CN103118742B - For photodynamic therapy or the dry compositions of photodynamic diagnosis and the device containing this dry compositions - Google Patents

Abstract

The present invention relates to comprise the pharmaceutical composition being dried of effective ingredient, described effective ingredient is 5 amino-laevulic acids (5 ALA) or the precursor of 5 ALA or derivant, or its pharmaceutically acceptable salt.Described compositions can be used in photodynamic therapy (PDT) or the photodynamic diagnosis (PDD) of cancer, pre-cancerous condition and non-canceration situation.The invention further relates to comprise the irradiation unit of dry compositions and this device photodynamic therapy (PDT) under cancer, pre-cancerous condition and non-canceration situation or the purposes in photodynamic diagnosis (PDD).

Description

For photodynamic therapy or the dry compositions of photodynamic diagnosis with containing this The device of dry compositions

Technical field

The present invention relates to comprise the pharmaceutical composition being dried of effective ingredient, described effective ingredient is 5- Amino-laevulic acid (5-ALA) or the precursor of 5-ALA or derivant or it is pharmaceutically acceptable Salt.Described compositions can be used for photodynamic therapy (PDT) or photodynamic diagnosis (PDD) In, it is preferred in PDT or PDD of cancer, pre-cancerous condition and non-canceration situation.This Bright further to comprising the irradiation unit of dry compositions and this device before cancer, canceration Photodynamic therapy (PDT) under situation and non-canceration situation or photodynamic diagnosis (PDD) In purposes.

Background technology

Photodynamic therapy (PDT) is treatment precancerous lesion, cancer and the one of non-canceration disease Plant the newest technology.PDT relates to using photosensitizer or its precursor to target area.Described photosensitive Agent or its precursor are ingested in entrance cell, and in cell, the precursor of photosensitizer is converted to photosensitizer. Once target area is by illumination, and the most described photosensitizer is excited, it will usually become from ground state singlet state Excited singlet state.It is then passed through intersystem crossing and becomes the excited triplet state of longer-term.Tissue has One in several chemical substances of ground state triplet is molecular oxygen.When described photosensitizer and oxygen molecule Close to time, it may occur that energy shift so that described photosensitizer is back to its ground state singlet state, generate The oxygen molecule of excited singlet state.Singlet oxygen is that one has an invasive chemical substance very much, can be with Biomolecule near any occurs very rapidly to react.Finally, these destructive reaction meetings Kill cell by apoptosis or necrosis, such as, by this reaction, cancerous cell can be selected Selecting property is killed.This mechanism is the most not exclusively understood, but research shows, result clinically is the most right Selectivity in cancerous cell is not due to the selectivity picked-up of cancerous cell and is caused.On the contrary, exist In all cells type, the level of picked-up is much like, but in malignant cell and generally in generation Thank to its process converting and eliminating in active cell (such as inflammatory cell or infected cell) Difference, thus between cancerous issue and normal structure, form Concentraton gradient.

The most known and describe several photosensitizer, including 5-ALA (5-ALA) And some derivant, such as 5-ALA ester.5-ALA and 5-ALA ester is the precursor of photosensitizer, Photosensitizer, i.e. protoporphyrin, such as protoporphyrin IX (PpIX) can be converted into.At present, have several Plant containing 5-ALA or medicine just being used clinically at PDT of its ester.One therein isIt is a kind of emulsifiable paste to comprise 5-ALA methyl ester skin products (Switzerland Gao De as form Company of U.S.), for actinic keratosis and the photodynamic therapy of basal cell carcinoma.Another kind is Levulan(Canada DUSA Pharmaceutical), be a kind of comprise 5-ALA for light Change the product of the photodynamic therapy of seborrheic keratosis.

Cervical the most serious a kind of infection is infected by human papillomavirus (HPV), this meeting Develop into cervical cancer.HPV infection is in the evolution of almost all of cervical cancer case Common factor.Estimation to the sickness rate of HPV infection is different, but logical in all women It is often about 30%.Recently, HPV vaccine is had been developed for, such asWith But, cervical cancer remains life-threatening a kind of disease.Owing to there is no symptom in early days in cancer, Until cancer development just there will be to late period, the most unfortunately, cancer is the most just diagnosed Go out.One possible early stage symptom of cervical cancer is vaginal hemorrhage.Cervical cancer is based on living tissue Inspection program is diagnosed.Main Therapeutic Method is operation, but, can this disease late period To use radiotherapy and chemotherapy.The prognosis of the patient suffering from cervical cancer is depended on being diagnosed Time disease stage.HPV infection can also affect other parts of female reproductive system, such as cloudy Road, and this infection can develop into cancer of vagina.Multi-infection site, such as vagina and cervix uteri It is all possible.

Cervical intraepithelial neoplasia (CIN) (CIN), also referred to as cervical dysplasia, is a kind of The possible premalignant transformation of squamous cell and misgrowth at cervical surfaces.Relatively Answering, tumor-like lesion in vagina epithelium (VAIN), also referred to as vagina abnormal development, be in vagina A kind of possible premalignant conversion of squamous cell and misgrowth, usually occur in vagina (may merge with cervical lesions) at top 1/3.Most of this dysplastic situations keep Stable, or removed by the immune system of health in the case of without interventional therapy.But, If without treatment, there is the situation of very small scale can develop into cancer, usually squamous cell carcinoma (SCC).The main cause of CIN and VAIN is the HPV16 by HPV, especially high risk Or 18 chronic infections of organ or tissue of type impact.

Identify more than 100 kinds of HPV.In these HPV type, about a dozen look Cervical dysplasia can be caused and be likely to result in the appearance of cervical cancer.For CIN, Under microscope early, change is Cervical epithelium or the abnormal development of epidermis tunicle, and this is the most not May be awared by women.The cellular change relevant with HPV infection, the most recessed ghost, also Would generally see in CIN.CIN is generally by Screening tests Papanicolaou or " Pasteur " smear Found, the most diagnosable VAIN of this Screening tests.The purpose of these tests is change to be detected earlier Change, and this change invasive carcinoma of vulva that develops into the most useless, it is easier to treatment.Abnormal pap smear Can the recommended colposcopy carrying out cervix uteri and/or vagina, in this inspection, can to organ and Tissue is amplified checking.Acetum or iodine solution can be added, to improve exceptions area to surface The image in territory.Any unusual appearance region is all carried out tissue biopsy because cervix uteri and The abnormal development of vagina can be diagnosed by the histology of biopsy specimen.

Need to cut or destroy Cervical sufferer for treating the method for above-mentioned intraepithelial neoplasia Epithelium, including deformed region and vagina.These methods include excision, cold cautery, electricity irons, laser irons, Loop Electrosurgical Excision Procedure (cervix uteri) and cervix uteri laser electrotomy.All these described methods are equal Likely have a side effect, such as (cervix uteri) constriction, infringement are become pregnant, cervical incompetence, Premature labor, baby's birth weight are relatively low, infect and hemorrhage.This process can cause patient anxiety, therefore Medically the tissue reservation treatment to this intraepithelial neoplasia has needs.PDT is demonstrate,proved Being exactly such a kind of selection in fact, the patient treated through the method shows good response rate.

In the PDT of CIN, 5-ALA and 5-ALA ester is all used.K.Bodner et al., Anticancer Res(anticancer research) 2003,23(2C): 1785-1788 employs a kind of containing Containing 5-ALA(12%w/v in 0.9%NaCl aqueous solution 1%EDTA(w/v)) solution. 5-ALA solution will be prepared before will carrying out PDT shortly.A.Barnett et al., Int.J.Cancer(state Border Journal of Cancer), 103,829-832(2003) employ a kind of at clear good gel The 3% or 5%(w/w of middle 5-ALA) solution, this solution to be prepared before using at once. Clear that good gel is a kind of hydrogel, comprise modified carboxy methyl cellulose (CMC) polymerization of 2.3% Thing and propylene glycol (20%) are as wetting agent and preservative.P.Hillemanns et al., Int.J.Cancer:81,34-38(1999) employ a kind of 5-ALA hydrochlorate, 5-ALA hydrochlorate Dissolved in aseptic 0.9%NaCl aqueous solution by fresh, final concentration of 20%(w/w), containing third Glycol, and use NaHCO₃By pH regulator to 5.5.P.Soergel et al., Lasers in Surgery and The application in surgery and medicine of the Medicine(laser) 40:611-615,2008 employ 5-ALA Hexyl ester, uses with the dosage form of heat setting glue.Employ Lutrol F-127(biology of powder Adhesion poloxamer) as hot gel base, described heat setting glue must pass through at site of administration Add sterilized water and prepare.The described 5-ALA hexyl ester containing heat setting glue must be the freshest Preparation.

As seen above, owing to the stability of these compounds is limited, at the PDT of CIN Time need to use the formula of freshly prepared 5-ALA and 5-ALA ester, this in turn limit them The shelf-life existed with drug form.

Have employed the most different countermeasures with the problem overcoming this stability: have been developed over Show the formula of the stability of raising, or, preparation is transported under cold conditions and store.

WO2010/142457 discloses a kind of semisolid compositions, is used for treating female reproductive system Intraepithelial neoplasia in system.This semi-solid dosage form (such as, ointment, paste, breast Unguentum or gel) show the stability being obviously enhanced.WO2009/074811 discloses one Plant solid medicine, the cancer in female reproductive system and the non-canceration shape being similar to HPV infection The PDT of condition.Described solid medicine can use with the form of suppository or vaginal suppository, and shows The stability strengthened.A kind of cream form containing 5-ALA methyl ester, is stored at cold Under the conditions of.

But, these methods have shortcoming.Such as, frequently not easily transport under cold conditions With storage medicine.

Have been developed for now irradiation unit for PDT with the cancer in treatment cervix uteri, canceration Front situation and non-canceration situation, i.e. HPV infection and CIN, see Photocure ASA(optics Treatment company) WO2010/078929.Described irradiation unit is fully inserted in vagina, and it is controlled Treat surface and cover cervix uteri top and cervical orifice.This device can be independent time inserted into the patient Operation.This device contains the district holding medicine (such as containing photosensitizer or the compositions of its precursor) Territory.This device can be combined with the semi-solid combination described in WO2010/142457: half Solid composite be applied on this device for holding at the region of medicine, by this device with Medicine is inserted in vagina and is placed on treatment site, such as on uterine cervix.

PDT device complete, ready-to-use, i.e. the PDT device containing medicine as above are provided, Can ensure that medicine uses with Exact concentrations, which ensure that the success for the treatment of.This includes cancer in treatment Particular importance during most of disease of disease, uses correct and effective therapeutic dose when treatment of cancer The most crucial.And, PDT device complete, ready-to-use is the most convenient to doctor, so they Just need not the cost time before this device is used for patient by medicament administration to described device Hold on the region of medicine.

Accordingly, it would be desirable to the formula of replacement of a kind of 5-ALA and 5-ALA ester and containing therefore The medicine of 5-ALA and 5-ALA ester, for cancer, pre-cancerous condition and the PDT of non-canceration situation, It is preferred for HPV infection, the PDT of the HPV infection of such as cervix uteri and vagina.

Summary of the invention

We have now surprisingly found that, containing effective ingredient 5-ALA or derivatives thereof (such as ALA Ester) dry compositions be suitably employed in cancer, pre-cancerous condition and the photodynamics of non-canceration situation In treatment.This dry compositions can cover/be arranged in by forming thin film or thin layer for holding The mode in the region of medicine contained in light-emitting device is made, and wherein said light-emitting device is i.e. for light Irradiation unit in photodynamic therapy.This device such as can be sealed to gas-tight and damp proof, from And described device and be contained in the storage at room temperature of the medicine contained by the dry compositions in described device The Tibetan life-span is the longest, the most up to 5 years.This device adds dry compositions and is easy to health officer behaviour Make.In use, described device adds medicine and is placed in treatment site.This treatment site refers to Be people or inhuman animal bodies body cavity in the environment of any humidity, i.e. mucosal pattern shape table Face, such as, be positioned at mucosal pattern shape surface in cervix uteri, vagina, rectum, anus, nose or ear. After once touching the region containing the dry compositions containing effective ingredient of described device/described device, Water and liquid in mucosa can react with dry compositions, make described dry compositions disintegrate/dissolving, Thus discharge effective ingredient, absorbed by cell, change into activated photosensitizer, formed former Porphyrin (PpIX).When reaching to treat effective PpIX level, the most described device is activated, and sends out Go out light for photodynamic therapy.Irradiation unit containing this dry compositions and this be dried Compositions can be used for cancer, pre-cancerous condition and the photodynamic diagnosis of non-canceration situation (PDD).

