GB2546356A

GB2546356A - Solid products and their use

Info

Publication number: GB2546356A
Application number: GB1616489.9A
Authority: GB
Inventors: Flechsler Insa
Original assignee: Photocure ASA
Current assignee: Photocure ASA
Priority date: 2016-09-28
Filing date: 2016-09-28
Publication date: 2017-07-19
Also published as: GB201616489D0

Abstract

Claimed is a solid product for oral administration comprising a photosensitising agent and a multimatrix structure. Such a product may be used for photodynamic treatment (PDT) and photodynamic diagnosis (PDD) of conditions affecting the gastrointestinal tract. Preferably, the matrix consists of lipophilic compounds with a melting point below 90 °C, in which the photosensitizing agent is at least partially incorporated, and an outer hydrophobic matrix in which the lipophilic matrix is dispersed. Most preferably, the photosensitising agent is at least partly incorporated in an inner matrix consisting of lipophilic compounds and amphiphilic compounds. In this preferred embodiment the outer matrix consists of hydrophilic compounds and amphiphilic compounds along with, optionally, other physiologically acceptable excipients and, optionally, a gastro-resistant coating. In worked embodiments the multi-matrix system is commercially available MMX (RTM). Most preferably, the photosensitiser is a derivative of 5-ALA (5-aminolevulinic acid).

Description

Solid products and their use

This invention relates to methods of photodynamic treatment and diagnosis of conditions such as pre-cancerous and cancerous conditions, and in particular to the use of solid products comprising a photosensitizing agent in such methods. The solid products which are described herein are particularly suited to use in the treatment or diagnosis of cancer and pre-cancerous and non-cancerous conditions in the gastrointestinal tract.

Photodynamic treatment (PDT) is a technique for the treatment of pre-cancerous lesions, cancer and non-cancerous diseases. PDT involves the administration of a photosensitizer or a precursor thereof (i.e. a "photosensitizing agent") to an area of interest. The photosensitizer or precursor thereof is taken up into the cells, where a precursor of a photosensitizer is converted into an active photosensitizer. Upon exposure of the area of interest to light, the photosensitizer is excited, usually from a ground singlet state to an excited singlet state. It then undergoes intersystem crossing to a longer-lived excited triplet state. One of the few chemical species present in tissue with a ground triplet state is molecular oxygen. When the activated photosensitizer and an oxygen molecule are in proximity, an energy transfer can take place that allows the photosensitizer to relax to its ground singlet state, and create an excited singlet state oxygen molecule. Singlet oxygen is a very aggressive chemical species and will rapidly react with any nearby biomolecules. Ultimately, these destructive reactions will kill cells through apoptosis or necrosis, whereby for instance cancer cells are selectively killed. The mechanisms are still not fully understood, but studies suggest that the clinical result (i.e. the selectivity for cancerous cells) is not due to selective uptake by cancerous cells. Rather, there are similar levels of uptake in all cell types, but the processes of conversion and elimination 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.

Several photosensitizing agents are known and described in the literature, including 5-aminolevulinic acid (5-ALA) and certain derivatives thereof, e g. 5-ALA esters, both of which are precursors of photosensitizers. These are converted intracellularly to protoporphyrins, such as protoporphyrin IX (PpIX), which are photosensitizers. Currently several pharmaceutical products comprising 5-ALA or an ester thereof are in clinical use for PDT and photodynamic diagnosis (PDD). 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 one is Levulan Kerastick® (DUSA Pharmaceuticals, Canada), a product for the photodynamic treatment of actinic keratosis which contains 5-ALA.

Hexvix® (developed by Photocure ASA) is an aqueous solution which comprises 5-ALA hexyl ester for instillation into the bladder for diagnosis of bladder cancer.

Although these products are clinically useful, they all suffer from the disadvantage of instability of 5-ALA. 5-ALA and esters thereof are subject to a broad spectrum of decomposition reactions which limit the shelf life of pharmaceutical products in which they are present. A number of different strategies have been adopted to try to overcome this problem. For instance, with the Metvix® product the problem of instability is addressed by storing the cream in cold conditions and with the Levulan Kerastick® product the 5-ALA is supplied separately from its diluent so the solution administered to the subject is only prepared immediately before use. Hexvix® is supplied as a lyophilised powder and dissolved in an aqueous solution immediately before use.

These approaches, however, have disadvantages For example, it is not always convenient to transport and store medicines in cold conditions. Moreover it is also generally preferable to provide pharmaceutical compositions in a ready-to-use form as these are most convenient for medical practitioners. Provision of ready-to-use forms also enables the compositions to be prepared with a reliable and accurate concentration. This is particularly important in the treatment and diagnosis of the majority of diseases including cancer where it can be critical that the correct dosage of therapeutic is administered. US 2003/125388 describes an alternative approach to provision of 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 which acts a stabiliser. It is hypothesised that the use of the non-aqueous liquid facilitates formation of the enol form of 5-ALA that then prevents its degradation. Examples of suitable non-aqueous liquids mentioned in US 2003/125388 include alcohols, ethers, esters, poly(alkylene glycols), phospholipids, DMSO, N-vinylpyrrolidone and Ν,Ν-dimethyl acetamide. 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 prior to use.

The approach in US 2003/125388 therefore suffers the same disadvantage as the Levulan Kerastick® in that it is generally undesirable to provide therapeutics in a form that requires the medical practitioner to formulate the pharmaceutical product that is actually administered. Moreover it may not always be desirable to administer a non-aqueous liquid to an animal. A further disadvantage suffered by all of the above-mentioned strategies is that liquid and cream formulations are difficult to use for treatment, especially topical treatment, of a number of areas of the body. This is particularly disadvantageous in the case of cancer treatment since cancer occurs throughout the body.

Areas of the body which are difficult to treat using conventional PDT or photodynamic diagnosis (PDD) methods include the gastrointestinal tract. WO 2010/072419 teaches improved enema formulations which comprise as a photosensitizing agent 5-ALA or an ester of 5-ALA for use in PDT or PDD. From a patient convenience and patient logistics point of view, enemas are not the preferred embodiment of a commercial product. Oral formulations comprising 5-ALA and derivatives thereof, such as solutions, suspensions, classical tablets and capsules (containing aqueous formulations) have several disadvantages when used for the diagnosis and/or therapeutic treatment of cancer and non-cancerous diseases in the lower part of the gastrointestinal tract. These relate to shelf life stability of the pharmaceutical product, in vivo stability of the product during its passage through the whole gastrointestinal tract, and systemic toxicity as result of absorption of 5-ALA or derivatives thereof. Systemic absorption in turn results in both the need to use an increased amount of the photosensitizing agent and in a reduction in clinical efficacy at the desired treatment site. WO 2009/074811 teaches solid products for oral administration which comprise as a photosensitizing agent 5-ALA or an ester of 5-ALA. The solid products may comprise an enteric coating, i.e. a coating that prevents degradation of the product (and thus release of the photosensitizing agent) in the stomach. Degradation only happens after the product has passed the stomach and/or the small intestines such that the photosensitizing agent is released in the lower part of the gastrointestinal system, i.e. the caecum or colon.

However, currently, there are no products available for clinical use in photodynamic diagnosis or therapy of these parts of the body. This remains a significant problem, especially in relation to the colon and rectum which may be associated with several serious and life-threatening diseases like colitis, colorectal cancer, Crohn's disease, irritable bowel disease and various local infections. There also remains a medical need for methods for earlier diagnosis of these diseases, especially colorectal cancer.

Current diagnostic methods for colorectal cancer include monitoring of clinical symptoms like blood in the stools, lower abdominal pain or weight loss, coloscopy with white light or dyes (chromoendoscopy) and X-ray based imaging methods. The prognosis of patients with colorectal cancer depends, as with most other cancer forms, on disease stage at the time of diagnosis and especially on whether the patient has developed distant metastasis. There are several therapeutic drugs in clinical use today for treating colorectal cancer, however, current drugs have their clinical limitations and there remains a medical need for further therapeutic regimes and alternative methods of early diagnosis. WO 2011/107945 discloses controlled release formulations for oral administration comprising dyes such as methylene blue for controlled release of said dyes in the gastrointestinal tract for use in diagnostic procedures with white light (chromoendoscopy). There are several disadvantages with dyes as imaging or contrast agent in such procedures: some dyes, e.g. indigo carmine, only highlight surface structures of the tissue, i.e. do not exhibit any difference for healthy and diseases tissue. Other dyes like e g. methylene blue only exhibit little sensitivity/specificity which requires a skilled practitioner to interpret the staining patterns correctly. Consequently, multiple reports have been published that have shown discrepant results and meta-analyses from studies concluded that methylene blue chromoendoscopy did not significantly increase the yield of detection compared with random biopsies (Ngamruengphong et al., Gastroint. Endosc 2009 (69), 1021. Also, since methylene blue is a known photosensitizer it is excited (photosensitized) upon illumination with white light. This photodynamic process can lead to DNA damage during endoscopy (Olliver et al., Lancet 2003 (362), 373). A need still therefore exists for alternative methods for photodynamic treatment and/or diagnosis of conditions such as, for example, cancer. In particular, a need exists for improved methods for the diagnosis and/or treatment of cancerous, pre-cancerous and non-cancerous conditions in the gastrointestinal tract, especially in the lower gastrointestinal tract, especially conditions in the lower small intestine, the colon and rectum.

