and/or ethoxylated fatty alcohols such as cetostearyl alcohol or cetomacrogol.

[0082] Still other preferred non-ionic emulsifiers are ethoxylated fatty acids, such as ethoxylated castor oil.

[0083] Still other preferred non-ionic emulsifiers are non-ethoxylated and ethoxylated esters of sorbitan and fatty acids, sold under the names "Span" and "Tween", that is, polysorbates, preferably (polyoxyethylene) sorbitan monolaurate, (polyoxyethylene) sorbitan monopalmitate, (polyoxyethylene) sorbitan monostearate, (polyoxyethylene) sorbitan monooleate, (polyoxyethylene) sorbitan tristearate or (polyoxyethylene) sorbitan trioleate.

[0084] Still other preferred non-ionic emulsifiers are lecithins, for example, eggshell lecithin or soy lecithin or lecithin-derived phospholipids, preferably phosphatidylcholine.

[0085] Still other preferred non-ionic emulsifiers are polyethylene glycol-based compounds such as polyethylene glycol monostearate 400.

[0086] Still other preferred non-ionic emulsifiers are ethoxylated glycerides, such as ethoxylated caprylocaproyl glyceride or products obtained from the reaction of polyethylene glycol and natural or hydrogenated oils, such as palm kernel oil, hydrogenated edible palm kernel oil, castor oil, hydrogenated castor oil, almond oil, edible apricot kernel oil and the like.

[0087] These preferred emulsifiers of the latest non-ionic emulsifiers are macrogol-32 lauroyl glyceride, Gelucire® 44/14 (Gattefossé); macrogol stearoyl glyceride, Gelucire® 50/13 (Gattefossé); PEG-50 castor oil, Emalex C-50 (Nihon Emulsion); Eumulgin® 30 HRE 40 (Cognis); PEG-45 hydrogenated castor oil, PEG-8 caprylic/capric glycerides, Labrasol® (Gattefossé); alone or in a mixture with other emulsifiers.

[0088] Still other preferred non-ionic emulsifiers are poloxamers, that is, triblock copolymers composed of a central hydrophobic polyoxypropylene chain flanked by two hydrophilic polyoxyethylene chains. Poloxamers are also known by their trade name Pluronics®. More preferred poloxamers are those that are liquid and have a pH below 7, preferably below 6, such as Pluronic® L43 or Pluronic® L44, alone or in a mixture with other emulsifiers, preferably other poloxamers such as Pluronic® F68.

[0089] If the active ingredient a) is a pharmaceutically acceptable C1-C10 alkyl ester of 5-ALA or a salt thereof, preferably non-ionic emulsifiers with high hydrophilic-lipophilic balance values (HLB values) are used, even more preferably with an HLB value of at least 7, preferably with an HLB value of at least 12, most preferably with an HLB value of about 12-18. If more than one emulsifier is used, it is also possible to use an emulsifier with an HLB value below 7 or above 18, provided that the resulting emulsifier mixture has an HLB value of at least 7 and preferably an HLB value of about 12-18.

[0090] Generally, the emulsifier is present in the semi-solid pharmaceutical product in an amount necessary to promote uniform distribution of the pharmaceutical product at the site of use, for example, in the vagina, in the anus. Usually, the emulsifier, if present, is present in an amount of 0.5 to 15%, preferably 1 to 10%, more preferably 2 to 8% by weight of the total weight of the semi-solid pharmaceutical product.

[0091] Emulsifiers that may optionally be used in the invention can be prepared using standard processes and procedures well known in the art, although many are commercially available from various manufacturers such as Sasol, Croda, Cognis, Gattefossé, American Lecithin Company, BASF, Cytec and others.

[0092] The semi-solid pharmaceutical product according to the invention optionally comprises one or more mucoadhesives, that is, one mucoadhesive or several different mucoadhesives.

[0093] The term "mucoadhesive" denotes a compound that exhibits an affinity for a mucosal surface, that is, it adheres to that surface through the formation of bonds that are generally non-covalent in nature, whether the bonding occurs through interaction with the mucosa and/or the underlying cells. In the context of the invention, the mucosal surface is a mucosal surface of the uterus, cervix, vagina, vulva, anus, and penis. Preferably, one or more mucoadhesives are optionally added to semi-solid pharmaceutical products that are intended for use in the uterus or cervix or in the vagina and anus.

[0094] The mucoadhesive that is optionally present in the semi-solid pharmaceutical product of the invention is preferably a compound mucoadhesive that is not degraded by the acidic environment and the presence of lactic acid in the vagina nor metabolized by bacterial and non-bacterial enzymes present in the female reproductive system, in particular in the vagina or cervix.