Therefore, from the point of view of first aspect, the invention provides a kind of for photodynamic therapy or light The irradiation unit of dynamical diagnosis, described device is containing at the region of pharmaceutical composition for holding The pharmaceutical composition being dried, wherein said dry pharmaceutical composition includes:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；

B) optional one or more polymer, described polymer have good filming performance and/ Or good gel-forming property；And

C) optional other pharmaceutically acceptable excipient.

In preferred embodiments, the invention provides a kind of irradiation for photodynamic therapy to fill Putting, described device is containing dry pharmaceutical composition for holding at the region of pharmaceutical composition, Wherein said dry pharmaceutical composition includes:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；

B) optional one or more polymer, described polymer have good filming performance and/ Or good gel-forming property；And

C) optional other pharmaceutically acceptable excipient.

In a further preferred embodiment, the invention provides a kind of for cervix uteri, vagina, Before the cancer of rectum, anus, nose or ear, canceration and the photodynamic therapy of non-canceration situation or The irradiation unit of photodynamic diagnosis, described device is for containing bag at the region of pharmaceutical composition Including dry pharmaceutical composition, wherein said dry pharmaceutical composition includes:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；

B) optional one or more polymer, described polymer have good filming performance and/ Or good gel-forming property；And

C) optional other pharmaceutically acceptable excipient.

In a further preferred embodiment, present invention provide for cervix uteri, vagina, rectum, Before the cancer of anus, nose or ear, canceration and non-canceration situation photodynamic therapy irradiation dress Put, described device for containing the pharmaceutical composition including at the region of pharmaceutical composition being dried, Wherein said dry pharmaceutical composition includes:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；

B) optional one or more polymer, described polymer have good filming performance and/ Or good gel-forming property；And

C) optional other pharmaceutically acceptable excipient.

Although the pharmaceutical composition described in the present invention should be substantially free of any solvent (such as water) It is preferred but it also may containing residual solvent.Therefore term " is dried " and should do corresponding solution Release.Preferably compositions is substantially free of solvent, such as according to any one side described in the invention Method is preparation-obtained.These methods need not to be directed to use with any be reduced or eliminated further any The subsequent processes of residual solvent.As described above, the use of dry compositions ensure that described Device (containing described compositions) has longer shelf-life.Described device is in dry environments Packaging and storage are also critically important.

Term " pre-cancerous condition " if referring to the most treated, can become cancer disease, Syndrome or discovery, such as abnormal development and neoplasia.

The Abnormal damage that term " non-canceration situation " includes not or low deterioration is possible, such as hypertrophy and Minor injury, infects, such as virus, antibacterial or fungal infection, preferably HPV infection, or scorching Disease.

Term " effective ingredient " represents 5-ALA and pharmaceutically acceptable salt, the precursor of 5-ALA And pharmaceutically acceptable salt and the derivant of 5-ALA and pharmaceutically acceptable salt thereof.

Term " 5-ALA " represents 5-ALA, i.e. 5-amino-4-oxygen-valeric acid.

Term " precursor of 5-ALA " represent through compound that metabolic conversion is 5-ALA and therefore with Its compound being substantially equal to.Therefore term " precursor of 5-ALA " covers the conjunction of haemachrome biology The bio-precursors of protoporphyrin in the metabolic pathway become.

Term " derivant of 5-ALA " represents the 5-ALA through chemical modification, i.e. through chemically derived 5-ALA, replacing or further the adding of chemical group of described chemically derived such as chemical group Become to modify or change its any physicochemical property (such as solubility or lipophile).Chemically derived Preferably take place 5-ALA carboxylic group, the amino group of 5-ALA or the oxo group of 5-ALA On, it is more highly preferred to occur on the carboxylic group or amino group of 5-ALA.Preferably derivant bag Include the ester of 5-ALA, amide and ether, most preferably 5-ALA ester.

Term " pharmaceutically acceptable salt " represents the medicine being suitable for being dried and meets and example As safety, bioavailability and toleration about etc. requirement salt (see for example P.H.Stahl etc. People's (editor) pharmacy salt handbook, the chemistry publication of Zurich Switzerland, 2002).

The irradiation unit of the present invention be preferably all and be fixedly inserted into health cavity (such as nose, Vagina, anus, ear or rectum) in and can independently operate when being positioned in described cavity Device.In a preferred embodiment, except in addition to holding the region of described pharmaceutical compositions, Described irradiation unit also includes for shell that is fully-inserted and that be fixed in cavity, described shell bag It is wound with LED lamp system and for the power supply for described LED lamp system energy supply.This device is in example Describing as in WO2010/078929, therefore the content of the document is fully incorporated in the application.

Preferably, described device farther include treat surface, i.e. install described LED lamp system with Sending the surface of radiation, irradiation is guided and/or focuses on by described treatment surface needs photodynamics to control At concrete region in the cavity treated or diagnose.For holding the district of described dry pharmaceutical composition Territory is preferably area for treatment itself, or for accommodating the medicine being dried contained in described device The reservoir of compositions.

Such as, described device cancer, pre-cancerous condition and non-canceration shape in vagina or rectum The PDT of condition.Fig. 5 A and 5B that the shape of this device is preferably similar in WO2010/078929 Device, i.e. include containing cone or the elongate housing of domed ends.Described elongate housing is along it Outer peripheral face includes a treatment surface, and this treatment surface and the contact internal walls of vagina/rectum, with to institute State inwall to be irradiated.That described treatment surface may or may not be stricture of vagina and hold described dry Pharmaceutical composition.This device is more suitable for so that its size and dimension is less inserting nose or ear In piece.

Citing further, described device is for Cervical cancer, pre-cancerous condition and non-canceration shape The PDT of condition.The shape of this device is preferably similar to Fig. 1-3 and 6-7 of WO2010/078929 Device, i.e. include a top housing section, shape be about cone, its front end constitute one Individual treatment surface, treatment surface is designed to can cover in use uterine cervix and cervical orifice Shape, so described region can be irradiated.Described treatment surface constitutes one for holding Receive the reservoir of dry pharmaceutical composition.

In one embodiment, described dry pharmaceutical composition is powder, i.e. by substantial amounts of Dry, the blocks of solid of the finest granule composition, more preferably the powder of compression, i.e. loses Remove fluid ability.In another embodiment, described dry pharmaceutical composition is pie, i.e. Form the dry blocks of solid of fritter.In a preferred embodiment, described dry medicine group Compound is film like, i.e. the material being dried/being dried of one or more layers (thin layer), is preferably basic The relatively uniform thin film on upper covering whole treatment surface.In further preferred embodiment, should Thin film attaches and keeps being excellently attached to described treatment surface well, is i.e. maintained at transport and dress Under the mechanical pressure being likely to occur during the described irradiation unit containing the pharmaceutical composition being dried of fortune it is Metastable.

Dry pharmaceutical composition can be deposited on Sheng by any by described dry pharmaceutical composition Put the method in its region (being hereinafter also referred to as " deposition region ") and obtain and be deposited on described On device.

In one embodiment, described dry pharmaceutical composition can be by known in the art Method for coating film, is preferably made by dip-coating (dip-coating) or spraying (spray-coating) Become thin film.

Immersion technique is described as being to immerse in liquid, then controlled by base material to be coated Carry out a kind of method lifted with clear and definite pull rate at temperature and atmospheric condition.Coating thickness master To be determined by pull rate, the solid content of liquid and viscosity.In dip-coating method, the present invention The deposition region of device be dipped in liquid, i.e. effective ingredient and optionally one or more polymerizations Thing and/or other pharmaceutically acceptable excipient are dissolved in the solution in one or more suitable solvents Or dispersion.Described deposition region is lifted from liquid, so that liquid deposition.Described lifting Preferably carrying out down, to generate consistent coating.Concomitantly, the liquid of excess is by from deposition The surface in region is discharged.Solvent evaporates from liquid, forms thin film.This method can be by adding Heat and accelerate.For volatile solvent, such as lower alcohols, during deposition and discharge step just Have begun to evaporation.Dip-coating be particularly suitable for including circumferentially face include treating surface elongated outside The device of shell, such as shown in Fig. 5 A and 5B of WO2010/078929 device.Will The device accommodating the pharmaceutical composition being dried being achieved in that is sealed in airtight/damp proof bag. Alternatively, will be used for holding the region overlay/sealing of dry pharmaceutical composition, so that at this It is damp proof.

Spraying relate to passing through spray gun so that liquid, i.e. effective ingredient and optionally one or more gather It is molten that compound and/or other pharmaceutically acceptable excipient are dissolved in one or more suitable solvents Liquid or dispersion, spray or be atomized, and is coated the deposition region of assembly of the invention. Preferably, spray gun can be by level, vertically and angularly regulate, it is also possible to rotates.Can make With heater to add the evaporation of quick-dissolving agent.Spraying is suitable for the treatment surface containing circumferentially face or storage Store the device of device.The described device of the pharmaceutical composition being dried being achieved in that will be accommodated, or If described device is made up of module, by described module sealing in airtight/damp proof bag. Alternatively, will be used for holding the region overlay/sealing of dry pharmaceutical composition, so that at this It is damp proof.

In another embodiment, described dry pharmaceutical composition is obtained by solvent evaporation. By by effective ingredient and optionally one or more polymer and/or other pharmaceutically acceptable taxes Shape agent is dissolved in or is suspended in one or more suitable solvents and prepares liquid, wherein said conjunction Suitable solvent preferably has lower boiling solvent, such as lower alcohols, ethers etc..Will so The liquid obtained is applied at deposition region, such as, load in reservoir.By described device, or If described device is made up of module, the module containing deposition region is heated one section and be enough to reality The time that existing solvent all evaporates.Within this period, described device can be moved, such as by Rotate, to promote evaporation, it is ensured that being uniformly distributed of liquid.According to the parameter of evaporation, such as temperature And humidity, and it is applied to the amount of liquid at the deposition region that gives, obtain film like or cake The pharmaceutical composition being dried of shape.To accommodate described in the pharmaceutical composition being dried being achieved in that Device is if described device is made up of module, airtight/anti-at one by described module sealing In wet bag.Alternatively, will be used for holding the region overlay/sealing of dry pharmaceutical composition, thus Make to be damp proof at this.

In a preferred embodiment, described dry pharmaceutical composition is obtained by lyophilization. In brief, usual lyophilization is made up of three steps: freezing, primary dry and secondary is dried.First By liquid, i.e. treat that the solution of the compound of lyophilizing or suspension are freezing.Generally cryogenic temperature be-50 to -80 DEG C, this depends on the solvent used.During first drying stage, reduce pressure, to cold The liquid frozen provides enough heats so that solvent (typically water) distils.It is dried rank in secondary Section, the solvent molecule not being lyophilized is removed.In order to by lyophilization obtain the present invention be dried Pharmaceutical composition, can be by by effective ingredient and optional one or more polymer and/or optional Other pharmaceutically acceptable excipient be dissolved in or be suspended in suitable solvent (typically water) And prepare liquid.It is also possible, however, to use mixed solvent, such as water and alcohols such as ethanol. The liquid being achieved in that is applied at deposition region, such as, loads in reservoir.Described in application During liquid, described device can be cooled and/or mobile, such as, rotated.By described device, If or described device is made up of module, the module containing deposition region is freezing, such as Quick freeze is to avoid generating bigger crystal.Then by described device or module as described above Carry out lyophilizing.The described dry pharmaceutical composition obtained is usually pie, powder (can be by Further compression) or preferably film like.The pharmaceutical composition being dried being achieved in that will be accommodated Described device, if described device is formed described module sealing impermeable at one by module In gas/damp proof bag.Alternatively, will be used for holding the region overlay/sealing of dry pharmaceutical composition, So that be damp proof at this.