It has now surprisingly been found that certain solid pharmaceutical products comprising a photosensitizing agent overcome these problems of the prior art. The solid pharmaceutical products have stability at room temperature, are easy to handle and convenient to use, and most importantly can also readily be delivered to the gastrointestinal tract in a targeted manner, i.e. to the segment of the gastrointestinal tract which is of interest. Such products also generally address the problem of reduced efficacy of known formulations when treating these areas of the body. More specifically, these are capable of providing an effective concentration photosensitizer at the desired treatment site and a substantially homogenous (i.e. uniform) distribution of the photosensitizing agent at the intended site thereby further improving treatment and diagnosis (PDT or PDD).

Thus, viewed from one aspect the invention provides a solid product for oral administration comprising a photosensitizing agent and a multimatrix structure.

An advantage of the solid products of the invention is that they are stable. In particular the photosensitizing agents present within the solid products of the invention are not prone to degradation and/or decomposition. As a result, the solid products can be stored, e.g. at room temperature and humidity, for at least 6 months, more preferably at least 12 months, still more preferably at least 24 months or more, e.g. up to 36 months.

Preferably, the photosensitizing agent is 5-ALA, a derivative of 5-ALA (e.g. a 5-ALA ester) or pharmaceutically acceptable salts thereof

Preferably, the multimatrix structure comprised in the solid product of the invention is one commercially known under the trade name MMX®, described in the international patent applications WO 00/76481, WO 00/76478, WO 2011/107945, WO 2014/060199 and US 2013/0058867, incorporated herein by reference.

The term "solid" refers to the physical state of the product being described, i.e. as being a solid, rather than a liquid or gas. Hence, liquids, solutions, suspensions, gels, creams, lotions or the like are therefore not encompassed by this term.

The term “photosensitizing agent” includes photosensitizers and precursors of photosensitizers, i.e. compounds which are converted to an active photosensitizer in the body and/or in a cell.

The term “5-ALA” denotes 5-aminolevulinic acid, i.e. 5-amino-4-oxo-pentanoic acid.

The term "derivative of 5-ALA" denotes chemically modified 5-ALA, i.e. 5-ALA having undergone a chemical derivation such as substitution of a chemical group or addition of a further chemical group to modify or change any of its physicochemical properties such as solubility or lipophilicity. Chemical derivation is preferably carried out at the carboxy group of 5-ALA, at the amino group of 5-ALA or at the keto group of 5-ALA, more preferably at the carboxy group or the amino group of 5-ALA. Preferred derivatives include esters, amides and ethers of 5-ALA, most preferred 5-ALA esters.

The term “pharmaceutically acceptable salt” denotes a salt that is suitable for use in the dry pharmaceutical product and which fulfils the requirements related to for instance safety, bioavailability and tolerability (see for instance P. H. Stahl et al. (eds.) Handbook of Pharmaceutical Salts, Publisher Helvetica Chimica Acta, Zurich, 2002)

The term “pre-cancerous condition” denotes a disease, syndrome, or finding that, if left untreated, may lead to cancer, e.g. dysplasia and neoplasia.

The term “non-cancerous conditions” includes abnormal lesions with no or low malignant potential such as hyperplasia and low-grade lesions, infections such as viral, bacterial or fungal infections, preferably HPV infection, or inflammation.

The term “gastrointestinal tract” includes all structures and organs between and including the mouth and the anus.

The term “upper gastrointestinal tract includes all structures and organs between and including the mouth and duodendum. Hence it includes the mouth, the esophagus the stomach and the duodendum.

The term “lower gastrointestinal tract includes some structures and organs of the small intestines, all structures and organs of the large intestines and the anus. Hence it includes the jejunum, ileum (small intestines), cecum, colon, rectum, anal canal (large intestines) and anus.

According to a preferred embodiment the solid product of the invention comprises a photosensitizing agent, preferably 5-ALA, a derivative of 5-ALA (e g. a 5-ALA ester) or pharmaceutically acceptable salts thereof, and a multimatrix structure comprising: a) a matrix which consists of lipophilic compounds with melting point below 90 °C, and optionally amphiphilic compounds, in which the photosensitizing agent is at least partly incorporated; b) an outer hydrophilic matrix in which the lipophilic matrix, and optionally the amphiphilic matrix are dispersed; c) optionally other physiologically acceptable excipients; d) optionally a gastro-resistant coating.

According to a further embodiment the solid product of the invention comprises a photosensitizing agent, preferably 5-ALA, a derivative of 5-ALA (e.g. a 5-ALA ester) or pharmaceutically acceptable salts thereof, and a multimatrix structure comprising: a) a matrix which consists of lipophilic compounds with melting point below 90 °C and amphiphilic compounds in which the photosensitizing agent is at least partly incorporated; b) an outer hydrophilic matrix in which the lipophilic and optionally the amphiphilic matrix are dispersed; c) optionally other physiologically acceptable excipients; and d) optionally a gastro-resistant coating.

According to a further embodiment the solid product of the invention comprises a photosensitizing agent, preferably 5-ALA, a derivative of 5-ALA (e.g. a 5-ALA ester) or pharmaceutically acceptable salts thereof, and a multimatrix structure comprising: a) a matrix which consists of lipophilic compounds with melting point below 90 °C and amphiphilic compounds in which the photosensitizing agent is at least partly incorporated; b) an outer hydrophilic matrix in which the lipophilic and the amphiphilic matrix are dispersed; c) optionally other physiologically acceptable excipients; and d) optionally a gastro-resistant coating.

According to another embodiment, the solid product of the invention comprises a photosensitizing agent, preferably 5-ALA, a derivative of 5-ALA (e.g. a 5-ALA ester) or pharmaceutically acceptable salts thereof, and a multimatrix structure comprising: a) a matrix which consists of lipophilic compounds with melting point below 90 °C, in which said photosensitizing agent is at least partly incorporated; b) an outer matrix which consists of hydrophilic compounds and optionally amphophilic compounds, in which the lipophilic matrix, is dispersed; c) optionally other physiologically acceptable excipients; and d) optionally a gastro-resistant coating.

The solid product of the invention, at least in preferred embodiments thereof, is for use in the photodynamic treatment or photodynamic diagnosis of non-cancerous, pre-cancerous and cancerous conditions in the gastrointestinal tract, i.e. for use in the photodynamic treatment or photodynamic diagnosis of non-cancerous, pre-cancerous and cancerous conditions in the upper or lower gastrointestinal tract, preferably for use in the photodynamic treatment or photodynamic diagnosis of non-cancerous, pre-cancerous and cancerous conditions in the lower gastrointestinal tract. In a preferred embodiment, the solid product of the invention is for use in the photodynamic diagnosis of non-cancerous, pre-cancerous and cancerous conditions in the gastrointestinal tract, i.e. for use in the photodynamic diagnosis of non-cancerous, pre-cancerous and cancerous conditions in the upper or lower gastrointestinal tract, preferably for use for use in the photodynamic diagnosis of non-cancerous, pre-cancerous and cancerous conditions in the lower gastrointestinal tract..

Photosensitizing agents for use in the solid product of embodiments of the invention include photosensitizers selected from hematoporphyrin derivative, a complex mixture of porphyrins derived from hematoporphyrin, hematoporphyrines such as Photofrin® hematoporphyrin IX, Photosan III, chlorins such as tetra (m-hydroxyphenyl) chlorins and their bacteriochlorins, mono-L-aspartyl chlorin e6, chlorin e6, benzoporphyrins such as benzoporphyrin derivative monoacid ring A, purpurines e.g. tin-ethyl etiopurpurin, dyes such as methylene blue, toluidine blue, neutral redphthalocyanines, e.g. zinc- aluminium- or silicon phthalocyanines, which may be sulphonated, in particular sulphonated phthalocyanines such as aluminium phthalocyanine di-sulphonate or aluminium phthalocyanine tetra-sulphonate, porphycenes, hypocrellins, protoporphyrin IX (PpIX), hematoporphyrin di-ethers, uroporphyrins, coproporphyrins, deuteroporphyrin, polyhematoporphyrin, lutetium texaphyrin and porphobilinogen.

Precursors of photosensitizers for use in the solid product according to embodiments of the invention include 5-ALA and derivatives thereof, e.g. 5-ALA esters and salts of 5-ALA and derivatives thereof.