[0095] Mucoadhesives that can be used in the semi-solid pharmaceutical products of the invention can be natural or synthetic compounds, polyanionic, polycationic or neutral, soluble in water or insoluble in water, but are preferably large, for example, having a molecular weight of 500 kDa to 3000 kDa, for example, 1000 kDa to 2000 kDa, crosslinked insoluble in water, for example, containing 0.05% to 2% crosslinked by weight of the total polymer, before any hydration, water-swellable polymers capable of forming bonds. Preferably, such mucoadhesive compounds have a mucoadhesive strength greater than 100, especially preferably greater than 120, particularly greater than 150, expressed as a percentage relative to an in vitro standard, as assessed according to the method of Smart et al., 1984, J. Pharm. Pharmacol., 36, pp 295-299.

[0096] Preferred mucoadhesive compounds are selected from polysaccharides, preferably dextran, pectin, amylopectin or agar; gums, preferably guar gum or locust bean gum; salts of alginic acid, preferably sodium alginate or magnesium alginate; poly(acrylic acid) and crosslinked or non-crosslinked copolymers of poly(acrylic acid) and derivatives of poly(acrylic acid) as salts and esters such as, for example, carbomer (carbopol).

[0097] Some of the viscosity enhancers mentioned above present in the semi-solid pharmaceutical composition also have mucoadhesive properties, and if such viscosity enhancers are used, additional mucoadhesives may not be necessary or desired.

[0098] When present, mucoadhesives can conveniently be provided in a concentration range of 0.05 to 30% by weight of the total weight of the pharmaceutical product in which it is present, for example, about 1 to 25% by weight of the total weight of the pharmaceutical product in which it is present.

[0099] The semi-solid pharmaceutical product according to the invention optionally comprises one or more pharmaceutically acceptable excipients that are different from excipients b), c) and the optional excipient d). Such one or more optional pharmaceutically acceptable excipients may be selected from the group of anti-adherents, fillers, binders, colorants, odor enhancers, glidants, lubricants, disintegrants, spreading agents, solvents or preservatives. A person skilled in the art will be able to select appropriate excipients based on their purposes. Common excipients that may be used in the pharmaceutical products described herein are listed in various manuals (e.g., 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)).

[00100] If the semi-solid pharmaceutical product according to the invention optionally comprises one or more pharmaceutically acceptable solvents, such solvents may be a free fatty acid, a free fatty alcohol, an aqueous solution, for example, a buffer or water. However, it is preferred that the semi-solid pharmaceutical product according to the invention does not contain any water, i.e., is water-free. By water-free it is meant that no water is added to the semi-solid pharmaceutical product, and that any measurable water content of the product is due to water possibly contained in any of the ingredients a)-h).

[00101] The semi-solid pharmaceutical product according to the invention optionally comprises one or more surface penetration aids. Such agents may have a beneficial effect by enhancing the photosensitizing effect of the active ingredient, i.e., 5-ALA, the 5-ALA derivative or the 5-ALA precursor present in the pharmaceutical products of the invention.

[00102] Surface penetration aids, especially dialkyl sulfoxides, such as dimethyl sulfoxide (DMSO), may thus be included in the products. The surface penetration aid may be any of the penetration aids described in the pharmaceutical literature, for example, chelating agents (e.g. EDTA), surfactants (e.g. sodium dodecyl sulfate), non-surfactants, bile salts (sodium deoxycholate), fatty alcohols, e.g. oleic alcohol, fatty acids, e.g. oleic acid, and fatty acid and alcohol esters, e.g. isopropyl myristate. Examples of surface penetration aids include isopropanol, 1-[2-(decylthio)ethyl]-azacyclopentan-2-one (HPE-101 available from Hisamitsu), DMSO and other dialkyl sulfoxides, in particular n-decylmethyl sulfoxide (NDMS), dimethylsulfacetamide, dimethylformamide (DMFA), dimethylacetamide, isopropyl myristate, oleyl alcohol and oleic acid, various pyrrolidone derivatives (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.

[00103] The use of glycols such as propylene glycol as surface penetration aids is not recommended, as it may promote the degradation of the active ingredient a) in the semi-solid pharmaceutical product according to the invention.

[00104] When present, the surface penetration aid may conveniently be provided in a concentration range of 0.2 to 20% by weight of the total weight of the pharmaceutical product in which it is present, for example, about 1 to 15%, and preferably 0.5 to 10% by weight of the total weight of the pharmaceutical product in which it is present.

[00105] The semi-solid pharmaceutical product according to the invention optionally comprises one or more chelating agents. Such agents may also have a beneficial effect in enhancing the photosensitizing effect of 5-ALA, the 5-ALA derivative or the 5-ALA precursor present in the pharmaceutical products of the invention.

[00106] Chelating agents can, for example, be included in order to intensify the accumulation of PpIX, since the chelation of iron by the iron chelating agent prevents its incorporation into PpIX to form blood through the action of the iron chelase enzyme, thus leading to the elaboration of PpIX. The photosensitization effect is thus intensified.