Concrete equipment for dip-coating, spraying and lyophilizing can be commercially available.

5-ALA and the purposes of derivant thereof, such as 5-ALA ester purposes in PDT and PDD Known to science and patent documentation are, for example, see WO2006/051269, WO 2005/092838、WO03/011265、WO02/09690、WO02/10120、WO 2003/041673 and US6,034,267, the content of these documents be incorporated into herein by reference as. The derivant of all these 5-ALA and pharmaceutically acceptable salt thereof are suitable for being retouched in this article The method stated.

The synthesis of 5-ALA is known in the art.Additionally, 5-ALA and pharmaceutically acceptable Salt can be commercially available, such as, buy from Sigma Aldrich.

5-ALA derivant for the present invention can be can to form protoporphyrin in vivo, such as PpIX, or the derivant of any 5-ALA of PpIX derivant.Generally, these derivants can be Before PpIX or PpIX derivant (the such as PpIX ester in the biosynthesis pathway of haemachrome) Body, therefore these derivants can be applied to the internal rear accumulation inducing PpIX.Suitably PpIX Or the precursor of PpIX derivant includes 5-ALA prodrug, 5-ALA prodrug likely can shape in vivo Become the 5-ALA of the intermediate as biosynthesis PpIX, or can be turned by such as enzymatic reaction Change porphyrin into and be formed without the 5-ALA as intermediate.5-ALA ester and pharmaceutically acceptable Salt belong to the preferred compound used in the present invention being described herein as.

The most in a preferred embodiment, the invention provides one for photodynamic therapy Or the irradiation unit of photodynamic diagnosis, described device contains in the region being used for holding pharmaceutical composition Dry pharmaceutical composition, wherein said dry pharmaceutical composition is had to include:

A) effective ingredient, described effective ingredient selected from the derivant of 5-ALA or its pharmaceutically can connect The salt being subject to, preferably 5-ALA ester or its pharmaceutically acceptable salt；

B) optional one or more polymer, described polymer have good filming performance and/ Or good gel-forming property；And

C) optional other pharmaceutically acceptable excipient.

The ester of the optional substituted 5-ALA of N-is preferred in the present invention.5-amino is unsubstituted Those compounds, i.e. 5-ALA ester is particularly preferred.These compounds are known in the literature And be described, for example, see WO96/28412 and WO02/10120 of optical therapeutic company, WO03/041673, and N.Fotinos et al., photochemistry and photobiology, 2006:82, 994-1015, the content of these documents be incorporated into herein by reference as.

The ester generated with unsubstituted or the reaction of alkanol that is replaced by 5-ALA, i.e. Arrcostab and The Arrcostab being replaced, and its pharmaceutically acceptable salt, be used in the present invention the most excellent The derivant of the 5-ALA of choosing.The example of these preferred 5-ALA esters includes compounds of formula I And pharmaceutically acceptable salt:

R² ₂N-CH₂COCH₂-CH₂CO-OR¹(I)

Wherein

R¹Represent substituted or unsubstituted alkyl；With

R²Each expression hydrogen atom or R independently¹Group

Unless stated otherwise, otherwise terminology used in this article " alkyl " includes any long-chain or short Chain, ring-type, straight or branched is saturated or undersaturated aliphatic hydrocarbon groups.Undersaturated alkyl can Unsaturated or polyunsaturated, including alkenyl and alkynyl group to be list.Unless stated otherwise, Otherwise these alkyl can at most contain 40 carbon atoms.However, it is preferred that alkyl is at most containing 30 Carbon atom, preferably up to containing 10, particularly preferably at most containing 8, particularly preferably up to containing 6 Carbon atom.

In the compound of Formulas I, R¹Group is substituted or unsubstituted alkyl.If R¹It is The alkyl being replaced, the most one or more substituent groups can be connected with this alkyl and/or by between this alkyl Separate.The suitable substituent group being connected with described alkyl is selected from hydroxyl, alkoxyl, acyloxy, alkane Epoxide carbonyloxy group, amino, aryl, nitro, oxo group, fluorine ,-SR³、-NR³ ₂With-PR³ ₂, its Middle R³For hydrogen atom or C_1-6Alkyl.It is spaced the suitable substituent group of described alkyl selected from-O-,-NR³-、 -S-or-PR³。

In a preferred embodiment, R¹By one or more aryl substituents, i.e. aryl base The substituted alkyl of group.Preferably, R¹The alkyl replaced by an aromatic yl group.

Terminology used in this article " aromatic yl group " represents can be containing maybe can not containing hetero atom The aromatic group of (such as nitrogen, oxygen or sulfur).Preferably without heteroatomic aromatic yl group.Preferably virtue Base group comprises most 20 carbon atoms, more preferably up to 12 carbon atoms, such as 10 or 6 Individual carbon atom.Preferably the embodiment of aromatic yl group is phenyl and naphthyl, especially phenyl.This Outward, aromatic yl group is the most one or more, and more preferably one or two substituent group is taken Generation.Preferably, aromatic yl group, in meta or para position, is most preferably replaced in para-position.Suitably take Dai Ji includes alkylhalide group (such as trifluoromethyl), alkoxyl (the preferably alkane containing 1-6 carbon atom Epoxide), halogen (such as iodine, bromine, chlorine or fluorine, preferably chlorine and fluorine), nitro and C_1-6Alkyl is (excellent Elect C as_1-4Alkyl).Preferably C_1-6Alkyl includes methyl, isopropyl and the tert-butyl group, particularly first Base.Particularly preferred aryl substituent is chlorine and nitro.But, it is more preferred to aromatic yl group Unsubstituted.

The substituted R of this aryl¹Group is preferably benzyl, 4-isopropylbenzyl group, 4-methylbenzene first Base, 2-methylbenzyl, 3-methylbenzyl, 4-[tert-butyl group] benzyl, 4-[trifluoromethyl] benzene first Base, 4-methoxybenzyl, 3,4-[two-chlorine] benzyl, 4-chlorophenylmethyl, 4-benzyl, 2-fluorine Benzyl, 3-benzyl, 2,3,4,5,6-pentafluoro-benzyl, 3-Nitrobenzol methyl, 4-nitrobenzoyl Base, 2-phenethyl, 4-benzene butyl, 3-pyridyl-methyl, 4-diphenyi-methyi and benzyl-5-[(1- Acetoxyethoxy)-carbonyl].This R being more highly preferred to¹Group is benzyl, 4-isopropylbenzene Methyl, 4-methylbenzyl, 4-Nitrobenzol methyl and 4-chlorophenylmethyl.Most preferably benzyl.

If R¹Being the alkyl being replaced, the most one or more oxygen substituent groups are preferred.Preferably, These groups are by one or more oxo groups, the straight chain preferably replaced by one to five oxo groups C_4-12Alkyl.Oxo group is positioned in the alkyl being replaced the most in alternating order, i.e. generates short Polyethylene Glycol substituent group.These group preferred embodiments include 3,6-dioxy-1-octyl and 3,6,9- Three oxygen-1-decyls.In a further preferred embodiment, R¹By between one or more oxygen atoms institute The alkyl (ether or polyether group) separated, preferably straight chain C_4-12Alkyl, more preferably by 1-4 The straight chain C that oxygen atom is spaced apart_6-10Alkyl, more preferably straight chain polyethylene group (-(CH₂)₂-O-) n, n be the integer of 1 to 5.

If R¹It is unsubstituted alkyl, then R¹Group is preferably saturated straight or branched alkyl. If R¹It is saturated straight chained alkyl, then C_1-10Straight chained alkyl is preferred.Suitably straight chained alkyl Representative example include methyl, ethyl, n-pro-pyl, normal-butyl, n-pentyl, n-hexyl and just Octyl.Particularly preferably C_1-6Straight chained alkyl, the most particularly preferably methyl and n-hexyl. If R¹Being saturated branched alkyl, this branched alkyl is preferably individual by 4-8, preferably by 5-8 The trunk composition of carbons, described trunk is by one or more C_1-6Alkyl, preferably by C_1-2 Alkyl branch.The example of this saturated branched alkyl includes 2-methyl amyl, 4-methyl amyl, 1- Ethyl-butyl and 3,3-dimethyl-1-butyl.

In the compound of Formulas I, each R²Represent hydrogen atom or R independently¹Group.Particularly preferably For the present invention is at least one R in Formulas I²Represent those compounds of hydrogen atom.The most excellent In the compound of choosing, each R²Represent hydrogen atom.

Preferably, the compound of Formulas I and pharmaceutically acceptable salt thereof are used as being dried of the present invention Effective ingredient in pharmaceutical composition, wherein R¹It is methyl or hexyl, more preferably n-hexyl and two Individual R²All represent hydrogen, i.e. 5-ALA methyl ester, the own ester of 5-ALA and pharmaceutically acceptable salt thereof, It is preferably hydrochlorate.The change of the effective ingredient being preferably used as in the pharmaceutical composition being dried of the present invention Compound is the own ester of 5-ALA and pharmaceutically acceptable salt, preferably hydrochlorate or sulfonate or sulphur Acid derivative salt.

5-ALA ester and pharmaceutically acceptable salt thereof for the present invention can be by existing in this area Any conventional method be prepared, such as at WO96/28412, WO02/10120, WO 03/041673 and in N.Fotinos et al., photochemistry and photobiology 2006:82,994-1015 and The method described in its list of references quoted.Inventionbriefly, 5-ALA ester can be by inciting somebody to action 5-ALA and suitable alcohol are at catalyst, such as in the presence of acid, reaction prepares.5-ALA ester Pharmaceutically acceptable salt can by method described above by pharmaceutically acceptable 5-ALA salt, such as 5-ALA hydrochlorate and suitable alcohol react and prepare.Optional for the present invention Compound, such as 5-ALA methyl ester or the own ester of 5-ALA, can from the market, such as from Norway Optical therapeutic company buys.

5-ALA ester for the present invention can be to be the form of unhindered amina, such as-NH₂、-NHR²Or -NR²R²Or the form of preferably pharmaceutically acceptable salt.These salt is preferably with pharmaceutically connecing The organic or inorganic acid being subject to carries out the salt of acid adduction.Suitably acid includes, such as, hydrochloric acid, nitric acid, Hydrobromic acid, phosphoric acid, sulphuric acid, sulfonic acid and sulfonic acid, the salt of ALA-ester and acid mentioned above Describing in the WO2005/092838 of optical therapeutic company, the full content of the document is combined To herein by reference as.Preferably acid is hydrochloric acid, HCl.Further preferred acid is sulfonic acid and sulphur Acid derivative.The method becoming salt is the conventional method in this area, such as at WO2005/092838 Described in method.

Therefore, in a preferred embodiment, the invention provides one to control for photodynamics Treating or the irradiation unit of photodynamic diagnosis, described device is in the region for holding pharmaceutical composition Place is containing the pharmaceutical composition being dried, and wherein said dry pharmaceutical composition includes:

A) derivant of 5-ALA or its pharmaceutically acceptable salt, preferably 5-ALA ester or its Pharmaceutically acceptable salt；

B) optional one or more polymer, described polymer have good filming performance and/ Or good gel-forming property；And

C) optional other pharmaceutically acceptable excipient.

In a preferred embodiment, the invention provides one for photodynamic therapy or light The irradiation unit of dynamical diagnosis, described device is containing at the region of pharmaceutical composition for holding The pharmaceutical composition being dried, wherein said dry pharmaceutical composition includes:

A) the 5-ALA ester of Formulas I or its pharmaceutically acceptable salt:

R² ₂N-CH₂COCH₂-CH₂CO-OR¹(I)

Wherein

R¹Represent substituted or unsubstituted alkyl；With

R²Each expression hydrogen atom or R independently¹Group；

B) optional one or more polymer, described polymer have good filming performance and/ Or good gel-forming property；And

C) optional other pharmaceutically acceptable excipient.