The use of 5-ALA and derivatives thereof, e.g. 5-ALA esters, in PDT and PDD is well known in the scientific and patent literature, see, for example, WO 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 derivatives of 5-ALA and their pharmaceutically acceptable salts are suitable for use in the solid product of embodiments of the invention herein described

The synthesis of 5-ALA is known in the art. Further, 5-ALA and pharmaceutically acceptable salts thereof are commercially available, for instance from Sigma Aldrich.

The 5-ALA derivatives useful in accordance with embodiments of the invention may be any derivative of 5-ALA capable of forming protoporphyrins, e.g. PpIX or a PpIX derivative in vivo. Typically, such derivatives will be a precursor of PpIX or of a PpIX derivative, e.g. a PpIX ester in the biosynthetic pathway for haem and which are therefore capable of inducing an accumulation of PpIX following administration in vivo. Suitable precursors of PpEX or PpEX derivatives include 5-ALA prodrugs which might be able to form 5-ALA in vivo as an intermediate in the biosynthesis of PpIX or which may be converted, e.g. enzymatically, to porphyrins without forming 5-ALA as an intermediate. 5-ALA esters and pharmaceutically acceptable salts thereof, are among the preferred compounds for use in the invention described herein. 5-ALA esters which 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, WO 02/10120, WO 2014/020164 to Photocure ASA, WO 03/041673 and in N. Fotinos et al., Photochemistry and Photobiology 2006: 82, 994-1015, the contents of which are incorporated herein by reference.

Esters resulting from a reaction of 5-ALA with unsubstituted or substituted alkanols, i.e. alkyl esters and substituted alkyl esters, and pharmaceutically acceptable salts thereof, are especially preferred derivatives of 5-ALA for use in embodiments of the invention. Examples of such preferred 5-ALA esters include those of general formula I and pharmaceutically acceptable salts thereof: R^N-CfLCOCfL-CfLCO-OR1 (I) wherein

R1 represents a substituted or unsubstituted alkyl group; and R each independently represents a hydrogen atom or a group R

As used herein, the term "alkyl", unless stated otherwise, includes any long or short chain, cyclic, straight-chained or branched saturated or unsaturated aliphatic hydrocarbon group. Unsaturated alkyl groups may be mono- or polyunsaturated and include both alkenyl and alkynyl groups. Unless stated otherwise, 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.

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 either attached to the alkyl group and/or interrupt the alkyl group. Suitable substituents that are attached to the alkyl group are those selected from hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo, fluoro, -SR3, -NR32 and -PR\ wherein R3 is a hydrogen atom or a Ci.6 alkyl group. Suitable substituents that interrupt the alkyl group are those selected from -0-, -NR3-, -S- or -PR3.

In a preferred embodiment, R1 is an alkyl group substituted with one or more aryl substituents, i.e. aryl groups. Preferably, R1 is an alkyl group substituted with one aryl group.

As used herein, the term "aryl group” denotes an aromatic group which may or may not contain heteroatoms like nitrogen, oxygen or sulfur. Aryl groups which 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. Further, the aryl group may optionally be substituted by one or more, more preferably one or two, substituents. Preferably, the aryl group is substituted at the meta or para position, most preferably the para position. Suitable substituents include halo alkyl, e g. trifluoromethyl, alkoxy, preferably alkoxy groups containing 1 to 6 carbon atoms, halo, e g. iodo, bromo, chloro or fluoro, preferably chloro and fluoro, nitro and Ci.6 alkyl, preferably Cm alkyl. Preferred Ci.6 alkyl groups include methyl, isopropyl and t-butyl, particularly methyl. Particularly preferred aryl substituents are chloro and nitro. However, still more preferably the aryl group is unsubstituted.

Preferred such aryl substituted R1 groups are benzyl, 4-isopropylbenzyl, 4-methylbenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-[t-butyl]benzyl, 4- [trifluoromethyl]benzyl, 4-methoxybenzyl, 3,4-[di-chloro]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- [(l-acetyloxyethoxy)-carbonyl], More preferred such R1 groups are benzyl, 4-isopropylbenzyl, 4-methylbenzyl 4-nitrobenzyl and 4-chlorobenzyl. Most preferred is benzyl.

If R1 is a substituted alkyl group, one or more oxo substituents are preferred. Preferably, such groups are straight-chained C4-12 alkyl groups which 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 short polyethylene glycol substituents. Preferred examples of such groups include 3,6-dioxa-l-octyl and 3,6,9-trioxa-l-decyl. In another preferred embodiment, R1 is an alkyl group interrupted by one or more oxygen atoms (ether or polyether group), preferably a straight-chained C4.12 alkyl and more preferably a straight-chained C6-io alkyl group being interrupted by 1 to 4 oxygen atoms, more preferably a straight-chained polyethylene glycol group (-(CH2)2-0-)n with n being an integer of from 1 to 5.

If R1 is an unsubstituted alkyl group, R1 groups that are saturated straight-chained or branched alkyl groups are preferred. If R1 is a saturated straight-chained alkyl group, Ci-io straight-chained alkyl group are preferred. Representative examples of suitable straight-chained alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and n-octyl. Particularly preferred are Ci.6 straight-chained alkyl group, most particularly preferred are methyl and n-hexyl. If R1 is a saturated branched alkyl group, such branched alkyl groups preferably consist of a stem of 4 to 8, preferably 5 to 8 straight-chained carbon atoms and said stem is branched by one or more Ci.6 alkyl groups, preferably Ci.2 alkyl groups. Examples of such saturated branched alkyl groups include 2-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 3,3-dimethyl-l-butyl.

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

Preferably, compounds of formula I and pharmaceutically acceptable salts thereof are used as active ingredients in the dry pharmaceutical compositions of embodiments of the invention, wherein R is methyl or hexyl, more preferably n-hexyl and both R represent hydrogen, i.e. 5-ALA methyl ester, 5-ALA hexyl ester and pharmaceutically acceptable salts thereof, preferably the HC1 salts. The preferred compound for use as photosensitizing agent in the solid product of embodiments of the invention is 5-ALA hexyl ester and pharmaceutically acceptable salts thereof, preferably the HC1 salt or sulfonic acid salts or sulfonic acid derivative salts. 5-ALA esters and pharmaceutically acceptable salts thereof for use in embodiments of the invention may be prepared by any conventional procedure available in the art, e.g. as described in WO 96/28412, WO 02/10120, WO 03/041673, WO 2014/020164 and in N. Fotinos et al., Photochemistry and Photobiology 2006: 82, 994-1015 and the cited literature references therein. Briefly, 5-ALA esters may be prepared by reaction of 5-ALA with the appropriate alcohol in the presence of a catalyst, e.g. an acid. Pharmaceutically acceptable salts of 5-ALA esters may be prepared as described hereinbefore by reaction of a pharmaceutically acceptable 5-ALA salt, e.g. 5-ALA hydrochloride with the appropriate alcohol. Alternatively compounds for use in embodiments of the invention like 5-ALA methyl ester or 5-ALA hexyl ester may be available commercially, e.g. from Photocure ASA, Norway.

The 5-ALA esters for use in embodiments of the invention may be in the form of a free amine, e.g. -NH2, -NHR or -NR R or preferably in the form of a pharmaceutically acceptable salt. Such salts preferably are 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 salts of ALA-esters and the latter acids are described in WO 2005/092838 to Photocure ASA, the entire contents of which are incorporated herein by reference. A preferred acid is hydrochloride acid, HC1. Further preferred acids are sulfonic acid and sulfonic acid derivatives. Procedures for salt formation are conventional in the art and are for instance described in WO 2005/092838.

The desired concentration of photosensitizing agent in the solid product according to embodiments of the invention will vary depending on several factors including the nature of the compound, the nature and form of the product in which this is presented, the nature of the disease to be treated or diagnosed and the subject to be treated. Generally, however, the concentration of the photosensitizing agent is conveniently in the range 1 to 50%, preferably 1 to 40%, e.g. 2 to 25%, preferably 5 to 20% by weight of the total weight of the solid product.

Suitable lipophilic compounds as disclosed herein can be selected from saturated, unsaturated and hydrogenated long chain alcohols, saturated and unsaturated and hydrogenated fatty acids, salts thereof, esters and amides, mono-, di- and triglycerides of fatty acids, polyethoxylated derivatives thereof, waxes, ceramides, cholesterol, cholesterol derivatives and mixtures thereof having a melting point below 90 °C, such as from 40 °C to below 90 °C, and further such as from 60 °C to 70 °C.

Suitable amphiphilic compounds as disclosed herein can be selected from among polar lipids of type I and II such as lecithin, phosphatidylcholine, phosphatidylethanolamine, and mixtures thereof, ceramides, glycol alkyl ethers, such as for example, diethylene glycol monomethyl ether, alkylsulfate and alkylsulfosuccinate salts, and mixtures thereof.

Suitable hydrophilic compounds as disclosed herein can be chosen from compounds forming hydrogels, i.e. compounds which form a hydrogel on contact with water or aqueous solvents. When passing from the dry state to the hydrated state, hydrogels undergo so-called "molecular relaxation", namely a remarkable increase in mass and weight following the coordination of a large number of water molecules by the polar end groups present in hydrogel-forming compounds.