[00107] Suitable chelating agents that may be included in the semi-solid pharmaceutical product of aminopolycarboxylic acids, such as any of the chelating agents described in the literature for metal detoxification or for chelation of paramagnetic metal ions in magnetic resonance imaging contrast agents. Particular mention may be made of EDTA, CDTA (cyclohexane triamine tetraacetic acid), DTPA and DOTA and well-known derivatives and analogues thereof. EDTA and DTPA are particularly preferred. Other suitable chelating agents are deferoxamine and siderophores and they may be used alone or in conjunction with aminopolycarboxylic acid chelating agents such as EDTA.

[00108] Some of the chelating agents mentioned above also exhibit surface penetration aid properties, for example EDTA.

[00109] When present, the chelating agent can conveniently be used at a concentration of 0.01 to 12%, for example, 0.1 to 10% by weight based on the composition in which it is present.

[00110] The semi-solid pharmaceutical products of the invention are formulated as a cream, ointment, paste, or gel. Conventional and known methods can be used to prepare such creams, ointments, pastes, and gels. Mixing of compounds a) and b) and, optionally, c) to h) can be promoted by methods known in the art, for example, stirring, optionally, along with heating of the mixture. Generally, compounds c) to h), if present, and one or more triglycerides are mixed during stirring and, optionally, heating until a homogeneous, preferably fluid, mixture is achieved. If the mixture is heated, the temperature is lowered while stirring, and the active ingredient a) is added during cooling and stirring at a temperature of about 40 °C or below. Stirring of the final product is continued until room temperature is reached.

[00111] One advantage of the semi-solid pharmaceutical products of the invention is that they are stable. In particular, the active ingredients present within the pharmaceutical products of the invention do not tend to degrade and/or decompose. As a result, the pharmaceutical products can be stored, for example, at or below ambient temperature and ambient humidity, preferably at ambient temperature and ambient 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.

[00112] The semi-solid pharmaceutical products according to the invention are preferably viscous, or to a certain extent viscous, at the patient's body temperature. This makes the product easy to handle; for example, the product can be easily administered to the female reproductive system, the anus, or the penis without immediately becoming low-viscosity or liquid upon elevation from room temperature to body temperature. It also ensures that the pharmaceutical product remains at the administration site, i.e., on the surface of the uterus, cervix, vagina, vulva, anus, or penis.

[00113] In one embodiment, the viscosity of the pharmaceutical product at the patient's body temperature is such that no additional means such as pessaries, diaphragms, hoods, plugs, adhesive bandages or plasters are needed to keep the product at the administration site for the desired time. This embodiment is preferred if the product is administered by a physician, for example, a gynecologist or andrologist, or a nurse, and the patient is preferably under the observation of a nurse, physician or other health personnel during the incubation period, i.e., in the time between administration and mild treatment.

[00114] In another embodiment, the viscosity of the pharmaceutical product at room temperature is such that it is preferred to apply it to pessaries, diaphragms, hoods, adhesive bandages or plasters, which are placed on the treatment site ensuring that the product remains on those administration sites.

[00115] In a preferred embodiment, the semi-solid pharmaceutical products according to the invention are for use in photodynamic therapy of dysplasia and HPV infections in the female reproductive system, anus and penis, more preferably endometrial, cervical, vaginal, vulvar, anal and penile dysplasia, and HPV infections of the uterus, cervix, vagina, vulva, anus and penis. In a more preferred embodiment, the semi-solid pharmaceutical products according to the invention are for use in photodynamic therapy of endometrial, cervical, vaginal and vulvar dysplasia and HPV infections in the uterus, cervix, vagina and vulva. In a more preferred embodiment, the semi-solid pharmaceutical products according to the invention are for use in photodynamic therapy of cervical and vaginal dysplasia and HPV infections in the cervix and vagina.

[00116] In said more preferred embodiments, it is preferred to use a device that is adapted to receive an effective quantity, i.e., dose of semi-solid pharmaceutical products according to the invention. The preferred device is body-shaped in order to allow complete and safe insertion into the vagina. The preferred device further comprises irradiation means, i.e., a light source that is suitable for irradiating light appropriate for photoactivation, i.e., to achieve the desired photodynamic effect. In a preferred embodiment, said device is inserted by a physician or nurse into the vagina and placed in the desired site (vagina, cervix) where it remains during incubation and photodynamic treatment. A timer may be part of said preferred device which, after being activated before the device is inserted, ensures that irradiation begins after the desired incubation period and continues for a specified period of light treatment. In a more preferred embodiment, the device is disposable and adapted to be removed by the patient without the need to see their physician again. Such devices, for example, hoods or rod-shaped devices, are described in international patent application number PCT/EP2009/009037 by Photocure ASA, and are preferably used in combination with the semi-solid pharmaceutical products according to the invention.

[00117] After administration of the pharmaceutical product to the site to be treated, said site is exposed to light to achieve the desired photoactivation and photodynamic treatment. The length of time between administration and light exposure (incubation time) will depend on the nature of the active ingredient and the nature of the pharmaceutical product. Generally, it is necessary for the active ingredient within said pharmaceutical product to be converted into a photosensitive substance and achieve an effective concentration in the tissue at the treatment site before photoactivation. The incubation time is approximately 30 minutes to 10 hours, preferably 1 hour to 7 hours, for example 3 hours to 5 hours.