In further preferred embodiment, the R of formula (I)¹Represent unsubstituted alkyl, preferably For unsubstituted saturated straight chain or branched alkyl, the most unsubstituted saturated straight chain C_1-10 Alkyl.Most preferably, described 5-ALA ester is the own ester of 5-ALA, in further preferred embodiment In, the pharmaceutically acceptable salt of the own ester of described 5-ALA is hydrochlorate or sulfonate or sulfonic acid derives Thing salt, such as mesylate, toluene fulfonate or naphthalene sulfonate.

In the embodiment that it is most basic, the invention provides one and be suitable for photodynamics and control Treating or the irradiation unit of photodynamic diagnosis, described irradiation unit is for holding pharmaceutical compositions Dry pharmaceutical composition is contained in region, wherein said dry pharmaceutical composition by selected from 5-ALA, The precursor of 5-ALA or the effective ingredient of the derivant of 5-ALA and pharmaceutically acceptable salt thereof form.

In a preferred embodiment, the invention provides one and be suitable for photodynamic therapy Or the irradiation unit of photodynamic diagnosis, described irradiation unit is in the district for holding pharmaceutical compositions Dry pharmaceutical composition, wherein said dry pharmaceutical composition spreading out by 5-ALA is contained at territory Biological or its pharmaceutically acceptable salt composition, preferably by 5-ALA ester or it is pharmaceutically acceptable Salt, more preferably 5-ALA ester or its pharmaceutically acceptable salt by Formulas I form.

This dry pharmaceutical composition being mainly made up of (the most only by) effective ingredient is the most logical Cross and effective ingredient is dissolved in the liquid (solution or suspension) that suitable solvent (preferably water) is formed Lyophilizing and obtain.Generally, preparing pie or powder, powder can be compressed.

Effective ingredient discharges in wet condition from described dry pharmaceutical composition, i.e. exists Discharge when contacting with mucosal pattern shape surface, described mucosal pattern shape surface such as cornea and conjunctiva, oral cavity The accessory organ of inner membrance, pharynx, esophagus, stomach, intestinal and intestinal, rectum and anus, nasal cavity inner membrance, nose Hole, nasopharynx, trachea-bronchial epithelial cell and bronchioles, endometrium, vagina, and cervix uteri, Ureter inner membrance, urinary bladder and urethra and auditory meatus inner membrance.The most viscous film-like surface includes uterus Neck and vagina inner membrance, rectum and anus inner membrance, nasal cavity inner membrance and auditory meatus inner membrance.

In a preferred embodiment, the invention provides a kind of for cervix uteri, vagina, straight The photodynamic therapy of intestinal, anus, nose or ear or the irradiation unit of photodynamic diagnosis, described Irradiation unit is containing dry pharmaceutical composition, wherein for holding at the region of pharmaceutical compositions Described dry pharmaceutical composition is by selected from the precursor of 5-ALA, 5-ALA or the derivant of 5-ALA Effective ingredient and pharmaceutically acceptable salt composition.

In a preferred embodiment, the pharmaceutical composition being dried is polymerized containing one or more Thing and optionally other pharmaceutically acceptable excipient.One or more polymer are preferably tool There are good filming performance and/or the polymer of good gel-forming property.Other are pharmaceutically acceptable Excipient is preferably selected from one or more in following compounds: plasticizer, coloring agent and thickening agent. Other pharmaceutically acceptable excipient that there may be present in described dry pharmaceutical composition are Disintegrating agent, mucoadhesive, surface penetration reinforcing agent and chelating agen.

If containing one or more polymer and/or pharmaceutically acceptable in the pharmaceutical composition being dried Excipient, then effective ingredient is by weight, accounts for the 0.25-50% of dry pharmaceutical composition gross weight, Such as 0.5-30%, such as 0.5-15% or 1-10% or 1-7%.Alternatively, if be dried medicine The most additionally contain one or more polymer in compositions, then effective ingredient is by weight, accounts for dry The 50-99%, such as 60-91%-or 75-90% of pharmaceutical composition gross weight.If effective ingredient Content higher than the content of one or more polymer if, then for depositing the liquid of described compositions The viscosity of body is lower, thus is more easily processed and operates.In another embodiment, if Containing one or more polymer and pharmaceutically can connect selected from plasticizer in the pharmaceutical composition being dried The excipient being subject to, then effective ingredient is by weight, accounts for the 15-85% of dry pharmaceutical composition gross weight, Such as 20-80%, such as 25-78% or 26-60%.

One or more polymer all of and pharmaceutically acceptable excipient should be nontoxic, stingless The impurity swashed and can not leach.They should be inert to effective ingredient, the most should not promote Effective ingredient is degraded.Can use the one in every kind of pharmaceutically acceptable excipient compound or Multiple, such as one or more plasticizers, one or more coloring agent etc..

One or more polymer in dry pharmaceutical composition can be natural, half-natural (derivant of the natural polymer i.e. obtained by chemical reaction), or can be the poly-of synthesis Compound；One or more polymer described can be homopolymer or copolymer.

Preferably, the polymer of use has good filming performance, i.e. when being deposited on described device When being used for holding drug regimen object area, it is possible to form thin film together with effective ingredient.This poly- The preferably group of compound is starch, cellulose and starch and the derivant of cellulose.Preferably starch derivatives Biology is acetic starch and carboxymethyl starch, preferably comprise content by weight be at least 18% straight Chain starch.A kind of preferably cellulose is microcrystalline Cellulose.Other preferred cellulose derivatives are Cellulose ether, such as methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl fibre Dimension element, hydroxypropyl methylcellulose, cellulose and carboxymethyl cellulose.These polymer Can be combined with other polymer, such as ethyl cellulose is combined with hydroxypropyl methylcellulose.Other Preferably cellulose derivative is CAP and nitrocellulose.Further preferred Polymer is Colophonium and rosin ester.Polymer another preferably organize into (methyl) acrylates gather Compound and copolymer." methyl " as prefix used in bracket, according to usual way, refers to Be that polymer molecule is derived from one or both the carbon atom skeleton with acrylic acid and methacrylate Monomer.These polymer and copolymer are such as based on methyl methacrylate, acrylic acid second Ester, methacrylic acid and trimethylammonio ethyl first acrylic acid hydrochloride (trimethylammonioethylmetyacrylate chloride), the anion of such as methacrylic acid With being total to of the polymer of cation, the copolymer of acrylic acid methyl ester., acrylate and acrylic acid methyl ester. The copolymer of polymers, ethyl acrylate and methyl methacrylate.Other preferred polymer are adjacent Phthalic acid polyvinyl acetate.In a highly preferred embodiment, cellulose and fiber Element derivant (especially cellulose ether), is used as in the pharmaceutical composition being dried of the present invention Plant or multiple polymers.

In another embodiment, employ the polymer with good gel-forming property, be i.e. polymerized Thing forms glue together with effective ingredient when touching water and the liquid of viscous film-like surface.Preferably this Planting polymer is natural gum, preferably gellan gum (gellan gum), xanthan gum and carrageenin.Its His preferred polymer is chitin, chitosan and chitosan derivant, such as chitosan Salt (hydrochlorate, lactate, aspartate, glutamate, Glu) and N-acetylation chitosan or N-alkylation chitosan.But other preferred polymer are pectin, alginate (such as sea Sodium alginate), amylopectin, hyaluronic acid and derivant thereof.

Preferably, in another embodiment, employ and there is good filming performance and well become The polymer of colloidality energy, such as cellulose ether (such as methylcellulose, ethyl cellulose), ties cold Glue, chitosan and chitosan derivant, amylopectin, alginate, hyaluronic acid, thoroughly Bright matter acid derivative or carrageenin.Preferably this base polymer is cellulose ether, and such as methyl is fine Dimension element, ethyl cellulose, hydroxyethyl cellulose, hydroxy propyl cellulose, hydroxypropyl methylcellulose, Cellulose and carboxymethyl cellulose, and chitosan and chitosan derivant.

If described dry pharmaceutical composition should form film, then it is preferably used and has well The polymer of filming performance.

Polymer can be water solublity or water-insoluble.In a preferred embodiment, use Water-soluble polymer.

The most in a preferred embodiment, the invention provides one for photodynamic therapy Or the irradiation unit of photodynamic diagnosis, described device contains in the region being used for holding pharmaceutical composition Dry pharmaceutical composition, wherein said dry pharmaceutical composition is had to include:

A) derivant of 5-ALA or its pharmaceutically acceptable salt, preferably 5-ALA ester or its Pharmaceutically acceptable salt；

B) there are good filming performance and/or one or more polymer of good gel-forming property, its Described in one or more polymer selected from cellulose ether, gellan gum, chitosan, chitosan Derivant, amylopectin, alginate, hyaluronic acid, derivatives of hyaluronic acids and carrageenin； And

C) optional other pharmaceutically acceptable excipient.

In further preferred embodiment, the invention provides a kind of for photodynamic therapy or The irradiation unit of photodynamic diagnosis, described device contains in the region being used for holding pharmaceutical composition The pharmaceutical composition being dried, wherein said dry pharmaceutical composition includes:

A) derivant of 5-ALA or its pharmaceutically acceptable salt, preferably 5-ALA ester or its Pharmaceutically acceptable salt；

B) there are good filming performance and/or one or more polymer of good gel-forming property, its Described in one or more polymer selected from chitosan, chitosan derivant and cellulose ether； And

C) optional other pharmaceutically acceptable excipient.

If the pharmaceutical composition being dried contains one or more polymer, the most described one or The suitable concentration range of multiple polymers can be to account for dry pharmaceutical composition gross weight by weight 50-99.75%, such as 70-99.5%, such as 85-99.5%, or 90-99% or 93-99%.Or Person, if the pharmaceutical composition being dried the most additionally contains one or more polymer, the most described one Kind or multiple polymers account for the 1-50% of dry pharmaceutical composition gross weight by weight, such as 9-40%-or 10-25%.If the content of effective ingredient is higher than the content of one or more polymer Words, then the viscosity of the liquid for depositing described compositions is lower, thus is more easily processed and grasps Make.In another embodiment, if the pharmaceutical composition being dried gathers containing one or more Compound and the pharmaceutically acceptable excipient selected from plasticizer, then one or more polymer are by weight Gauge accounts for the 20-65% of dry pharmaceutical composition gross weight, such as 25-62%, such as 30-55% Or 40-54%.

In another embodiment, the invention provides one to move for photodynamic therapy or light The irradiation unit of mechanics diagnosis, described device contains dry in the region being used for holding pharmaceutical composition Pharmaceutical composition, wherein said dry pharmaceutical composition includes:

A) derivant of 5-ALA or its pharmaceutically acceptable salt, preferably 5-ALA ester or its Pharmaceutically acceptable salt；

B) one or more polymer, described polymer has good filming performance and/or good Gel-forming property；And

C) other pharmaceutically acceptable excipient, preferably other pharmaceutically acceptable figurations Agent strengthens selected from plasticizer, coloring agent, thickening agent, disintegrating agent, mucoadhesive, surface penetration Agent and/or chelating agen.

Other the pharmaceutically acceptable excipient contained in the pharmaceutical composition being dried are plasticizer. The generally use of plasticizer is to reduce the glass transition temperature of polymer so that it is more elastic and can Morphotropism is the most pliable and the toughest.Therefore, if if containing one or more polymer, preferably contained If having one or more film forming polymers, then plasticizer may reside in dry pharmaceutical composition In.Plasticizer preferably can select in the way of matching with given polymer by it.A reality Executing in scheme, suitable plasticizer serves the work of the good solvent as the polymer in being considered With.In another embodiment, if employing water miscible polymer, then plasticizer is preferred For the mixable compound of water.Suitably plasticizer is low molecular poly, phthalic acid Ester derivant such as dimethyl phthalate, diethylester and dibutyl ester, citrate such as Fructus Citri Limoniae Triethylenetetraminehexaacetic acid ester, tributyl and acetonyl ester, dibutyl sebacate, camphor, glyceryl triacetate, oil Class and glycerin esters such as Oleum Ricini, acetylated monoglyceride and the Oleum Cocois of fractional distillation.Glycerol and third Glycol is also conventional plasticizer, if but the effective ingredient contained in the pharmaceutical composition being dried It is low alkyl group ALA ester or its salt, such as C₁-C₈-alkyl ALA ester, the most should not use sweet Oil and propylene glycol, because they likely promote the degraded of these effective ingredient.