Compounds forming hydrogels include polymers and copolymers of acrylic acid, copolymers of methacrylic acid, alkyl vinylpolymers, alkyl celluloses, hydroxyalkyl celluloses, carboxyalkyl cellulose, modified and/or plurisubstituted celluloses, polysaccharides, dextrins, pectins, starches, complex starches and starch derivatives, alginic acid, synthetic rubber, natural rubber, polyalcohols and mixtures thereof. A suitable gastro-resistant coating, as disclosed herein, can comprise compounds chosen from polymers of acrylic acid, polymers of methacrylic acid, copolymers of acrylic acid and/or copolymers of methacrylic acid, cellulose derivatives such as for example cellulose acetate phthalate, hydroxybutyrate-based polymers, shellac and mixtures thereof. Such gastro-resistant coatings of embodiments of the invention can also comprise plasticisers, opacifiers, dyes and mixtures thereof.

The solid product as disclosed herein can be provided in various dosage forms including tablets, capsules, granules, microgranules, powders or pellets. If in the form of a capsule, the capsule may in turn contain granules, microgranules, powders and/or pellets. Also, if in the form of a tablet, the tablet may further contain granules, microgranules, powders and/or pellets which are compressed to a tablet.

The solid products of embodiments of the invention may additionally comprise one or more anti-cancer agents. Preferred anti-cancer agents are anti-neoplastic agents. Representative examples of anti-neoplastic agents include alkaloids (e.g. incristine, vinblastine, vinorelbine, topotecan, teniposiode, paclitaxel, etoposide and docetaxel), alkylating agents (e.g. alkyl sulfonates such as busulfan), aziridines (e.g. carboquone, ethylenimines and methylmelamines), nitrogen mustards (e.g. chlorambucil, cyclophosphamide, estramustin, ifosfamide and melphalan), nitrosurea derivatives (e.g. carmustine and lomustine), antibiotics (e.g. mitomycins, doxorubicin, daunorubicin, epirubicin and bleomycins), antimetabolites (e.g. folic acid analogues and antagonists such as methotrexate and raltitrexed), purine analogues (e.g. 6-mercaptopurine), pyrimidine analogues (e.g. tegafur, gemcitabine, fluorouracil and cytarabine), cytokines, enzymes (e.g. L-asparginase, ranpirnase), immunomodulators (e.g. interferons, immunotoxins, monoclonal antibodies), taxanes, topoisomerase inhibitors, platinum complexes (e.g. carboplatin, oxaliplatin and cisplatin) and hormonal agents (e.g. androgens, estrogens, anti estrogens) and aromatase inhibitors. Other anti-neoplastic agents for use in embodiments of the invention include imiquimod, irenotecan, leucovorin, levamisole, etopisde and hydroxyurea.

Particularly referred anti-cancer agents for use in embodiments of the invention include 5-fluorouracil, imiquimod, cytokines, mitomycin C, epirubicin, irenotecan, oxalipatin, leucovorin, levamisole, doxorubicin, cisplatin, etoposide, doxirubicin, methotrexate, taxanes, topoisomerase inhibitors, hydoroxyurea and vinorelbine. Yet more preferred for use as anticancer agents are antibiotics such as mitomycin and pyrimidine analogues such as 5-fluorouracil.

The solid products of embodiments of the invention may additionally comprise one or more anti-inflammatory agents. Preferred anti-inflammatory agents are ketoprofen, ibuprofen, diclofenac, diflunisal, piroxicam, naproxen, ketorolac, nimesulide, thiaprophenic acid, mesalazine (5-aminosalicylic acid), olsalazine, sulfasalazine, budenoside.

The solid products of embodiments of the invention may additionally comprise one or more oral cavity disinfectants or antimicrobials, such as benzalkonium chloride, cetylpyridinium chloride or tibezonium iodide.

The pharmaceutical products may additionally include lubricating agents, wetting agents, preserving agents, flavouring agents and/or odour enhancers.

For preparing the solid product according to embodiments of the invention, the photosensitizing agent (and any additional agents or excipients) is first mixed or granulated with the material capable of forming a lipophilic matrix, such as in the presence of one or more amphophilic substances with surfactant properties, and lastly this matrix of powders, at any degree of aggregation, is inserted into a dominant structure formed by polymers or copolymers of the hydrophilic type, also known as hydrogels, in the anhydrous state or with some residual moisture value.

Alternatively, the photosensitizing agent (and any additional agents or excipients) is first mixed or granulated with the material capable of forming a lipophilic matrix, and after granulation this matrix structure, at any degree of aggregation, is inserted into a dominant structure formed by polymers or copolymers of hydrophilic type in anhydrous state or with some residual moisture value in the presence, for example, of one or more amphiphilic substances with surfactant properties. Subsequently the final mixture is subjected to compression. A gastro-resistant coating may subsequently be applied to the surface of the compressed mixture.

The solid product of embodiments of the present invention can be instant-release or controlled-release type.

The expression "instant-release” is used to indicate an instant, immediate and rapid release, i.e. a solid product capable of disintegrating quickly and dissolving in the upper gastrointestinal tract, preferably in the mouth, the esophagus, the stomach or the duodendum, more preferably in the mouth, the esophagus or the stomach, simultaneously releasing the entire amount of photosensitizing agent contained therein.

The instant-release composition of embodiments of the invention preferably comprises physiologically acceptable excipients that ensure the quick disintegration and dissolution of the photosensitizing agent. Such excipients are instant release agents or disintegrants and are known in the art. In a preferred embodiment, so-called super disintegrants are used, i.e. polymeric substances capable of swelling on contact with aqueous fluids and triggering a hydrodynamic tension within the solid product which leads to the breakage thereof into fragments with the ensuing considerable increase of the surface/volume ratio and, thus, to rapid release and dissolution of the photosensitizing agents contained in therein. Suitable super disintegrants are preferably selected from modified starches, modified celluloses, polymers or cross-linked copolymers, such as, for example, cross- linked polyvinylpyrrolidone or mixtures thereof.

The instant-release composition of embodiments of the invention may also comprise an outer coating, which may be a gastro-resistant coating in case the solid product is for use in the duodendum. If used in other structures and organs of the upper gastrointestinal tract, the outer coating may be useful for enhancing the shelf-life of the product and/or for masking the taste of the solid product (provided it is not for use in the mouth) during the uptake and swallowing by the patient. Suitable coating compounds are preferably selected from among polymers and copolymers of the acrylic or methacrylic acid, alkyl or hydroxyalkyl cellulose derivatives or mixtures thereof.

The solid product of embodiments of the present invention can be of the controlled-release type and such types are preferred.

The expression '"controlled release" is used to indicate a solid product capable of releasing the photosensitizing agent in a selective site-time manner, i.e. progressive in the areas of interest. Thus, such expression comprises the "prolonged, sustained, extended, delayed or modified” release definition.

The technology suitable for such controlled release in the context of embodiments of the invention is the matrix technologies, i.e. the multimatrix structure comprised in the solid product of embodiments of the invention.

The administration of a controlled release solid product of embodiments of the invention allows the release of the photosensitizing agent in the lower gastrointestinal tract, i.e. in the jejunum, ileum (small intestines), cecum, colon, rectum, anal canal (large intestines) and anus. Preferably, the administration of a controlled release solid product of embodiments of the invention allows the release of the photosensitizing agent in the distal ileum and/or cecum, allowing for the controlled release and subsequent uniform distribution of the photosensitizing agent from the distal ileum/cecum throughout the large intestines to the anal canal.

Hence the administration of a controlled release solid product as disclosed herein actually allows releasing the photosensitizing agent contained in the solid product precisely starting from the segment in the lower gastrointestinal tract intended to be targeted, i.e. treated or diagnosed.

For the preparation of a controlled release solid product, the photosensitizing agent can be formulated with excipients, i.e. release agents capable of imparting prolonged, sustained, extended, delayed or modified release of the photosensitizing agent from the solid product.

Additionally, the controlled release solid product preferably comprises a gastro-resistant coating, which may also contribute to prolonged, sustained, extended, delayed or modified release of the photosensitizing agent from the solid product.

The solid product of embodiments of the invention preferably comprises a gastro-resistant coating that only dissolves upon reaching a specific pH, i.e. a pH which can be found in the segment of the lower gastrointestinal tract which is targeted for treatment or diagnosis. Upon reaching the segment of interest, characterised by a specific pH value at which the gastro-resistant coating starts dissolving, the release of the photosensitizing agent can be controlled in terms of speed so as to ensure that it occurs within the time required by the intestinal transit, such as the time to reach all structures and organs of the lower gastrointestinal tract, generally running from 4 to 24 hours.

For use in the photodynamic treatment or diagnosis of the small intestines, the solid product of embodiments of the invention is preferably a controlled release solid product comprising a gastro-resistant coating that dissolves when the pH is about 5 or 5.5. Such a coating preferably comprises mixtures of acrylic and methacrylic copolymers of type A (Eudragit L, or RL, for example).