[00118] Irradiation will generally be applied for a short time with a high light intensity, i.e., a high flow rate, or for a longer time with a low light intensity, i.e., a low flow rate. The latter is preferred for a PDT procedure where the semi-solid pharmaceutical product is applied to pessaries, diaphragms, hoods, adhesive bandages, or plasters, for example, to a device as described in international patent application number PCT/EP2009/009037. If, for example, cancer, pre-cancerous conditions, and non-cancerous conditions in the female reproductive system are treated, such a device, for example, a hood, can be filled with the semi-solid pharmaceutical product according to the invention, which is placed on the treatment site, for example, the cervix. The device is hardly noticeable to the patient, since it is fully inserted into the body. After an incubation period to allow for the structuring of protoporphyrins, the device will automatically begin to emit irradiation. Again, since the patient hardly notices the device, light therapy can be performed at a low flow rate for a longer period of time, for example, at a flow rate of 1-10 mW/cm2 for several hours. This is beneficial in terms of reduced discomfort for the patient and the effectiveness of the treatment.

[00119] Generally, suitable light sources are lasers, lamps, and preferably LED lamps. The energy consumption per unit time of the lamp or laser system should be such that tissue heating does not result in discomfort or damage to the patient. Irradiation will generally be applied at a dose level of 10 to 200 Joules/cm², for example, at 50 Joules/cm². The lamp or laser system is thus preferably arranged to provide, in operation, a light intensity in the range of 0.5 - 100 mW/cm², and more preferably in the range of 1 - 10 mW/cm².

[00120] The wavelength of light used for irradiation can be selected to achieve an effective photodynamic effect. Light having wavelengths between 300-800 nm, for example, the 400-700 nm range has been found to be particularly effective. It may be particularly important to include wavelengths of 630 and 690 nm. Red light (600-670 nm) is particularly preferred, as light at this wavelength is known to penetrate well into tissue. In this way, preferably the lamp or laser in use emits light having wavelengths between 630-690 nm. In some embodiments, the laser or lamp system comprises filters to ensure that only light within a certain wavelength range, such as those mentioned above, is emitted. Alternatively, the treatment surface of a device, as mentioned above, can be designed in such a way that only light having this preferred wavelength is transmitted.

[00121] A single irradiation can be used or, alternatively, a light dividing those is distributed in several fractions, for example, a little up to several minutes between irradiations, can be used. Multiple irradiations can also be applied, but are not preferred.

[00122] Patient treatment is preferably carried out with a single dose of the semi-solid pharmaceutical product. However, if the treatment is not complete, it may be repeated.

[00123] The semi-solid pharmaceutical products according to the invention may be provided separately (e.g., in a tube or jar) or already containing a drug delivery system, for example, pessaries, diaphragms, caps, adhesive bandages or plasters or a device, for example, a cap, as described in international patent application number PCT/EP2009/009037.

[00124] Alternatively, the semi-solid pharmaceutical products according to the invention may be provided in the form of a kit comprising the pharmaceutical product and a drug delivery system.

[00125] Semi-solid pharmaceutical products and the method for photodynamic therapy can be combined with other therapeutic procedures, for example, administration of other therapeutic drugs. These therapeutic drugs may be administered to the patient before, along with, or subsequent to the semi-solid pharmaceutical products. Other routes of administration may be oral, intravascular, or dermal. Typical drugs include hormones, antibacterial agents, antifungal agents, antiviral agents, anticancer agents, or combinations of such drugs.

[00126] In a second aspect, the invention provides the use of a) an active ingredient selected from 5-ALA, a 5-ALA precursor or a 5-ALA derivative and pharmaceutically acceptable salts thereof; b) one or more triglycerides; and c) optionally, one or more viscosity enhancers in the manufacture of a semi-solid pharmaceutical product or semi-solid composition for use in the photodynamic treatment of cancer, precancerous conditions and non-cancerous conditions in the female reproductive system, the anus and the penis.

[00127] In a third aspect, the invention provides a photodynamic treatment method for cancer, precancerous conditions and non-cancerous conditions in the female reproductive system, the anus and the penis, said method comprising the steps of: (a) administering to an individual, preferably a human individual, a semi-solid pharmaceutical product or a semi-solid composition according to the invention; (b) waiting for a period of time necessary for the active ingredient within said pharmaceutical product to be converted into a photosensitive and to reach an effective tissue concentration at the desired site; and (c) photoactivating the photosensitive.