If the pharmaceutical composition being dried contains plasticizer, the suitable concn of the most described plasticizer Scope can be the 1-30% accounting for total polymer weight, such as 5-20% or 7-15% by weight.Can Selection of land, the concentration range of plasticizer can be some higher, and such as concentration range is total for accounting for by weight The 10-175% of polymer weight, or 35-150% or 37-80%.

Other the pharmaceutically acceptable excipient that may contain in the pharmaceutical composition being dried are coloring Agent, such as synthetic dyestuffs or pigment, such as titanium dioxide or yellow iron oxide.Pigment would generally drop Low dry pharmaceutical composition is to steam and the permeability of oxygen, it is therefore possible to it can be increased Shelf-life.Additionally, pigment contributes to all of the liquid for forming dry pharmaceutical composition Solid, without significantly increasing its viscosity.Therefore the process time is made by the most rapid being dried Faster being possible to, this point is particularly important for the water fluid used in spraying.

If the pharmaceutical composition being dried contains coloring agent, the suitable concn of the most described coloring agent Scope agent by weight can account for total pharmaceutical composition being dried 0.1-20%, such as 0.5-10% or 1-5%。

Other the pharmaceutically acceptable excipient contained in the pharmaceutical composition being dried are thickening agent. This reagent is swelling along with absorption liquid, therefore can be used for improving for obtaining dry medicine The viscosity of the liquid of compositions and denseness.Preferably, thickening agent is used for the liquid used during dip-coating In.The selection of thickening agent depends on that whether liquid is water or water fluid, or whether use non-aqueous Property solvent is to constitute described liquid.Some above-mentioned polymer have thickening characteristic, such as natural gum, as Guar gum, cellulose derivative, such as carboxymethyl cellulose and (methyl) acrylate.Its His suitable thickening agent is polyacrylic acid (carbomer) or wax or waxy solid, such as hard fat Alcohol or solid fatty acid.

If the pharmaceutical composition being dried contains thickening agent, then the appropriate amount of the thickening agent added Can be so that liquid as above obtains desired viscosity.Actual amount can depend on described One or more solvents that liquid is comprised and the character of described thickening agent.

Other the pharmaceutically acceptable excipient contained in the pharmaceutical composition being dried are disintegrating agent. Generally, when being placed in wet condition, disintegrating agent can help the pharmaceutical composition being dried to divide Solve.Some above-mentioned polymer show the characteristic of disintegrating agent, such as some cellulose, shallow lake really Powder and derivant thereof.If containing these polymer, then may no longer have interpolation any its The needs of his disintegrating agent or requirement.More efficiently disintegrating agent is referred to as super-disintegrant.Super collapse Solve agent and include such as alginic acid, croscarmellose, polyvinylpolypyrrolidone and sodium starch glycolate. This compound can expand when touching fluid, but can't form the disintegrative that can reduce them Glue.

If the pharmaceutical composition being dried contains disintegrating agent, then the appropriate concentration range of disintegrating agent The 0.1-10% of dry pharmaceutical composition gross weight can be accounted for by weight, the most by weight 0.25-5% or 0.5-4%.

The pharmaceutical composition being dried can comprise one or more mucoadhesives further.Term is " viscous Film sticker " refer to show the compound of mucomembranous surface affinity, i.e. by forming usual character Stick on mucomembranous surface for non-covalent combination, this combination can by with myxocyte and/ Or lower floor's cell interaction and formed.

Mucoadhesive is preferably the chemical combination do not degraded because of pH or the bacterial condition of viscous film-like surface Thing, i.e. because of the sour environment of the vagina containing lactic acid, or in vagina and will not contain in cervix uteri Antibacterial and non-bacterial enzyme or rectum in the antibacterial that contains and be degraded.

Suitably mucoadhesive can be naturally occurring or synthetic compound, polyanion, poly-sun from Sub or neutral, water solublity or water-insoluble, but the biggest (such as molecular weight is 500kDa-3000kDa, such as 1000kDa-2000kDa), water-insoluble crosslinking before any hydration (such as containing the cross-linking agent of the 0.05%-2% accounting for total polymer by weight), water-swellable polymerization Thing.The mucoadhesive forces of this mucosa-adherent compound is preferably greater than 100, is particularly preferably greater than 120, especially preferred more than 150, with relative to according to Smart et al., 1984, J.Pharm.Pharmacol. (pharmacy and pharmacology's impurity), the method external test in 36,295-299 page relative to the hundred of standard Proportion by subtraction represents.

Some above-mentioned polymer show mucoadhesive properties, and such as natural gum is such as guar gum, chitin Polysaccharide and chitosan derivant, amylopectin, sodium alginate or hyaluronic acid.If containing this If a little polymer, then may no longer have needs or the requirement adding any other mucoadhesive.

Suitably mucoadhesive is selected from polysaccharide, preferably glucosan, pectin, amylopectin or fine jade Fat；Natural gum, preferably guar gum or carob；Alginate, such as alginic acid magnesium；Poly- (acrylic acid) and the crosslinking of poly-(acrylic acid) or noncrosslinking copolymer and poly-(acrylic acid) Derivant, such as salt and ester, such as carbomer (carbopol).

When containing mucoadhesive, the appropriate concentration range of the most described mucoadhesive is by weight Can be the 0.05-30% accounting for dry pharmaceutical composition gross weight, the most about 1-25%.

The pharmaceutical composition being dried can comprise one or more surface penetration reinforcing agents further.This Kind of reagent can have and improves the effective ingredient contained in the pharmaceutical composition being dried, i.e. 5-ALA, The beneficial effect of the photosensitization of the derivant of 5-ALA or the precursor of 5-ALA.

Preferably surface penetration reinforcing agent be chelating agen (such as EDTA), surfactant (such as Sodium lauryl sulphate), non-surface-active agent, bile salts (NaTDC), fatty alcohol (example Such as oleyl alcohol), fatty acid (such as oleic acid) and fatty acid and the ester of alcohol, such as isopropyl myristate.

When containing surface penetration agent, the appropriate concentration range of the most described surface penetration reinforcing agent is by weight Gauge can account for the 0.2-20% of dry pharmaceutical composition gross weight, such as, account for dry drug regimen About 1-15% or 0.5-10% of thing gross weight.

The pharmaceutical composition being dried can comprise one or more chelating agen further.This reagent is also Can have improve the derivant of 5-ALA, 5-ALA contained in the pharmaceutical compositions of the present invention or The beneficial effect of the photosensitization of 5-ALA precursor.

Chelating agen is permissible, such as, is included to improve the accumulation of PpIX, because ferrum is chelated Make ferrum be incorporated in PpIX after agent chelating and form haemachrome by the effect of ferrochelatase, thus Cause the foundation of PpIX.Therefore photosensitization can be enhanced.

Suitably chelating agen be aminopolycarboxylic and described in the literature for metal detoxification or Any chelating agen chelated for the paramagnetic metal ion in magnetic resonance image (MRI) contrast medium.Can be right EDTA, CDTA(CDTA), DTPA and DOTA and it is well-known Derivant and analog are specifically mentioned once.EDTA and DTPA is particularly preferred.Other are suitable Chelating agen for desferrioxamining and siderophore, they can be used alone, or with aminopolycarboxylic chelate Agent (such as EDTA) is used in combination.

Some above-mentioned chelating agen show the characteristic of surface penetration reinforcing agent, such as EDTA the most really.

When containing chelating agen, the suitable concn of described chelating agen can account for dry medicine by weight The 0.01-12% of compositions gross weight, such as 0.1-5%.

It is pharmaceutically acceptable and upper that the pharmaceutical composition being dried can comprise one or more further State the excipient that excipient is different.This kind of excipients surfactant in this way, emulsifying agent, preferably For nonionic or cationic emulsifier, filler, binding agent, dispersant, stabilizer or preservative. Those skilled in the art can select suitable excipient according to their purpose.Can be in this paper institute The usual excipients used in the medicine described lists (such as D.E.Bugay in various handbooks Edit with W.P.Findlay() Pharmaceutical excipients(pharmaceutical excipient) (Marcel Dekker company, New York, 1999), E-M Hoepfner, A.Reng and P.C.Schmidt(edit) Fiedler Encyclopedia of Excipients for Pharmaceuticals(for medicine, cosmetic The Fiedler encyclopedia of the excipient of product and association area) (Edition Cantor, Munich, 2002) Edit with H.P.Fielder() Lexikon der Hilfsstoffe f ü r Pharmazie, Kosmetik und Angrenzende Gebiete(Edition Cantor Aulendorf, 1989)).

All above-mentioned pharmaceutically acceptable excipient are known in the art, and can be from respectively Individual manufacturer is purchased commercially.

One or more polymer above-mentioned and optional pharmaceutically acceptable excipient be selected from The precursor of 5-ALA, 5-ALA or the derivant of 5-ALA and the combination of pharmaceutically acceptable salt thereof Generate the novel pharmaceutical composition being dried, which constitute another aspect of the present invention.

Therefore, another aspect of the present invention is a kind of dry pharmaceutical composition, including:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；With

B) one or more polymer.

In another embodiment, the invention provides a kind of dry pharmaceutical composition, including:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；With

B) one or more polymer, described polymer has good filming performance and/or good Gel-forming property.

In a preferred embodiment, one or more polymer described be cellulose or its derive Thing, or starch or derivatives thereof, such as starch acetate and carboxymethyl starch, preferably containing by weight The amylose of gauge at least 18%.A kind of preferably cellulose is microcrystalline Cellulose.The most fine Dimension element derivant be cellulose ether, such as methylcellulose, ethyl cellulose, hydroxyethyl cellulose, Hydroxy propyl cellulose, hydroxypropyl methylcellulose, cellulose, and carboxymethyl cellulose, CAP and nitrocellulose.In another embodiment, one or more polymerizations described Thing is (methyl) acrylate polymer and copolymer.In another embodiment, described one Plant or multiple polymers is natural gum, preferably gellan gum, xanthan gum and carrageenin.Other one In individual embodiment, one or more polymer described are chitin, chitosan and chitosan Derivant, such as chitosan salt (hydrochlorate, lactate, aspartate, glutamate, Glu) Poly-with N-acetylation chitosan or N-alkylation chitosan, more preferably chitosan and chitin Sugar derivatives.And other polymer is pectin, alginate, such as sodium alginate, side chain form sediment Powder, hyaluronic acid and derivant thereof.

In a preferred embodiment, the invention provides a kind of dry pharmaceutical composition, bag Include:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；With

B) there is good filming performance and/or one or more polymer of good gel-forming property, choosing From cellulose ether, gellan gum, chitosan, chitosan derivant, amylopectin, alginic acid Salt, hyaluronic acid, derivatives of hyaluronic acids and carrageenin, one or more polymerizations preferred Thing is selected from chitosan, chitosan derivant and cellulose ether.

One or more pharmaceutically acceptable excipient can also be contained.Such as, if be dried Pharmaceutical composition is the form of thin film, then can contain plasticizer.

The pharmaceutical composition being dried can be dissolved in one by effective ingredient and one or more polymer described Kind or multiple suitable solvent in formed liquid (solution or suspension) and prepare.Excellent at one Selecting in embodiment, one or more polymer described are water-soluble polymer, and suitable solvent is The mixture of water or water and the mixable solvent of non-aqueous water (such as alcohols, such as ethanol or methanol).