For use in the photodynamic treatment or diagnosis of the large intestines, the solid product of embodiments of the invention is preferably a controlled release solid product comprising a gastro-resistant coating that dissolves when the pH is about 6.5 or 7. Such a coating preferably comprises mixtures of acrylic and methacrylic copolymers of type A (Eudragit L, or RL, for example), type B (such as for example those commercially known under the trade name Eudragit S or RS), and/or mixtures based on cellulose acetate phthaiate, insoluble in an acid environment which become soluble when the pH is neutralized and acquires a value of about 7.

In order to allow a homogeneous distribution of the photosensitizing agent in the whole lower gastrointestinal tract, preferably in all segments of the colon from the ileocecal area to the ascending, transverse, descending, sigmoid and rectal colon, the release of the photosensitizing agent should be progressive and in line with the advancement of the solid product.

For use in photodynamic diagnosis - given that the transit time of the solid product through the gastrointestinal tract is in the range of several hours - the administration of the solid product of embodiments of the invention should be carried out suitably in advance with respect to the diagnostic procedure, e.g. the endoscopic procedure. Generally, for such procedures the administration of the solid product should be 4-24 hours prior to the procedure, so as to allow the release of the photosensitizing agent in the target segment, the intracellular conversion of the photosensitizing agent to an active photosensitizer and the formation of a diagnostically sufficient amount of photosensitizer prior to said procedure.

For use in photodynamic diagnosis, to achieve a high and substantially homogeneous (i.e. uniform) concentration of photosensitizing agent the lower part of the gastrointestinal tract, e.g. in the whole of the colon, certain dosage forms or dosage regimes are preferred.

Such dosage forms comprise a plurality of individual doses, which are capable of releasing the photosensitizing agent at different rates and/or at different time intervals following administration. The individual doses may be contained within a single dosage form, for example a plurality of granules, pellets, tiny pills or mini-tablets (hereinafter particulates) may be provided within a single tablet or single capsule in which the individual particulates are capable of providing different release profiles for the photosensitizing agent. Alternatively, the dosage form may be one comprising several single dose forms, e.g. tablets or capsules intended for simultaneous or for separate, successive administration in which the individual single dose forms differ in their release profiles. By way of example, 3 capsules may be used, each of them comprising a gastro-resistant coating and each of them providing a different controlled release profile of the photosensitizing agent, e g. a prolonged, extended and delayed release. Due to the gastro-resistant coat, the photosensitizing agent is not released prior to entering the lower gastrointestinal tract. Here, the prolonged release profile capsule provides release of the photosensitizing agent in the distal ileum/cecum, the extended release profile capsule provides release of the photosensitizing agent in the middle part of the colon and the delayed release profile capsule provides release of the photosensitizing agent in the distal part of the colon. Hence, it is possible to target the whole length of the colon.

Suitable dosage regimes include the timed administration, i.e. administration according to a specifically designed administration schedule, of two or more unit doses of the solid product, which all provide the same release profile. Said two or more unit dosages are, for example, four, six or eight individual dosages administered in the 48 hours prior to a diagnostic procedure, e.g. in the 24 hours prior to a diagnostic procedure. Preferred administration schedules for solid products according to the invention for use in photodynamic diagnosis are disclosed in WO 2014/060199, the disclosure of which are incorporated by reference herein.

To facilitate the observation of the surface of the lower gastrointestinal tract, e.g. the surface of the colon in photodynamic diagnosis with the solid product of embodiments of the invention, the patient, prior to the diagnostic procedure, is asked to carry out a bowel cleansing procedure by the administration of bowel cleansing solution(s) to quantitatively remove the stool and mucous residuals. This cleansing procedure is carried out generally in the 48 hour period prior to the diagnostic procedure, e.g. in the 24 hour period prior to the diagnostic procedure.

The bowel cleansing procedure is carried out by drinking the volume fractions of the bowel cleansing solution consecutively during the day before the diagnostic procedure. Alternatively, the bowel cleansing procedure is carried out by dividing the administration of the cleansing solution volume in two parts, one to be administered the day before the diagnostic procedure and one to be administered in the morning of the day on which the diagnostic procedure is to be performed (“split version”).

Suitable bowel cleansing solutions are, for example, saline and/or polyethylenglycol (PEG) aqueous solution, such as a polyethylene glycol aqueous solution. Said aqueous solutions usually contain, excluding water, from 50% to 95% by weight of polyethylene glycol and sometimes also include salts and flavours, such as sodium salts, potassium salts, ascorbic acid, and mixtures thereof. For example, sodium sulphate, sodium sulphate anhydrous, sodium chloride, sodium ascorbate, sodium bicarbonate, sodium salt of ascorbic acid, potassium sulphate, potassium chloride and mixtures thereof can be used. As a further example, the bowel cleansing solution is an aqueous solution of commercially available products sold under such names as Moviprep®, Golytely®, Nulytely®, Halflytely®, Movicol®, Macro-P®, Colirei®, Delcoprep®, Isocolan® or Selg 1000®. However, as disclosed herein, also other bowel cleansing solutions can be used, as long as they are provided with a toxicity profile that does not represent an obstacle to oral systemic administration thereof. For example, bowel cleansing solution containing only salts or other small chemical laxatives, but not PEG, are available on the market under the brands Phospho-Lax®, Picoprep®, or Suprep®. Also, different bowel cleansing solutions can be used in one bowel cleansing procedure.

According to one embodiment, eight unit dosages of the solid product are orally administered to a patient in the 48 hour period prior to the photodynamic diagnostic procedure. According to another embodiment, six unit dosages of the solid product are orally administered to said patient in the 48 hour period prior to the photodynamic diagnostic procedure. According to a yet one other embodiment, four unit dosages of the solid product, are orally administered to a patient in the 48 hour period prior to the photodynamic diagnostic procedure.

The bowel cleansing solution can be administered in a total amount of four litres, which can be fractionated in one or more unit dosages, for example, in four unit dosages of about one litre each.

The solid composition, as disclosed herein, can be thus administered together and/or after the intake of each unit dosage of said bowel cleansing solution, prior to the photodynamic diagnostic procedure. Afterwards, water can also be additionally administered, if necessary.

For example, four unit dosages of the solid product are orally administered to a patient according to a fractionated schedule in the 48 hour period prior to the photodynamic diagnostic procedure as follows: one unit dosage of the solid product after intake of the first litre of bowel cleansing solution; one unit dosage of the solid product after intake of the second litre of bowel cleansing solution; one unit dosage of the solid product after intake of the third litre of bowel cleansing solution and one unit dosage of the solid product after intake of the forth litre of bowel cleansing solution.

For example, four unit dosages of the solid product are orally administered to a patient according to a fractionated schedule in the 48 hour period prior to the photodynamic diagnostic procedure as follows: two unit dosages of the solid product after intake of the first litre of bowel cleansing solution; two unit dosages of the solid product after intake of the second litre of bowel cleansing solution; two unit dosages of the solid product after intake of the third litre of bowel cleansing solution and two unit dosages of the solid product after intake of the forth litre of bowel cleansing solution.

For example, eight unit dosages of the solid product are orally administered to a patient according to a fractionated schedule in the 48 hour period prior to the photodynamic diagnostic procedure as follows: zero unit dosages of the solid product after intake of the first litre of bowel cleansing solution; two unit dosages of the solid product after intake of the second litre of bowel cleansing solution; three unit dosages of the solid product after intake of the third litre of bowel cleansing solution and three unit dosages of the solid product after intake of the forth litre of bowel cleansing solution.

For example, eight unit dosages of the solid product are orally administered to a patient according to a fractionated schedule in the 48 hour period prior to the photodynamic diagnostic procedure as follows: zero unit dosages of the solid product after intake of the first litre of bowel cleansing solution; four unit dosages of the solid product after intake of the second litre of bowel cleansing solution; four unit dosages of the solid product after intake of the third litre of bowel cleansing solution and zero unit dosages of the solid product after intake of the forth litre of bowel cleansing solution.

As a yet further example, eight unit dosages of the solid product are orally administered to a patient according to a fractionated schedule in the 48 hour period prior to the photodynamic diagnostic procedure as follows: zero unit dosages of the solid product after intake of the first litre of bowel cleansing solution; three unit dosages of the solid product after intake of the second litre of bowel cleansing solution; three unit dosages of the solid product after intake of the third litre of bowel cleansing solution and two unit dosages of the solid product after intake of the forth litre of bowel cleansing solution.

As a yet further example, four unit dosages of the solid product are orally administered to a patient according to a fractionated schedule in the 48 hour period prior to the photodynamic diagnostic procedure as follows: zero unit dosages of the solid product after intake of the first litre of bowel cleansing solution; one unit dosages of the solid product after intake of the second litre of bowel cleansing solution; one unit dosages of the solid product after intake of the third litre of bowel cleansing solution and two unit dosages of the solid product after intake of the forth litre of bowel cleansing solution.