[00128] In a fourth aspect, the invention provides a semi-solid pharmaceutical product or a semi-solid composition contained in a drug delivery system for use in the photodynamic treatment of cancer, precancerous conditions and non-cancerous conditions in the female reproductive system, anus and penis, comprising, in the case of the semi-solid pharmaceutical composition, or containing, in the case of the semi-solid compositions; a) an active ingredient selected from 5-ALA, a 5-ALA precursor or a 5-ALA derivative and pharmaceutically acceptable salts thereof; b) one or more triglycerides; and c) optionally, one or more viscosity enhancers.

[00129] In a preferred embodiment, said drug delivery system is selected from pessaries, diaphragms, hoods, adhesive bandages or plasters or a device, for example, a hood, as described in international patent application number PCT/EP2009/009037.

[00130] In a fifth aspect, the invention provides a kit comprising: (i) a semi-solid pharmaceutical product or a semi-solid composition for use in the photodynamic treatment of cancer, pre-cancerous conditions and non-cancerous conditions in the female reproductive system, the anus and the penis, comprising, in the case of the semi-solid pharmaceutical composition, or containing in the case of the semi-solid compositions: a) an active ingredient selected from 5-ALA, a 5-ALA precursor or a 5-ALA derivative and pharmaceutically acceptable salts thereof; b) one or more triglycerides; and c) optionally, one or more viscosity enhancers; and (ii) a drug delivery device.

[00131] In a preferred embodiment, said drug delivery device is selected from pessaries, diaphragms, hoods, adhesive bandages or plasters or a device, for example, a hood, as described in international patent application number PCT/EP2009/009037.

[00132] Some of the semi-solid pharmaceutical products are novel compositions and, therefore, in a sixth aspect, the invention provides semi-solid compositions consisting of a) an active ingredient selected from 5-ALA, a 5-ALA precursor or a pharmaceutically acceptable 5-ALA derivative and salt thereof; b) one or more triglycerides; and c) optionally one or more viscosity enhancers.

[00133] The preferred embodiments of the semisolid compositions are identical to the preferred embodiments of the semisolid pharmaceutical products described previously, that is, the preferred compounds a), b) and optionally c) and preferred combinations thereof, also described previously.

[00134] Preferably, the semi-solid compositions according to the invention are those in which the active ingredient is a 5-ALA derivative, preferably a 5-ALA ester or a pharmaceutically acceptable salt thereof, one or more triglycerides is a liquid triglyceride, preferably selected from glycerol triglycerides and 3 identical or different C2-C22 fatty acids, more preferably 3 identical or different C4-C18 fatty acids, even more preferably 3 identical or different C6-C18 fatty acids and most preferably 3 identical or different C6-C12 fatty acids, and one or more viscosity enhancers are present. In a more preferred embodiment, said one or more viscosity enhancers are selected from a wax or a waxy solid, and more preferably selected from a solid fatty alcohol or solid fatty acid.

[00135] The semi-solid compositions, according to the invention, consist of: a) 0.25 to 50%, preferably 0.5 to 30%, for example 0.5 to 15%, preferably 1 to 10% and more preferably 1 to 7% by weight of the total weight of the semi-solid composition, and, if compound c) is not present, b) 50 to 99.75%, preferably 70 to 99.5%, for example 85 to 99.5%, more preferably 90 to 99% and even more preferably 93 to 99% by weight of the total weight of the semi-solid composition.

[00136] If compound c) is present, the concentration of compound b) is conveniently in the range of about 50 to 98%, preferably 60 to 96% and most preferably 65 to 94% by weight of the total weight of the semi-solid composition.

[00137] In a seventh aspect, the invention provides the semi-solid composition, according to the invention, for use as a medicament.

[00138] In an eighth aspect, the invention provides the semi-solid composition according to the invention for use in the photodynamic treatment of dysplasia and HPV infections in the female reproductive system, anus and penis, more preferably endometrial, cervical, vaginal, vulvar, anal and penile dysplasia, and HPV infections of the uterus, cervix, vagina, vulva, anus and penis. In a more preferred embodiment, the semi-solid compositions according to the invention are for use in the photodynamic treatment of endometrial, cervical, vaginal and vulvar dysplasia, and HPV infections in the uterus, cervix, vagina and vulva. In a still more preferred embodiment, the semi-solid compositions according to the invention are for use in the photodynamic treatment of cervical and vaginal dysplasia and HPV infections in the cervix and vagina.

Description of the Figures:

[00139] Figure 1 shows the fluorescence over time caused by porphyrin structuring in the tissue of individual 1(^) and individual 2 (■) after administration of a solid pharmaceutical product not covered by the invention.

[00140] Figure 2 shows the fluorescence over time caused by porphyrin structuring in the tissue of individual 1 (▲) and individual 2 (■) after administration of a semi-solid pharmaceutical product according to the invention.