In a preferred embodiment, dry pharmaceutical composition of the present invention can be by freezing Dry method, prepares the form of powder, thin film or pie from aforesaid liquid.In another side of being preferable to carry out In case, dry pharmaceutical composition of the present invention can pass through dip-coating or spraying, from aforesaid liquid Prepare the form of thin film.In a further preferred embodiment, dry medicine of the present invention Compositions can be evaporated by solvent, prepares the form of thin film or pie from aforesaid liquid.

As mentioned above, in wet condition, after i.e. contacting with mucosal pattern shape surface, effectively Composition discharges from dry pharmaceutical composition.Preferably mucosal pattern shape surface include cervix uteri and Vagina inner membrance, rectum and anus inner membrance, nasal cavity inner membrance and auditory meatus inner membrance.

In a preferred embodiment, the invention provides a kind of for cervix uteri, vagina, straight The pharmaceutical composition being dried of the PDT of intestinal, anus, nose or ear, described compositions includes:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；With

B) one or more polymer.

In order to make effective ingredient discharge completely, need one or more polymer described or other medicines On, acceptable excipient selects so that they can be after touching mucosal pattern shape surface Just dissolve or at least decompose so that effective ingredient is released.The excipient contained, especially Any polymer is it is thus desirable to dissolve or decompose on described mucosal pattern shape surface under given pH. PH in intravaginal and cervical surfaces is about 3.8-4.5, and the pH in rectum is about 7.9. PH in nasal cavity is about 6.3-6.4.

The pharmaceutical compositions of the present invention the region needing treatment release profiles (directly/quickly, hold Continuous and postpone release) and the time of staying also can be affected by selected polymer.In treatment If site needs relatively high concentration of effective ingredient, then effective ingredient quickly discharge possibility It is preferred.If need the effective ingredient of low concentration in treatment site, then effective ingredient Postpone release to be probably preferably.When moist pharmaceutical compositions is preferably capable ensureing longer stop Between form, the most preferably form of gel rather than the liquid form of dissolving.

Illustrate that release profiles and the time of staying are the most affected with polymer chitosan: several Fourth polysaccharide is a kind of weak base, its pK_aValue be about 6.2-7.0, and therefore its neutral and alkaline Under pH value insoluble.Therefore the chitosan possible quilt of the pharmaceutical composition being dried as polymer is contained For realizing effective ingredient under sour environment, the such as quick release in vagina and in cervix uteri. On the other hand, containing chitosan as polymer be dried pharmaceutical composition be likely to be used for reality Existing effective ingredient at pH higher than 7, the most in the rectum continue/postpone release: chitosan with Showing swelling ability after the mucosal contact of rectum, effective ingredient is slowly discharged.Chitin The dissolubility of polysaccharide can be affected by derivatization: it can pass through in the dissolubility of near neutral pH Introduce hydrophilic functional group's (such as carboxymethyl) or be improved by selectivity N-acetylation. Chitosan is a kind of mucoadhesive, but its time of staying in vaginal mucosa is proved to lead to Crossing introducing mercapto and be improved, the introducing of mercapto can cause the most controlled the releasing of effective ingredient Put (seeing C.E.Kast, J Control Release(controlled release magazine) volume 2002,81,354-374.). Release profiles/time of staying can be subject to used chitosan/chitosan derivant further Molecular weight, the amount of the chitosan in the liquid preparing dry pharmaceutical composition used And the impact of the ratio between effective ingredient and chitosan.From the chitosan containing lower content Liquid in obtain be dried pharmaceutical composition typically exhibit because of its low denseness/low compactness Effective ingredient the most quickly discharges.Containing hydrophilic effective ingredient, the shortest alkyl 5-ALA ester In the pharmaceutical composition being dried, both chitosan molecule and effective ingredient molecule can fight for hydrone.

In a preferred embodiment, the invention provides a kind of dry pharmaceutical composition, bag Include:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；With

B) one or more polymer, described polymer derives selected from chitosan, chitosan Thing and cellulose ether.

In a highly preferred embodiment, the invention provides a kind of dry drug regimen Thing, including:

A) derivant of 5-ALA or its pharmaceutically acceptable salt, preferably 5-ALA ester or its Pharmaceutically acceptable salt；With

B) one or more polymer, described polymer derives selected from chitosan, chitosan Thing and cellulose ether.

In another preferred embodiment, the invention provides a kind of dry pharmaceutical composition, By forming as follows:

A) effective ingredient, described effective ingredient is selected from precursor or the 5-ALA of 5-ALA, 5-ALA Derivant, the derivant of preferably 5-ALA or its pharmaceutically acceptable salt, preferably 5-ALA Ester or its pharmaceutically acceptable salt；With

B) one or more polymer, described polymer derives selected from chitosan, chitosan Thing and cellulose ether.

Described dry pharmaceutical composition is preferably by comprising effective ingredient and selected from chitosan, several The liquid of one or more polymer of fourth polysaccharid derivative and cellulose ether, preferably waterborne liquid Lyophilizing and prepare.

In a further preferred embodiment, the invention provides a kind of for photodynamic therapy or The irradiation unit of photodynamic diagnosis, described device contains in the region being used for holding pharmaceutical composition The pharmaceutical composition being dried, wherein said dry pharmaceutical composition includes:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；With

B) one or more polymer, described polymer derives selected from chitosan, chitosan Thing and cellulose ether.

In a highly preferred embodiment, the invention provides one and control for photodynamics Treating or the irradiation unit of photodynamic diagnosis, described device is in the region for holding pharmaceutical composition Containing the pharmaceutical composition being dried, wherein said dry pharmaceutical composition includes:

A) derivant of 5-ALA or its pharmaceutically acceptable salt, preferably 5-ALA ester or its Pharmaceutically acceptable salt；With

B) one or more polymer, described polymer derives selected from chitosan, chitosan Thing and cellulose ether.

In a further preferred embodiment, the invention provides a kind of for photodynamic therapy or The irradiation unit of photodynamic diagnosis, described device contains in the region being used for holding pharmaceutical composition The pharmaceutical composition being dried, wherein said dry pharmaceutical composition consists of:

A) effective ingredient, described effective ingredient is selected from precursor or the 5-ALA of 5-ALA, 5-ALA Derivant, the derivant of preferably 5-ALA or its pharmaceutically acceptable salt, preferably 5-ALA Ester or its pharmaceutically acceptable salt；

B) one or more polymer, described polymer derives selected from chitosan, chitosan Thing and cellulose ether；With

C) optional other pharmaceutically acceptable excipient.

In a further preferred embodiment, the invention provides a kind of for photodynamic therapy or The irradiation unit of photodynamic diagnosis, described device contains in the region being used for holding pharmaceutical composition The pharmaceutical composition being dried, wherein said dry pharmaceutical composition consists of:

A) effective ingredient, described effective ingredient is selected from precursor or the 5-ALA of 5-ALA, 5-ALA Derivant, the derivant of preferably 5-ALA or its pharmaceutically acceptable salt, preferably 5-ALA Ester or its pharmaceutically acceptable salt；

B) one or more polymer, described polymer derives selected from chitosan, chitosan Thing and cellulose ether；With

C) one or more plasticizers.

In a further preferred embodiment, present invention provide for cervix uteri, vagina, rectum, The photograph of the photodynamic therapy of the cancer of anus, nose or ear, pre-cancerous condition and non-canceration situation Injection device, described device includes the pharmaceutical composition being dried in the region for containing pharmaceutical composition, Wherein said dry pharmaceutical composition includes:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；With

B) one or more polymer, described polymer derives selected from chitosan, chitosan Thing and cellulose ether.

In a further preferred embodiment, present invention provide for cervix uteri, vagina, rectum, The photograph of the photodynamic therapy of the cancer of anus, nose or ear, pre-cancerous condition and non-canceration situation Injection device, described device is for containing the drug regimen including at the region of pharmaceutical composition being dried Thing, wherein said dry pharmaceutical composition includes:

A) derivant of 5-ALA or its pharmaceutically acceptable salt, preferably 5-ALA ester or its Pharmaceutically acceptable salt；With

B) one or more polymer, described polymer derives selected from chitosan, chitosan Thing and cellulose ether.

In a further preferred embodiment, present invention provide for cervix uteri, vagina, rectum, The photograph of the photodynamic therapy of the cancer of anus, nose or ear, pre-cancerous condition and non-canceration situation Injection device, described device includes the pharmaceutical composition being dried in the region for containing pharmaceutical composition, Wherein said dry pharmaceutical composition is by forming as follows:

A) effective ingredient, described effective ingredient is selected from precursor or the 5-ALA of 5-ALA, 5-ALA Derivant, the derivant of preferably 5-ALA or its pharmaceutically acceptable salt, preferably 5-ALA Ester or its pharmaceutically acceptable salt；

B) one or more polymer, described polymer derives selected from chitosan, chitosan Thing and cellulose ether；With

C) optional other pharmaceutically acceptable excipient.

In a further preferred embodiment, present invention provide for cervix uteri, vagina, rectum, The photograph of the photodynamic therapy of the cancer of anus, nose or ear, pre-cancerous condition and non-canceration situation Injection device, described device includes the pharmaceutical composition being dried in the region for containing pharmaceutical composition, Wherein said dry pharmaceutical composition is by forming as follows:

A) effective ingredient, described effective ingredient is selected from precursor or the 5-ALA of 5-ALA, 5-ALA Derivant, the derivant of preferably 5-ALA or its pharmaceutically acceptable salt, preferably 5-ALA Ester or its pharmaceutically acceptable salt；

B) one or more polymer, described polymer derives selected from chitosan, chitosan Thing and cellulose ether；With

C) one or more plasticizers.

Comprise selected from the precursor of 5-ALA, 5-ALA or the effective ingredient of the derivant of 5-ALA, with And the medicine group being dried of one or more polymer selected from chitosan or chitosan derivant Compound prepares the most by the following method:

Water-insoluble chitosan is dissolved in hydrochloric acid (0.1M), then evaporation drying.By remnants The soluble derivative of thing or chitosan is soluble in water.Effective ingredient is added and is dissolved in chitin and gather In sugar juice, generate containing the chitosan/chitosan derivant dissolved and the liquid of effective ingredient.

Comprise selected from the precursor of 5-ALA, 5-ALA or the effective ingredient of the derivant of 5-ALA, with And the pharmaceutical composition being dried being selected from one or more polymer of cellulose ether preferably passes through as follows Method prepares:

By cellulose ether, such as methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl first Propyl cellulose, hydroxy propyl cellulose or carboxymethyl cellulose and effective ingredient add solvent, It is preferably in the mixture of water or water and organic solvent (preferably alcohols, such as ethanol).Will system The process that the liquid obtained is discussed below.

The pharmaceutical composition being dried of the present invention is preferably evaporated or spray by lyophilizing as the aforementioned, solvent The mode being coated with prepares from above-mentioned liquid.

In a preferred embodiment, fill to the irradiation for photodynamic therapy or photodynamics Put liquid described in the included area applications for holding pharmaceutical composition, i.e. insert or apply To as disclosed in Fig. 1-3 and 6-7 of WO2010/078929 for Cervical cancer, cancer Before becoming in the reservoir on the irradiation unit of the photodynamic therapy of situation and non-canceration situation.Described Device or its module (being the most only reservoir) are lyophilized plus liquid, or are evaporated by solvent The deposition of the pharmaceutical composition being dried is obtained in reservoir.In a further preferred embodiment, Described liquid is applied to the irradiation unit for PDT (such as at WO by spraying A kind of device disclosed in Fig. 1-7 of 2010/078929) contained by be used for hold pharmaceutical composition Region on.

In a preferred embodiment, the present invention be dried pharmaceutical composition and comprise dry The irradiation unit of pharmaceutical composition is used for cervix uteri, vagina, rectum, anus, nose or ear In the PDT of cancer, pre-cancerous condition and non-canceration situation, it is preferred for cervix uteri, vagina and straight In the pre-cancerous condition of intestinal and the PDT of non-canceration situation.Described irradiation unit includes treating with PDT The pharmaceutical composition being dried of the effective dose of these situations.