As a yet further example, two unit dosages of the solid product are orally administered to a patient according to a fractionated schedule in the 48 hour period prior to the photodynamic diagnostic procedure as follows: zero unit dosages of the solid product after intake of the first litre of bowel cleansing solution; one unit dosages of the solid product after intake of the second litre of bowel cleansing solution; one unit dosages of the solid product after intake of the third litre of bowel cleansing solution and zero unit dosages of the solid product after intake of the forth litre of bowel cleansing solution.

As a yet further example, six unit dosages of the solid product are orally administered to a patient according to a fractionated schedule in the 48 hour period prior to the photodynamic diagnostic procedure as follows: two unit dosages of the solid product prior to the intake of the first litre of bowel cleansing solution; two unit dosages of the solid product after intake of the first litre of bowel cleansing solution; two unit dosages of the solid product after intake of the second litre of bowel cleansing solution, zero unit dosages of the solid product after intake of the third and forth litre of bowel cleansing solution.

The above indicated administration schedule can also be carried out applying also the "split" bowel cleansing procedure. In such a case, the administration of the solid product done over the two days of bowel cleansing procedure, maintaining the relevant schedule here described. As an example, eight unit dosages of the solid product are orally administered to a patient according to a fractionated schedule in the 24 hour period prior to the photodynamic diagnostic procedure as follows: three unit dosages of the solid product after intake of the first litre of bowel cleansing solution on the day before the diagnostic procedure; three unit dosages of the solid product after intake of the second litre of bowel cleansing solution on the day before the diagnostic procedure; two unit dosages of the solid product after intake of the third litre of bowel cleansing solution on the day of the diagnostic procedure and zero unit dosages of the solid product after intake of the forth litre of bowel cleansing solution on the day of the diagnostic procedure.

As an example, eight unit dosages of the solid product are orally administered to a patient according to a fractionated schedule in the 24 hour period prior to the photodynamic diagnostic procedure as follows: zero unit dosages of the solid product after intake of the first litre of bowel cleansing solution on the day before the diagnostic procedure; six unit dosages of the solid product after intake of the second litre of bowel cleansing solution on the day before the diagnostic procedure; two unit dosages of the solid product after intake of the third litre of bowel cleansing solution on the day of the diagnostic procedure and zero unit dosages of the solid product after intake of the forth litre of bowel cleansing solution on the day of the diagnostic procedure.

The photodynamic diagnostic procedures disclosed herein are aimed at the diagnosis of inflammatory, ulcerative, pre-neoplastic, dysplastic and/or neoplastic pathologies and/or alterations of the gastrointestinal tract, such as of the colon and further such as the right part of the colon. For example, the photodynamic diagnostic method disclosed herein can be aimed at the diagnosis of cancerous forms, precancerous forms, interval cancers, adenomas, carcinomas, serrated lesions, dysplasias, polyps, pseudopolyps, pre-polyps hyperplastic lesions and different inflammatory pathologies and/or lesions of the gastrointestinal tract, such as of the colon and further such as of the right part of the colon. The photodynamic diagnostic procedure of the right part of the colon can also be aimed at the diagnosis of right colon adenomas, right colon polyps, serrated adenomas and right serrated lesions or interval cancers. An interval cancer relates to lesions able to become cancers (tumors) in the time between two consecutive colon endoscopies (colonoscopies). Such time generally corresponds to a period of 2-5 years. The solid products disclosed herein can help to increase and improve the diagnosis of those small size lesions and flat lesions that are mostly missed during white light colonoscopy. As used herein, the term "small size" is a size equal to or less than 10 mm, such as equal or less than 5 mm. For example, polyps, adenomas and serrated lesion of the right colon of size less than 5 mm in diameter are considered to be "small size."

Right colon lesions are in fact considered difficult to be seen and detected in this field, because of the anatomical conformation of the colon mucosal tissues and the possibility to have an unclean mucosal surface. Those factors make it very difficult to detect such lesions in standard white light colonoscopy procedures.

Also, the smaller colon lesions are the more difficult to be identified because of the possibility to be confused with the colonic plicas. Also an unclean mucosal surface that “hides” such smaller lesions may make it difficult to detect such smaller lesions.

As disclosed herein, the photodynamic diagnostic procedures can also be used for the diagnosis of the above mentioned pathologies and/or lesions in a patient previously suffering from an inflammatory disease such as inflammatory bowel disease (IBD), ulcerative colitis (UC) or Crohn's disease. Patients suffering from the aforementioned inflammatory diseases generally have a higher risk of developing subsequent pathologies and/or lesions of the intestinal and colonic mucosa since the mucosa is affected by chronic flogistic processes that in the long-term may be associated with uncontrolled cell proliferation and neoplastic development. Particularly, the risk significantly increases at colonic level where for example colon carcinoma and/or colon dysplasia and/or intraepithelial neoplasias can more likely arise in patients with long-standing ulcerative colitis and Crohn's disease. A first advantage of the solid product disclosed herein is to provide an improved diagnostic quality in the area to be investigated, such as the colon regions (ascending, descending, rectosigmoid and transverse colon) and even further such as the right part of the colon.

This improved diagnostic quality is related to a number of different factors. First, the photosensitizing agent is homogenously delivered throughout the entire length of the lower gastrointestinal tract due to the multimatrix structure and the specific schedule of the administration of the solid product that ensures long-lasting and anatomically consistent availability of the photosensitizing agent. Second, the controlled release of the photosensitizing agent from the solid product and the time period between the administration of the solid product and the photodynamic diagnostic procedure allows for (i) the solid product to reach the target segment in the gastrointestinal tract, (ii) allow the photosensitizing agent to enter the cells, (iii) in the case the photosensitizing agent is a precursor of a photosensitizer, allow the intracellular conversion of the precursor into an active photosensitizer, and (iv) allow the photosensitizer to achieve an effective tissue concentration. All those factors contribute to a successful diagnosis.

The easier identification of diseased tissue with help of the solid product of embodiments of the invention in a photodynamic diagnostic procedure in the lower gastrointestinal tract increases specificity and sensitivity, thus reducing the occurrence of false-negatives and false-positives and allowing pathological or malignant areas to be more correctly identified and detected. As such, the solid products disclosed herein reduce subjectivity associated with common white light endoscopy, which is caused by varying levels of experience and training of the endoscopists carrying out the endoscopic procedures.

The photodynamic diagnostic methods described herein may also be performed during surgery in which the solid product is given to the patient and surgery is then performed under blue light. The fact that the lesions or disease areas fluoresce under blue light aids the surgeon in defining the "surgical border" and thereby enables a more selective resection of the diseased area, e g. a tumor, to be performed. Use of the solid products herein described in methods of surgery forms a further aspect of the invention.

The photodynamic therapeutic and diagnostic methods herein described may also be used in the form of a combined therapy. For example, a course of PDT performed in relation to a cancerous or non-cancerous condition using the solid products of embodiments of the invention in any of the methods herein described may be followed by a PDD method to determine the extent to which PDT has been effective and/or to detect any re-occurrence of the condition.

In a still further aspect the invention provides a method of photodynamic treatment or diagnosis of non-cancerous, pre-cancerous and cancerous conditions in the gastrointestinal tract, said method comprising the steps of: (a) orally administering to a patient a solid product as hereinbefore defined; (b) waiting for a time period; and (c) photoactivating the photosensitizer.

If the solid product of embodiments of the invention comprises as a photosensitizing agent a precursor of a photosensitizer, the time period in step (b) needs to be long enough to (i) allow the solid product to reach the target segment in the gastrointestinal tract, (ii) allow the precursor of photosensitizer to enter the cells, (iii) allow the intracellular conversion of the precursor into an active photosensitizer, and (iv) allow the photosensitizer to achieve an effective tissue concentration, i.e. to achieve successful treatment or diagnosis. If the solid product of embodiments of the invention comprises as a photosensitizing agent an active photosensitizer, the time period in step (b) is shorter since no time is needed for the intracellular conversion (iii).

For photodynamic therapeutic purposes, methods for irradiation of different areas of the body, e g. by LED or xenon lamps or lasers are well known in the art (see for example Van den Bergh, Chemistry in Britain, May 1986 p. 430-439). The wavelength of light used for irradiation is selected to achieve an efficacious excitation of the photosensitizer, i.e. to achieve an efficacious photosensitizing effect. Polychromatic or monochromatic light may be used. The most effective light is light in the wavelength range 300-800 nm, typically 400-700 nm where the penetration of the light is found to be relatively deep. The irradiation will in general be applied at a light dose level of 10 to 200 Joules/cm with a fluence rate of 20-200 2 2 mW/cm when a laser is used or a light dose of 10-200 J/cm with fluence rate of 50-150 mW/cm when a lamp is applied. Irradiation is performed for so many seconds needed to achieve the desired light dose with the selected fluence rate. A single irradiation may be used or alternatively a light split dose in which the light dose is delivered in a number of fractions, e.g. a few minutes to a few hours between irradiations, may be used. Multiple irradiations may also be applied.