[00141] The following examples illustrate the invention:

Example 1: Semi-solid compositions according to the invention

[00142] Semi-solid compositions according to the invention were prepared as follows: caprylic/capric triglyceride (Miglyol® 812, Sasol, Witten) and compounds c) to h), if present, were mixed during stirring with an overhead stirrer (IKA RW 20n, IKA Werke, Germany) at a stirring rate of 240 rpm and heating to about 50 °C until a homogeneous fluid was achieved. The temperature was allowed to decrease to about 40 °C while stirring, and an n-hexyl aminolevulinic acid ester hydrochloride (HAL) was added (HAL HCl, Photocure, Norway). The mixture was homogenized at 17500 rpm for 1.5 min for ideal mixing. After that, the mixture was allowed to cool to room temperature (about 21 °C) under further stirring. Stirring was continued manually using a spatula, in case the mixture became too viscous to be stirred by the overhead stirrer.

[00143] The dropping point of the prepared products was determined as described in European Pharmacopoeia 6.0 section 2.2.17. The numbers in the tables below represent % by weight of the total product.

[00144] The following compounds were used in the compositions: a) HAL HCl: active ingredient b) caprylic/capric triglyceride: triglyceride c) stearic acid (Mallinckrodt), cetostearyl alcohol (Cognis): viscosity enhancer d) polysorbate 80 (Croda), polysorbate 60 (Croda), sorbitan stearate (Uniqema), sorbitan trioleate (ICI): emulsifier e) dimethicone (Sikema): blowing agent; oleyl alcohol (Zelmic), isopropyl myristate (Croda): solvent f) polypropylene glycol (Albion): surface penetration aid

Example 2: Stability

[00145] Compositions 30, 31, 32, and 33 were prepared as described in Example 1. Immediately after preparation, the compositions were visually assessed, and the HAL HCl content was determined by HPLC. 20 g of freshly prepared compositions were transferred into clear glass containers (3 containers per composition) with a screw cap. One glass container with each composition was stored for 2 months at 25 °C/60% RH, 30 °C/65% RH, and 40 °C/75% RH. Three samples were taken from each glass container after 1 month, and the HAL HCl content was determined by HPLC. The average HAL HCl content was determined. Additionally, the compositions were visually assessed. Dropping point 0 Point in Time 1 month * higher values due to the separation phase (composition drop point 30 is below 40 °C)

[00146] Composition 30, which does not contain any propylene glycol, exhibited better stability than other compositions containing propylene glycol. Of the propylene glycol-containing compositions, the two with the lowest propylene glycol content (compositions 31 and 32 containing 5% propylene glycol, respectively) exhibited relatively better stability than composition 33 containing 10% propylene glycol.

[00147] Composition 30 was chosen based on a long-term stability assessment: the composition was stored at 25 °C/60% RH and 40 °C/75% RH, respectively. Visual assessment and HAL HCl determination were performed as described above after 1, 2, 6, and 9 months, respectively. * higher values due to phase separation (composition drop point 30 is below 40°C)

[00148] Composition 30 showed excellent stability at room temperature over an extended period of time (9 months).

Example 3: Stability comparison Example 3a: Comparison of a semi-solid composition according to the invention, and a semi-solid composition comprising glycerol instead of compound b)

[00149] US 2003/125388 suggests formulations, for example, waterless formulations of 5-ALA or a derivative thereof, in non-aqueous liquids having a dielectric constant of less than 80 at 25 °C, which acts as a stabilizer of 5-ALA or a derivative thereof. Such formulations are, for example, appropriate for the treatment of epithelial neoplasia of the vulva. Glycerol is described as a preferred non-aqueous liquid. Glycerol has a dielectric constant of 42.5 at 25 °C.

[00150] Semisolid compositions A and B were prepared by dissolving/dispersing HAL HCl in glycerol (Speziol G pharma grade, Cognis, 99.8%) or in caprylic/capric triglyceride (Miglyol® 812, Sasol) and adding a viscosity enhancer.

[00151] Composition A was prepared by adding glycerol and HALHCl to a glass beaker. The mixture was stirred with an overhead stirrer (IKA RW 20n, IKA Werke, Germany) at a stirring rate of 240 rpm–1000 rpm. 1-Ethenyl-2-pyrrolidinone (PVP) homopolymer (Plasdone K85-95, ISP) was added slowly as a viscosity enhancer to prevent lump formation. Stirring was continued until a homogeneous mixture was formed. A clear, filamentous gel was obtained. Composition B was prepared according to Example 1 with caprylic/capric triglyceride and stearic acid as viscosity enhancers. A white, granular ointment was obtained. Compositions A* and B* were prepared as previously described herein, but without any HAL HCl. Composition A* was obtained as a clear, filamentous gel, composition B* as a white, granulated ointment. The numbers in the table below represent % by weight of the total product.