Alternatively, the pharmaceutical composition being dried of the present invention and the photograph comprising dry pharmaceutical composition Injection device is used for shape before the cancer of cervix uteri, vagina, rectum, anus, nose or ear, canceration In the PDD of condition and non-canceration situation, it is preferred for the pre-cancerous condition of cervix uteri, vagina and rectum With in the PDD of non-canceration situation.Described irradiation unit includes diagnosing having of these situations with PDD The pharmaceutical composition being dried of effect amount (i.e. dosage).

Described device is opened by doctor or nurse, inserts in vagina, rectum, anus, nose or ear And it is placed on required site (such as vagina or cervix uteri), in dry pharmaceutical composition disintegrate During/dissolving, hatch (i.e. the accumulation of porphyrin) and photodynamic therapy or diagnosis during, described dress Put and be maintained at this site.If described device is made up of module, then will comprise described dry medicine The module (such as holding the region of pharmaceutical composition, such as reservoir) of compositions is opened, And other module in device is combined, form complete equipment.Intervalometer can be described A part for preferred embodiment, after described intervalometer is activated before device inserts, ensure that respectively I.e. start after desired disintegrate/dissolving/incubation period to irradiate, and proceed the optical therapeutic determined Cycle and diagnotor.In a highly preferred embodiment, PDT device can be to use That can be dropped and be suitable to patient and just can remove without again seeking medical advice.

After incubation, site to be treated touches light, with the photoactivation desired by realization and light Photodynamic therapy or diagnosis.Using and touching between light (disintegrate/dissolving/incubation time) The length of time cycle will depend upon which character and the character of dry pharmaceutical composition of effective ingredient. Generally, thin with by tissue to be treated of the enough release of the effective ingredient in described pharmaceutical composition Born of the same parents are absorbed, and are converted into photosensitizer and reach effectively to organize dense in treatment site before photoactivation Degree is necessary.For PDT, incubation time is about 30 minutes-10 hours, and preferably 1 is little Time by 7 hours, such as 3 hours to 5 hours.

Would generally be irradiated with relatively short period of time, higher intensity of illumination, the highest fluence Rate (fluence rate), or be irradiated with longer time, relatively low intensity of illumination, the lowest Fluence rate.The latter is preferred for PDT program, and the pharmaceutical composition being wherein dried is included in In the device of description in WO2010/078929.Utilize this device, can amass in relatively low Divide under flux rate, within a long term, such as at 1 10mW/cm²Fluence rate under, Optical therapeutic is carried out within the period of a few hours.This is for reducing the discomfort of patient, and for controlling The effect treated is all favourable.

The wavelength irradiating the light used can select, to realize effective photodynamics effect Should.Wavelength is between 300-800nm, and the such as light in the range of 400-700nm is considered as Particularly effective.For PDT, the wavelength including 630 and 690nm is particular importance.Red Light (600 670nm) is particularly preferred, because it is known that the light of this wavelength can penetrate well Tissue.Therefore, described irradiation unit the most preferably sends wavelength between 630-690nm Light, but more preferably there is concrete wavelength, the light of the most about 630nm wavelength.

For PDT, it is possible to use single fraction irradiation, or light can be separated and with multiple portions Divide and deliver, such as space-number minute during each time irradiates.It is used as repeatedly irradiating, but It is not preferred.Patient is treated by the pharmaceutical composition being preferably dried by single. But, if treatment does not complete, it is also possible to repeat.

Dry pharmaceutical composition disclosed in this invention, irradiation unit containing this compositions and Method for photodynamic therapy can such as use other treatment medicine with other treatment method It is combined.These medicines can before using dry pharmaceutical composition, simultaneously or it After be administered.Other administration route can be administered orally, intravenously administrable or percutaneous drug delivery.Generally this A little medicines include hormone, antibacterial, antifungal, antiviral agent, anticarcinogen or these medicines In conjunction with.

On the other hand, the invention provides the pharmaceutical composition being dried comprising following material in system Make the purposes in irradiation unit:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；

B) optional one or more polymer, described polymer have good filming performance and/ Or good gel-forming property；And

C) optional other pharmaceutically acceptable excipient；

Wherein, described irradiation unit contains for cervix uteri, the moon in the region being used for holding pharmaceutical composition The cancer of road, rectum, anus, nose or ear, pre-cancerous condition and the light power of non-canceration situation Learn treatment or the described dry pharmaceutical composition of photodynamic diagnosis.

On the other hand, the invention provides the pharmaceutical composition being dried comprising following material in system Make the purposes in irradiation unit:

A) effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；

B) optional one or more polymer, described polymer have good filming performance and/ Or good gel-forming property；And

C) optional other pharmaceutically acceptable excipient；

Wherein, described irradiation unit contains for cervix uteri, the moon in the region being used for holding pharmaceutical composition The cancer of road, rectum, anus, nose or ear, pre-cancerous condition and the light power of non-canceration situation Learn the described dry pharmaceutical composition for the treatment of.

On the other hand, the invention provides a cervical, vagina, rectum, anus, nose or The method of the photodynamic therapy of the cancer of ear, pre-cancerous condition and non-canceration situation, described side Method comprises the steps:

A) irradiation unit is placed on the mankind or the cervix uteri of inhuman animal subjects, vagina, The treatment site of rectum, anus, nose or ear, described irradiation unit holds medicine group being used for The region of compound includes that the pharmaceutical composition being dried, described dry pharmaceutical composition include:

I. effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；

Ii. one or more polymer optional, described polymer have good filming performance and/ Or good gel-forming property；And

Iii. other pharmaceutically acceptable excipient optional；

B) wait for a period of time, the effective ingredient in described dry pharmaceutical composition need to be made Change into photosensitizer and reach effectively to treat tissue concentration in desired site；Then

C) by making photosensitizer touch the light of described device release, described photosensitizer light is lived Change.

On the other hand, the invention provides a cervical, vagina, rectum, anus, nose or The method of the photodynamic diagnosis of the cancer of ear, pre-cancerous condition and non-canceration situation, described side Method comprises the steps:

A) irradiation unit is placed on the mankind or the cervix uteri of inhuman animal subjects, vagina, At the diagnosis site of rectum, anus, nose or ear, described irradiation unit holds medicine group being used for The region of compound includes that the pharmaceutical composition being dried, described dry pharmaceutical composition include:

I. effective ingredient, described effective ingredient is selected from 5-ALA, 5-ALA precursor or 5-ALA Derivant and pharmaceutically acceptable salt thereof；

Ii. one or more polymer optional, described polymer have good filming performance and/ Or good gel-forming property；And

Iii. other pharmaceutically acceptable excipient optional；

B) wait for a period of time, the effective ingredient in described dry pharmaceutical composition need to be made Change into photosensitizer and reach efficient diagnosis tissue concentration in desired site；Then

C) by making photosensitizer touch the light of described device release, described photosensitizer light is lived Change.

The present invention is illustrated by following non-limiting embodiment:

Detailed description of the invention

The own ester of 5-ALA hydrochloric acid (HAL HCl) is prepared according to the description in WO96/28412；Press 5-ALA hydrochloric acid benzene methyl (BAL HCl) is prepared according to the description in WO02/10120.By Silver salt method described in WO2005/092838, from 5-ALA hydrochloric acid methyl ester (according to WO Prepared by the description in 96/28412) prepare 5-ALA methyl nitrate (MAL nitrate).By Silver salt method described in WO2005/092838, from the own ester of 5-ALA hydrochloric acid (according to WO Prepared by the description in 96/28412) prepare 5-ALA methanesulfonic acid own ester salt (HAL Mes).

Embodiment 1

By the nitrocellulose of 4 weight portions being dissolved in diethyl ether and 25 parts by volume of 75 parts by volume Ethanol in and prepare collodion elastique.Add the camphor and by weight 3% of by weight 2% Oleum Ricini (plasticizer), stir mixture, until generate the most light yellow, syrupy liq. Adding the own ester hydrochloride of 500mg5-ALA (HAL HCl) in 10g collodion elastique, stirring is mixed Compound, until generating uniform liquid.

By aforesaid liquid in the device dip-coating of the Fig. 5 according to WO2010/078929.Described liquid exists The surface (treatment surface) of described device is upper to be dried, and forms thin film.

Alternatively, in the reservoir of the device of Fig. 1-3 and 6-7 according to WO2010/078929 Load the liquid of the above-mentioned acquisition of 2g.Described liquid is uniformly distributed in reservoir, is evaporated by solvent And be dried, form thin film.

Embodiment 2

Distill by 0.75g methylcellulose and 0.08g PEG400 being under agitation dissolved in 8.67g Water prepares liquid.Adding 500mg HAL HCl, stirring mixture, until generating uniform liquid Body.

The device of the Fig. 5 according to WO2010/078929 is sprayed aforesaid liquid.Described liquid is in institute The surface (treatment surface) stating device is upper dry, forms thin film.

Embodiment 3

Distill by 0.75g methylcellulose and 0.16g PEG400 being under agitation dissolved in 8.15g Water prepares liquid.Adding 500mg5-ALA own ester mesylate (HAL Mes), stirring is mixed Compound, until generating uniform liquid.

The device of the Fig. 5 according to WO2010/078929 is sprayed aforesaid liquid.Described liquid is in institute The surface (treatment surface) stating device is upper dry, forms thin film.

Embodiment 4

By 500mg HAL HCl, 4.5g chitosan glutamate, Glu and 5g distilled water are mixed system Obtain liquid.Stir described mixture, until being dissolved uniformly.

Load in the reservoir parts of the device of Fig. 1-3 and 6-7 according to WO2010/078929 The liquid of the above-mentioned acquisition of 2g.By the freezing and lyophilizing in liquid nitrogen of reservoir parts.At described reservoir In obtained the several of HAL HCl and 90% containing account for dry pharmaceutical composition by weight 10% The pharmaceutical composition being dried of fourth polysaccharide glutamate, Glu.Described reservoir and other portions of described device Divide and connect.Described device containing the pharmaceutical composition being dried can be used for Cervical cancer, canceration Before or the photodynamic therapy of non-canceration situation.

Embodiment 5

By 500mg HAL Mes, 4.5g chitosan lactate and 5g distilled water are mixed to prepare Liquid.Stir described mixture, until being dissolved uniformly.

Load in the reservoir parts of the device of Fig. 1-3 and 6-7 according to WO2010/078929 The liquid of the above-mentioned acquisition of 2g.By the freezing and lyophilizing in liquid nitrogen of reservoir parts.At described reservoir In obtained the several of HAL Mes and 90% containing account for dry pharmaceutical composition by weight 10% The Lactated dry pharmaceutical composition of fourth polysaccharide.Described reservoir and other parts of described device Connect.Described device adds before medicine can be used for Cervical cancer, canceration or non-canceration situation Photodynamic therapy.

Embodiment 6

Being prepared for waterborne liquid, the Eudragit RL30D(containing by weight 5.5% is as 30%w/w Dispersion), the Citroflex2(plasticizer of 1.1%) and the HAL HCl of 5%.

The device of the Fig. 5 according to WO2010/078929 is sprayed aforesaid liquid.Described liquid is in institute The surface (treatment surface) stating device is upper dry, forms thin film.

Embodiment 7

It is prepared for the waterborne liquid of 9.5g, containing amylopectin and the Sargassum of 1% of by weight 20% Acid sodium.Described liquid is placed overnight.Addition 0.5g HAL HCl, firmly agitated liquid, until Generate uniform, the liquid of relatively low viscosity.

The device of the Fig. 5 according to WO2010/078929 is sprayed aforesaid liquid 2g.Described liquid Upper dry on the surface (treatment surface) of described device, form thin film.

Embodiment 8

It is prepared for the waterborne liquid of 9.5g, containing amylopectin and the Sargassum of 1% of by weight 20% Acid sodium.Described liquid is placed overnight.The pH dilute hydrochloric acid of described liquid regulates to 3.5.Add 0.5g HAL HCl, firmly agitated liquid, until generate uniformly, the most full-bodied liquid.