For photodynamic diagnostic use, the area is preferably first inspected using white light, i.e. white light endoscopy. Suspicious areas are then exposed to light exciting the photosensitizer, e.g. white light or more preferably blue light, typically ranging from 400 -450 nm, especially when precursors of photosensitizers have been used. The emitted fluorescence, typically in the range of 600-650 nm is then used to selectively detect diseased tissue.

The invention will be further illustrated by the non-limiting examples below.

Examples

Example 1: Instant-release solid product Per tablet:

HAL HC1, lecithin, stearic acid and mannitol were mixed until a homogeneous mixture is obtained. Microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate and colloidal hydrated silica are added to the mixture and mixed once again. After adding magnesium stearate, the mixture is compressed into a tablets. The tablets are then transferred into a tablet mixer and coated with the above coating. The coated tablets thus obtained are subjected to a dissolution test in an acid environment for two hours, where no dissolution/degradation is observed. The tablets release HAL HC1 within a few minutes upon introduction into a neutral pH environment.

Example 2: Instant-release solid product Per tablet:

HAL HC1, lecithin, stearic acid and mannitol were mixed until a homogeneous mixture is obtained. Microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate and colloidal hydrated silica are added to the mixture and mixed once again. After adding magnesium stearate, the mixture is compressed into tablets. The tablets thus obtained are subjected to a dissolution test in an aqueous environment of neutral pH where they release HAL HC1 within a few minutes.

Example 3: Instant release solid product Per tablet:

The coated tablets are obtained as described in Example 1 and are subjected to a dissolution test in an acid environment of pH 1 where no dissolution/degradation is observed. The tablets release HAL HC1 upon introduction into an aqueous buffer of pH 6.8.

Example 4: Instant-release solid product Per tablet:

The coated tablets are obtained as described in Example 1 and are subjected to a dissolution test in an acid environment of pH 1 where no dissolution/degradation is observed. The tablets release MAL HC1 upon introduction into an aqueous buffer of pH 6.8.

Example 5: Controlled-release solid product Per tablet:

HAL HC1, lecithin, stearic acid, mannitol and half of the amount of magnesium stearate are mixed. After compacting the mixture followed by granulation, cellulose, sodium starch glycolate, colloidal silica and the remaining magnesium stearate are added and the mixture is compressed to tablets. The tablets are coated with the above-mentioned coating, so as to extend the resistance to the dissolution in vitro up to a pH > 7, characteristic of the ileocecal and colon environment.

Example 6: Controlled-release solid product Per tablet:

MAL HC1, lecithin surfactant, stearic acid and mannitol are mixed to homogeneously disperse the photosensitizing agent in the mixture. Cellulose, sodium starch glycolate, colloidal silica and the lubricant magnesium stearate are added and then, after further mixing, the final compression is carried out to obtain tablets. The tables are coated with the above-stated coating. The coated tablets resist to the dissolution in vitro in an acid environment and they dissolve at a pH > 7, characteristic of the ileocecal and colon environment.

Example 7: controlled release solid product Per tablet:

HAL HC1, lecithin, stearic acid and microcrystalline cellulose are compacted into wafers followed by dry granulation, mixing with the remaining components of the core and the final compression into tablets. The tablets are coated with the above-mentioned coating using the methacrylic acid copolymers as base and an alcohol solvent as application phase. The coated tablets thus obtained were subjected to dissolution test in vitro, revealing a good resistance to the acid environment (mimicking the stomach) and a progressive release of HAL HC1 in the neutral environment with pH at 7.2.

Example 7: Controlled release solid product Per tablet

The composition is obtained through mixing and granulation of the photosensitizing agent, the lecithin as amphiphilic component, the stearic acid as component of the lipophilic matrix, mannitol and part of the magnesium stearate. After screening the granules obtained preliminarily, the remaining components and in particular cellulose, capable of producing the hydrophilic matrix structure are added. The final tablets, obtained by compressing the mixture of powders and granules, are subjected to coating with the coating ingredients stated above, using ethylic alcohol as solvent. The coated tablets thus obtained did not dissolve/disintegrate at acid pH for 2 hours but showed a progressive dissolution for about 6 hours in a simulated intestinal medium with pH 7.2.

Example 9: Photodynamic diagnosis using the solid product of an embodiment of the invention

The coated tablet of Example 8 is used for carrying out photodynamic endoscopic diagnosis in a patient. A single coated tablet is orally administered to a patient about 12 hours before carrying out the endoscopy, during the bowel cleansing procedure step, followed by the uptake of about further 500 ml of water. The time that elapses between the administration of the tablet and the endoscopic procedure, about 12 hours, allows the tablet to reach the colon region and progressively and slowly release the photosensitizing agent, leading to a homogeneous distribution of the photosensitizing agent throughout the colon. Photodynamic diagnostic endoscopy carried out with blue light reveals more diseased areas than endoscopy with white light alone

Example 10: Photodynamic diagnosis using the solid product of an embodiment of the invention

The coated tablet of Example 8 is used for carrying out photodynamic endoscopic diagnosis in a patient. Two coated tablets are orally administered to a patient, one at the end of the bowel cleansing procedure and one about 6 hours before carrying out the endoscopy. Photodynamic diagnostic endoscopy carried out with blue light reveals more diseased areas than endoscopy with white light alone.

Example 11: Controlled-release solid product Per tablet

The composition is obtained through mixing and granulation of the photosensitizing agent, lecithin, stearic acid, mannitol and part of the magnesium stearate. After compaction and reduction into granules through screening, the remaining components of the core are added. The final tablets, obtained by compressing, are subjected to coating with the coating ingredients stated above, using ethylic alcohol as solvent. The coated tablets thus obtained resist to dissolution in vitro in buffers with pH < 2 and progressively release of the photosensitizing agent in buffers with pH > 7.

Example 12: Instant-release solid product Per tablet:

Coated tablets are obtained through the direct compression of the core ingredients, followed by coating with the coating ingredients in an aqueous solvent. The coated tablets dissolve rapidly in vitro within a few minutes and hence may be used for photodynamic endoscopic evaluations of the duodenum.

Example 13: Combined instant- and controlled release solid product Per tablet:

The following components of layer 2 were compacted: photosensitizing agent, lecithin, stearic acid, microcrystalline cellulose, mannitol and half of the magnesium stearate. The components of layer 1 are mixed and compressed. The compressed layer 1 and 2 mixtures were mixed with the remaining core components, compressed into tablets and coated. The obtained coated tablet provides for instant release of MAL HC1 in the gastric sector and subsequent controlled release of HAL HC1 in the intestinal sector.

Example 14: Controlled-release solid product Per tablet:

The photosensitizing agent, lecithin, stearic acid, mannitol and half of the magnesium stearate are mixed, compacted and granulated. The remaining core ingredients are added and, after further mixing, a final compression is carried out to obtain tablets. The tablets are coated with the coating ingredients above. The coated tablets extend the resistance to dissolution in vitro up to a pH > 7, characteristic of the ileocecal and colon environment.

Example 15: Controlled-release solid product

Per tablet:

HAL HC1, the lecithin as amphiphilic component, the stearic acid as a component of the lipophilic matrix, mannitol and part of the magnesium stearate are mixed and granulated.

After screening the granules obtained preliminarily, the remaining components of the core, such as cellulose, capable of producing the hydrophilic matrix structure, are added. The final pharmaceutical form is a tablet obtained by compressing the mixture of powders and granules. The tablets are coated with a mixture of copolymers of methacrylic derivatives of type A and B, supported by a plasticiser, i.e., triethyl citrate, by a dye pigment, i.e., titanium dioxide, and by an anti-stick agent, i.e. talc, using ethyl alcohol as a solvent. The coated tablets thus

obtained resist dissolution in vitro in buffers with pH < 2 and allow a progressive controlled release of the photosensitizing agent in buffers with pH > 7 as follows: • Dissolution of the coated tablet after 2 hours in a dissolution medium of pH 1: 0% (spec < 10%) • Dissolution of the coated tablet after 4 hours in a dissolution medium of pH 7.2: 27% • Dissolution of the coated tablet after 8 hours in a dissolution medium of pH 7.2: 84 % (spec > 80%)

Example 16: Controlled-release solid product Per tablet:

The core ingredients are mixed, compacted, granulated and compressed into tablets. The tablets obtained are coated with the coating ingredients above.