[00152] Immediately after preparation, the compositions were visually assessed and the HAL HCl content of A and B was determined by HPLC. 5 g of the freshly prepared compositions were transferred into clear glass containers (3 containers per composition) with screw caps. One glass container with each composition was stored for 1-6 months at 5 °C/room RH, 25 °C/60% RH and 40 °C/75% RH. Three samples were taken from each glass container after 1, 2, 3 and 6 months, and the HAL HCl content was determined by HPLC. The average HAL HCl content was determined. Additionally, the compositions were visually assessed. Compositions A* and B* were stored under the same conditions, they were visually assessed after 1, 2, 3 and 6 months and were used as an "empty" sample in the HPLC assay. Composition A

[00153] Composition A* maintained a clear appearance under all storage conditions. Composition B:

[00154] Composition B* maintained a white, granular appearance under all storage conditions.

[00155] Although composition B remained stable for a period of 6 months at 25 °C, the concentration of HAL HCl in composition A decreased considerably under these three conditions with approximately 5% loss of HAL HCl after 6 months. At 40 °C, composition B showed a notable decrease in HAL, with approximately 1.5% loss of HAL HCl after 2 months, while composition A showed a much more pronounced decrease in HAL with approximately 6% loss of HAL HCl. It is evident that HAL HCl is more stable in composition B, i.e., a composition containing one or more triglycerides, than in composition A, a composition containing glycerol.

Example 3b: Comparison of a semi-solid composition according to the invention and a solid pharmaceutical composition comprising a solid triglyceride instead of a liquid or semi-solid triglyceride.

[00156] A solid pharmaceutical product C was prepared by melting solid hard fat (Witepsol® H 32, Sasol, Witten) at a temperature of about 40 °C. A defined quantity of HAL HCl was mixed with the melted hard fat at a temperature of about 37-39 °C. The mixture was dispensed into suppository forms and allowed to cool and solidify. White, unbreakable suppositories weighing 2 g were obtained. The melting point of the suppositories was determined to be 32.6 °C, i.e., suitable for dissolving at human body temperature. Witepsol® H 32 is a pharmaceutical-grade hard fat that is mainly comprised of triglycerides with max. 15% diglycerides and max. 1% monoglycerides, respectively. A semi-solid pharmaceutical product D was prepared as described in Example 1 with caprylic/capric triglycerides and stearic acid as a viscosity enhancer. A white ointment was obtained. Compositions C* and D* were prepared as previously described herein, but without any HAL HCl. Composition C* was obtained as a white, unbroken suppository, composition B* as a white ointment.

[00157] The numbers in the table below represent % by weight of the total product.

[00158] Immediately after preparation, the compositions were visually assessed and the HAL HCl content of C and D was determined by HPLC. Freshly prepared suppositories of composition C were packaged in ampoule packs made of PVC plastic trays and aluminum/PVC laminate. 5 g of freshly prepared composition D were transferred into clear glass containers (3 containers per composition) with a screw cap. The ampoule packs and glass containers were stored for 1 to 9 months at 5°C/room RH, and 25°C/60% RH, i.e., below the melting and dropping points of the compositions. Three samples were taken from each glass container after 1, 2, 3, 6, and 9 months, and the HAL HCl content was determined by HPLC. The average HAL HCl content was determined. Additionally, the compositions were visually assessed. Compositions C* and D* were stored under the same conditions, visually assessed after 1, 2, 3, 6, and 9 months, and used as a "blank" sample in the HPLC assay. Composition C ND (not determined) Composition C* turned whitish in 6 months. Composition D:

[00159] Composition D* maintained a whitish appearance under all storage conditions.

[00160] Although composition D was stable for a period of 9 months at 25 °C, the concentration of HAL HCl in composition C decreased considerably with approximately 3% loss of HAL HCl after 3 months, 23% after 6 months, and 29% after 9 months. It is evident that HAL HCl is more stable in composition D.

Example 4: In vivo study of porphyrin formed in the oral cavity.

[00161] Compositions C and D were selected to study porphyrin formation in vivo. The lining mucosa of the oral cavity was chosen as a model, since it is a non-keratinized stratified squamous epithelium, which is also found in the anal canal, vagina, and ectocervix.

[00162] Porphyrin formation is an indicator that the HAL HCl precursor photosensitizer has been released from the composition, entered the cells, and been converted into photosensitizing porphyrins.

[00163] Porphyrin formation was measured in two human volunteer subjects using a fiber point measuring device consisting of a bundle of optical fibers connected to a spectrofluorometer that produced excitation light at 407 nm. The excitation light, capable of penetrating 0.1–0.5 mm into the tissue, was conducted through half of the fibers to the lining mucosa in the oral cavity. The fluorescence spectrum of the resulting emission (around 635 nm) was collected and carried through the remaining fibers to a photomultiplier for quantification. Each subject received a 2 g suppository (composition C), which was placed in the lining mucosa between the inside of the upper lip and the mandible (administration site). On another day, each subject received a 2 g sample of composition D, which was placed at the same administration site. Due to their respective melting points/breaking points, both compositions dissolved slowly after administration. The subjects were allowed to spit out the dissolved compositions. The fluorescence spectrum at the administration site was determined at multiple time points by selecting five points within the administration area and measuring the fluorescence as described above. Reference fluorescence was determined at the same time points at five selected points under the arm. The mean fluorescence and reference fluorescence were calculated from the five points. The fluorescence data were reference corrected and plotted against time (Figures 1 and 2). Figure 1 shows the fluorescence of composition C and Figure 2 shows the fluorescence of composition D. It is evident that composition D induces porphyrin formation more efficiently than composition C.