Example 17: Controlled-release solid product Per tablet:

HAL HC1, the lecithin as amphiphilic component, the stearic acid as a component of the lipophilic matrix, mannitol and part of the magnesium stearate are mixed and granulated. After screening the granules obtained preliminarily, the remaining components of the core, such as cellulose, capable of producing the hydrophilic matrix structure, are added. The final

pharmaceutical form is a tablet obtained by compressing the mixture of powders and granules. The tablets are coated with a mixture of copolymers of methacrylic derivatives of type A and B, supported by a plasticiser, i.e., triethyl citrate, by a dye pigment, i.e., titanium dioxide, and by an anti-stick agent, i.e. talc, using ethyl alcohol as a solvent. The coated tablets thus obtained resist dissolution in vitro in buffers with pH < 1 for 2 hours and allow a progressive controlled release of the photosensitizing agent in a buffer with pH 7.2 as follows: • Dissolution of the coated tablet after 1 hours in a dissolution medium of pH 7.2: 10% (spec < 30%) • Dissolution of the coated tablet after 4 hours in a dissolution medium of pH 7.2: 44% • Dissolution of the coated tablet after 8 hours in a dissolution medium of pH 7.2: more than 90% (spec > 80%)

In order to optimize the way to administer the tablets as function of the photodynamic endoscopic detection, a clinical trial is carried out with the above described tablets, using as discriminating parameter a detection scoring system composed of a number between 0 and 20 which is calculated as the sum of the individual detection score ranging 0 to 4, where 0 is no fluorescence at all, 1 is "traces”, i.e. poor fluorescence, 2 "detectable", 3 is "acceptable" and 4 is "good”, measured in the 4 segments of the colon and indicated as right or ascending colon, transverse colon, descending colon and sigma-rectum. This scoring system is used to select the most reliable administration schedule of the solid product with the aim of optimizing the administration and the lesions detection possibilities during the photodynamic colonoscopy procedure. Using the solid product of Example 17, different administration schedules are tested in a small group of patients corresponding detection score is determined. The results are as followed: • 2 tablets (tbs.) are administered before drinking the bowel cleansing solution, 2 tbs. after the first litre (L) of bowel cleansing solution and 2 tbs. after the second L. The mean detection score is 6.8±4.0 and the mean number colonic segments where fluorescence can be detected is 1.3. • 6 tablets (tbs.) are administered before drinking the bowel cleansing solution. The mean detection score is 2.3±2.4 and the mean number of colonic segments where fluorescence can be detected is 0.4. 6 tablets (tbs.) are administered at the end of the bowel cleansing procedure. The mean detection score is 8.1±3.6 and the mean number of colonic segments where fluorescence can be detected is 1.5 • 4 tablets (tbs.) are administered prior to the bowel cleansing procedure, 2 tbs. after the first litre (L) of bowel cleansing solution and 2 tbs. after the second L. The mean detection score is 7.0±5.0 and the mean number colonic segments where fluorescence can be detected is 1.3. • 8 tablets (tbs.) are administered after the bowel cleansing procedure. The mean detection score is 9.8±4.4 and the mean number of colonic segments where fluorescence can be detected is 2.3 • 2 tablets (tbs.) are administered before drinking the bowel cleansing solution, 2 tbs. after the first litre (L) of bowel cleansing solution and 2 tbs. after the second L and 2 tbs. at the end of the bowel cleansing procedure. The mean detection score is 9.3±5.4 and the mean number colonic segments where fluorescence can be detected is 2.2. • 4 tablets (tbs.) are administered after drinking the third L of bowel cleansing and 4 tbs. at the end of the bowel cleansing procedure. The mean detection score is 10.0±3.2 and the mean number colonic segments where fluorescence can be detected is 2.1. • 4 tablets (tbs.) are administered after drinking the second L of bowel cleansing and 4 tbs. after drinking the third L. The mean detection score is 11.4±3.8 and the mean number colonic segments where fluorescence can be detected is 2.8. • 2 tablets (tbs.) are administered after drinking the second L of bowel cleansing. 3 tbs. after drinking the third L and 3 tbs. after the end of the bowel cleansing procedure.

The mean detection score is 11.6±3.5 and the mean number colonic segments where fluorescence can be detected is 2.6.

Claims

Claims:

1. A solid product for oral administration comprising a photosensitizing agent and a multimatrix structure.

2. The solid product of claim 1 comprising a photosensitizing agent and a multimatrix structure comprising a) a matrix which consists of lipophilic compounds with melting point below 90 °C, and optionally amphiphilic compounds, in which the photosensitizing agent is at least partly incorporated; b) an outer hydrophilic matrix in which the lipophilic matrix, and optionally the amphiphilic matrix are dispersed; c) optionally other physiologically acceptable excipients; and d) optionally a gastro-resistant coating.

3. The solid product of claim 1 comprising a photosensitizing agent and a multimatrix structure comprising: a) a matrix which consists of lipophilic compounds with melting point below 90 °C and amphiphilic compounds in which the photosensitizing agent is at least partly incorporated; b) an outer hydrophilic matrix in which the lipophilic and optionally the amphiphilic matrix are dispersed; c) optionally other physiologically acceptable excipients; and d) optionally a gastro-resistant coating.

4. The solid product of claim 1 comprising a photosensitizing agent and a multimatrix structure comprising a) a matrix which consists of lipophilic compounds with melting point below 90 °C and amphiphilic compounds in which the photosensitizing agent is at least partly incorporated; b) an outer hydrophilic matrix in which the lipophilic and the amphiphilic matrix are dispersed; c) optionally other physiologically acceptable excipients; and d) optionally a gastro-resistant coating.

5. The solid product of claim 1 comprising a photosensitizing agent and a multimatrix structure comprising a) a matrix which consists of lipophilic compounds with melting point below 90 °C, in which said photosensitizing agent is at least partly incorporated; b) an outer matrix which consists of hydrophilic compounds and optionally amphophilic compounds, in which the lipophilic matrix, is dispersed; c) optionally other physiologically acceptable excipients; and d) optionally a gastro-resistant coating.

6. The solid product according to any of claims 2- 5 wherein the lipophilic compounds are selected from saturated, unsaturated and hydrogenated long chain alcohols, saturated and unsaturated and hydrogenated fatty acids, salts thereof, esters and amides, mono-, di- and triglycerides of fatty acids, polyethoxylated derivatives thereof, waxes, ceramides, cholesterol, cholesterol derivatives and mixtures thereof.

7. The solid product according to claim 6 wherein the lipophilic compounds have a melting point from 40 °C to below 90 °C, preferably from 60 °C to 70 °C.

8. The solid product according to any of claims 2-7 wherein the amphiphilic compounds are selected from among polar lipids of type I and II, lecithin, phosphatidylcholine, phosphatidylethanolamine, and mixtures thereof, ceramides, glycol alkyl ethers, diethylene glycol monomethyl ether, alkylsulfate and alkylsulfosuccinate salts, and mixtures thereof

9. The solid product according to any of claims 2-8, wherein the hydrophilic compounds are selected from compounds forming hydrogels.

10. The solid product according to claim 9, wherein the compounds forming hydrogels are selected from polymers and copolymers of acrylic acid, copolymers of methacrylic acid, alkyl vinylpolymers, alkyl celluloses, hydroxyalkyl celluloses, carboxyalkyl cellulose, modified and/or plurisubstituted celluloses, polysaccharides, dextrins, pectins, starches, complex starches and starch derivatives, alginic acid, synthetic rubber, natural rubber, polyalcohols and mixtures thereof.

11. The solid product of any of the preceding claims comprising a gastro-resistant coating.

12. The solid product of claim 11, wherein the gastro-resistant coating comprises compounds selected from polymers of acrylic acid, polymers of methacrylic acid, copolymers of acrylic acid and/or copolymers of methacrylic acid, cellulose derivatives such as for example cellulose acetate phthalate, hydroxybutyrate-based polymers, shellac and mixtures thereof.

13. The solid product according to any of the preceding claims wherein the photosensitizing agent is a photosensitizer.

14. The solid product according to any of claims 1-12 wherein the photosensitizing agent is a precursor of a photosensitizer.

15. The solid product according to claim 14 wherein the precursor of a photosensitizer is 5-ALA or a derivative of 5-ALA or a pharmaceutically acceptable salt thereof.

16. The solid product according to claim 15, wherein the precursor of a photosensitizer is a 5-ALA ester or a pharmaceutically acceptable salt thereof.

17. The solid product of according to any of the preceding claims for use in the photodynamic treatment or photodynamic diagnosis of non-cancerous, pre-cancerous and cancerous conditions in the gastrointestinal tract.

18. The solid product according to claim 17 for use in the photodynamic treatment or photodynamic diagnosis of non-cancerous, pre-cancerous and cancerous conditions in the upper gastrointestinal tract, preferably for use for use in the photodynamic diagnosis of non-cancerous, pre-cancerous and cancerous conditions in the upper gastrointestinal tract.

19. The solid product according to claim 17 for use in the photodynamic treatment or photodynamic diagnosis of non-cancerous, pre-cancerous and cancerous conditions in the lower gastrointestinal tract, preferably for use for use in the photodynamic diagnosis of non-cancerous, pre-cancerous and cancerous conditions in the lower gastrointestinal tract.