Example 5: In vivo study of porphyrin formation in the cervix

[00164] Composition D was selected to study porphyrin formations in vivo in the cervix in eight healthy human female volunteer subjects.

[00165] Each individual received a 3 g sample of composition D which was applied to the ectocervix, that is, the portion of the cervix that projects into the vagina. A FemCap, a latex-free device intended for non-hormonal contraception, was placed over the ectocervix to hold the composition in place. The fluorescence spectrum at the administration site was determined before administration of the composition and 7 hours thereafter. Six points within the administration area were selected to measure fluorescence as described in Example 4. The mean and average fluorescence were calculated from the six points for each individual and are shown in the table below in relative units.

[00166] All individuals showed pronounced porphyrin formation after 7 hours of incubation of composition D.

Claims (16)

1. Semi-solid composition, characterized in that it consists of: a) an active ingredient selected from 5-ALA ester and its pharmaceutically acceptable salt; b) one or more triglycerides that are triglycerides of glycerol and 3 identical or different C2-C22 fatty acids; and c) optionally one or more viscosity enhancers that are selected from cellulose and derivatives thereof, synthetic polymers, polyethylene glycols, vegetable gums, starch and starch derivatives, carrageenan, agar, gelatin, wax and waxy solids, wherein the concentration of the active ingredient is 0.5 to 30% by weight of the total weight of the composition, wherein the concentration of one or more triglycerides is in the range of 60 to 96% by weight of the total weight of the composition if one or more viscosity enhancers are present or in the range of 70 to 99.5% by weight of the total weight of the composition if one or more viscosity enhancers are not present. 2. Semi-solid composition according to claim 1, characterized in that the active ingredient is a compound of formula I or its pharmaceutically acceptable salt. where R1 represents a substituted or unsubstituted alkyl group, and R2 represents a hydrogen atom. 3. Semi-solid composition according to claim 1 or 2, characterized in that one or more triglycerides are glycerol triglycerides and 3 identical or different C4-C18 fatty acids, preferably 3 identical or different C6-C18 fatty acids, and more preferably 3 identical or different C6-C12 fatty acids. 4. Semi-solid composition according to any one of claims 1 to 3, characterized in that one or more triglycerides are liquid triglycerides and one or more viscosity enhancers are present. 5. Semi-solid composition according to claim 4, characterized in that one or more viscosity enhancers are selected from a wax or a waxy solid, more preferably selected from a solid fatty alcohol or fatty acid. 6. Semi-solid composition, according to any one of claims 1 to 5, characterized in that the active ingredient is the hexyl ester of 5-ALA or a pharmaceutically acceptable salt thereof. 7. Semi-solid composition according to claim 1, characterized in that it consists of: 5-ALA hexyl ester or a pharmaceutically acceptable salt thereof; a caprylic/capric triglyceride; and stearic acid. 8. Semi-solid composition, according to claim 1, characterized in that it consists of: 5% by weight of 5-ALA hexyl ester in the form of its hydrochloride salt; 77% by weight of caprylic/capric triglyceride; and 18% by weight of stearic acid. 9. Kit, characterized in that it comprises a semi-solid composition as defined in any one of claims 1 to 8 and a drug delivery system. 10. Kit, according to claim 9, characterized in that the drug delivery system is selected from pessaries, diaphragms, hoods, adhesive bandages or plasters. 11. Use of a semi-solid composition, as defined in any one of claims 1 to 8, characterized in that it is for preparing a medicament for use in the photodynamic treatment of cancer, pre-cancerous conditions, infections or inflammation in the female reproductive system, anus and penis. 12. Use according to claim 11, characterized in that the medicine is for use in the photodynamic treatment of dysplasia and HPV infections in the female reproductive system, anus and penis. 13. Use according to claim 12, characterized in that the medicament is for use in the photodynamic treatment of endometrial, cervical, vaginal, vulvar, anal and penile dysplasia and HPV infections of the uterus, cervix, vagina, vulva, anus and penis. 14. Use of the kit as defined in claim 9 or 10, characterized by the fact that it is for preparing a medicament for use in the photodynamic treatment of cancer, pre-cancerous conditions, infections or inflammation in the female reproductive system, anus and penis. 15. Use according to claim 14, characterized in that the medicine is for use in the photodynamic treatment of dysplasia and HPV infections in the female reproductive system, anus and penis. 16. Use according to claim 15, characterized in that the medicament is for use in the photodynamic treatment of endometrial, cervical, vaginal, vulvar, anal and penile dysplasia and HPV infections of the uterus, cervix, vagina, vulva, anus and penis.