Incline dip-coating aforesaid liquid 2g by the device of the Fig. 5 according to WO2010/078929.Described liquid Body is upper on the surface (treatment surface) of described device to be dried, and forms thin film.

Embodiment 9

Be prepared for the waterborne liquid of 9.5g, containing by weight 10% chitosan and 1%(volume/ Volume) acetic acid.Add 0.5g HAL HCl, stir mixture, until uniformly.

Load in the reservoir parts of the device of Fig. 1-3 and 6-7 according to WO2010/078929 The liquid of the above-mentioned acquisition of 2g.By the freezing and lyophilizing in liquid nitrogen of reservoir parts.At described reservoir In obtained the Lactated dry medicine of chitosan of the HAL HCl and 65.5% containing 34.5% Compositions.Described reservoir is connected with other parts of described device.Described device adds medicine can quilt Before Cervical cancer, canceration or the photodynamic therapy of non-canceration situation.

In following test, use glass round bottom flask to replicate according to WO2010/078929's The spill of the reservoir of the device of Fig. 1-3 and 6-7/trochoidal surface shape.Although this round bottom glass Glass flask is suitable for simulating the shape of reservoir, and different yet with its material, i.e. glass is to medical treatment Elastomeric material conventional in apparatus, such as rubber, latex, silicones or other polymer and copolymerization Thing, and make it have different surfaces characteristic.

Embodiment 10

By by 100mg HAL HCl and 10mg methylcellulose 1500(Apotekproduksjon AS, Olso, Norway) water (10ml) that is dissolved in glass round bottom flask and 96% ethanol (10ml) Mixture in and prepare liquid.After freeze drying, the uniform thin film of mechanically stable has been obtained.

Embodiment 11

By by 100mg HAL HCl and 25mg methylcellulose 1500(Apotekproduksjon AS, Olso, Norway) water (10ml) that is dissolved in glass round bottom flask and 96% ethanol (10ml) Mixture in and prepare liquid.After freeze drying, obtained depending on glass surface the most completely Uniformly thin film.

Embodiment 12

By by 100mg HAL HCl and 50mg methylcellulose 1500(Apotekproduksjon AS, Olso, Norway) water (10ml) that is dissolved in glass round bottom flask and 96% ethanol (10ml) Mixture in and prepare liquid.After freeze drying, obtained depending on glass surface the most completely Uniformly thin film.

Embodiment 13

By by 100mg HAL HCl and 10mg ethyl cellulose (Sigma Aldrich#200646) The water (10ml) being dissolved in glass round bottom flask prepares liquid.After freeze drying, pine has been obtained Soft cake.

Embodiment 14

By by 100mg HAL HCl and 10mg hydroxyethyl cellulose 250HX Pharm (Fagron GmbH&Co KG, Bath Bitter, Germany) is dissolved in the water in glass round bottom flask (10ml) liquid is prepared in.After freeze drying, obtained depending on having of glass surface the most completely The most uneven thin film.

Embodiment 15

By by 100mg HAL HCl and 10mg chitosan (Sigma Aldrich#448877) The water (10ml) being dissolved in glass round bottom flask prepares liquid.After freeze drying, do not had There is some the uneven reticulated film depending on glass surface completely.

Embodiment 16

By by 100mg HAL HCl and 10mg sanlose (Sigma Aldrich# C5678) water (10ml) being dissolved in glass round bottom flask prepares liquid.After freeze drying, To some the uneven reticulated film depending on glass surface the most completely.

Embodiment 17

By by 100mg5-ALA benzyl esters hydrochlorate (BAL HCl) and methylcellulose 1500 The water (10ml) that (Apotekproduksjon AS, Olso, Norway) is dissolved in glass round bottom flask In and prepare liquid.The amount of methylcellulose is respectively 10mg, 25mg and 50mg.After freeze drying, Obtain the reticulated film of some inequality depending on glass surface the most completely.

Embodiment 18

By by 100mg HAL HCl, 25mg methylcellulose 1500(Apotekproduksjon AS, Olso, Norway) and 3mg triethyl citrate (Merck chemistry, Northern Europe) be dissolved in round bottom Water (10ml) in glass flask prepares liquid.After freeze drying, obtained relatively uniform, The flexible film of mechanically stable.

Embodiment 19

By by 100mg HAL HCl and 25mg methylcellulose 1500(Apotekproduksjon AS, Olso, Norway) water (10ml) that is dissolved in glass round bottom flask prepares liquid.? After lyophilizing, obtain relatively uniform, the flexible film of mechanically stable.

Embodiment 20

By by 100mg BAL HCl, 25mg hydroxypropyl cellulose and 3mg citric acid three The water (10ml) that ethyl ester (Merck chemistry, Northern Europe) is dissolved in glass round bottom flask prepares liquid Body.After freeze drying, relatively uniform, the flexible film of mechanically stable has been obtained.

Embodiment 21

By 100mg BAL HCl and 25mg hydroxypropyl cellulose are dissolved in glass round bottom flask In water (10ml) in and prepare liquid.After freeze drying, obtained relatively uniform, machinery is steady Fixed flexible film.

Embodiment 22

By 100mg HAL HCl, 200mg Kollicoat IR White(mono-kind are contained titanium dioxide The polyvinyl alcohol-polyethylene glycol scion grafting polymer (BASF, Ludwigshafen, Germany) of titanium pigment) and The 50mg Kollicoat IR Yellow(mono-kind polyvinyl alcohol containing titanium dioxide and iron oxide pigment-poly- Ethylene glycol scion grafting polymer (BASF, Ludwigshafen, Germany)) it is dissolved in glass round bottom flask Water (10ml) in prepare liquid.After freeze drying, obtained relatively uniform, mechanically stable Yellow film.

In the following experiments, the irradiation unit of the Fig. 6 according to WO2010/078929 is used. The reservoir (in Fig. 6 63) of described device is made up of silicones.

Embodiment 23

By by 100mg HAL HCl, 25mg methylcellulose 1500(Apotekproduksjon AS, Olso, Norway) and 3mg triethyl citrate (Merck chemistry, Northern Europe) be dissolved in 2ml Water prepares liquid.The reservoir of described irradiation unit is coated with described solution, then by institute State device lyophilizing.After freeze drying, the thin film of the mechanically stable of homogeneous soft has been obtained.

Embodiment 24

By by 100mg HAL HCl and 25mg methylcellulose 1500(Apotekproduksjon AS, Olso, Norway) it is dissolved in 2ml water prepared liquid.The reservoir of described irradiation unit With the upper described solution of brush coating, then by described device lyophilizing.After freeze drying, obtained uniformly, Soft, the most frangible thin film, more weaker than the thin film mechanically stable obtained in embodiment 23.

Embodiment 25

By by 100mg BAL HCl, 25mg methylcellulose 1500(Apotekproduksjon AS, Olso, Norway) and 3mg triethyl citrate (Merck chemistry, Northern Europe) be dissolved in 2ml Water prepares liquid.The upper described solution of reservoir brush coating of described irradiation unit, then By described device lyophilizing.After freeze drying, obtain uniform, soft, the most frangible thin film, than The thin film mechanically stable obtained in embodiment 23 is more weaker.

Embodiment 26

By by 100mg BAL HCl and 25mg methylcellulose 1500(Apotekproduksjon AS, Olso, Norway) it is dissolved in 2ml water prepared liquid.The reservoir of described irradiation unit With the upper described solution of brush coating, then by described device lyophilizing.After freeze drying, obtained uniformly, Soft, the most frangible thin film, more weaker than the thin film mechanically stable obtained in embodiment 23.

Embodiment 27

By 100mg HAL HCl and 25mg hydroxypropyl cellulose are dissolved in, 2ml water is made Obtain liquid.The upper described solution of reservoir brush coating of described irradiation unit, then by described dress Put lyophilizing.After freeze drying, having obtained uniform, soft, the most frangible thin film, ratio is in embodiment The thin film mechanically stable obtained in 23 is more weaker.

Embodiment 28

By 100mg BAL HCl and 25mg hydroxypropyl cellulose are dissolved in, 2ml water is made Obtain liquid.The upper described solution of reservoir brush coating of described irradiation unit, then by described dress Put lyophilizing.After freeze drying, the cake of mechanically stable has been obtained.

Embodiment 29

By by 100mg BAL HCl, 25mg hydroxypropyl cellulose and 3mg citric acid three Ethyl ester (Merck chemistry, Northern Europe) is dissolved in 2ml water and prepares liquid.The storage of described irradiation unit Store the upper described solution of device brush coating, then by described device lyophilizing.After freeze drying, obtain The cake of mechanically stable.

In the following experiments, the described irradiation unit used in embodiment 23-29 has carried out pretreatment, To improve the silicone material wetting characteristics to aqueous solution: load 12N in the reservoir of described device Hydrochloric acid (aqueous solution), places 30 minutes.Reservoir is turned, and washes with water for several times.Will not Observe that visible change occurs in silicone material.

Embodiment 30

By by 100mg HAL HCl and 10mg methylcellulose 1500(Apotekproduksjon AS, Olso, Norway) it is dissolved in 2ml water prepared liquid.Described device is put before coating Put in dry ice upper 15 minute.The upper described solution of reservoir brush coating of described irradiation unit, so After by described device lyophilizing.After freeze drying, obtained softness uniform, medium, mechanically stable thin Film.

Embodiment 31

By by 100mg BAL HCl and 10mg methylcellulose 1500(Apotekproduksjon AS, Olso, Norway) it is dissolved in 2ml water prepared liquid.Described device is put before coating Put in dry ice upper 15 minute.The upper described solution of reservoir brush coating of described irradiation unit, so After by described device lyophilizing.After freeze drying, obtained softness uniform, medium, mechanically stable thin Film.

Embodiment 32

By 100mg HAL HCl and 12.5mg hydroxypropyl methylcellulose are dissolved in 5ml water Prepare liquid.The upper described solution of reservoir brush coating of described irradiation unit, then by described Device lyophilizing.After freeze drying, soft cake has been obtained.

Embodiment 33

By 100mg HAL HCl and 10mg hydroxypropyl methylcellulose are dissolved in, 2ml water is made Obtain liquid.Described device is placed on before coating dry ice upper 15 minute.The storage of described irradiation unit Store the upper described solution of device brush coating, then by described device lyophilizing.After freeze drying, obtain Uniformly, the thin film of medium softness, mechanically stable.

Embodiment 34

By 100mg BAL HCl and 10mg hydroxypropyl methylcellulose are dissolved in, 2ml water is made Obtain liquid.Described device is placed on before coating dry ice upper 15 minute.The storage of described irradiation unit Store the upper described solution of device brush coating, then by described device lyophilizing.After freeze drying, obtain Uniformly, the thin film of medium softness, mechanically stable.

Embodiment 35

Liquid is prepared by following compounds being dissolved in 2ml water:

35a:20mg HAL HCl and 40mg hydroxypropyl methylcellulose

35b:20mg HAL HCl, 40mg hydroxypropyl methylcellulose and 5mg PEG600

35c:20mg HAL HCl, 40mg hydroxypropyl methylcellulose and 15mg PEG600

35d:20mg HAL HCl, 40mg hydroxypropyl methylcellulose and 60mg PEG600

Described device is placed on before coating dry ice upper 15 minute.The reservoir of described irradiation unit With the upper described solution of brush coating, then by described device lyophilizing.

After freeze drying, following material has been obtained:

35a: medium softness, the thin film that some is uneven.Mechanically stable.

35b: relative rigid, uniform thin film.Mechanically stable.

35c: relative rigid, uniform thin film.Mechanically stable.

35d: thin film hard, uniform.Mechanically stable.

Embodiment 36

Liquid is prepared by following compounds being dissolved in 2ml water:

36a:20mg5-ALA methyl nitrate (MAL nitrate), 40mg hydroxypropyl methylcellulose With 30mg PEG600

36b:20mg MAL nitrate, 40mg hydroxypropyl methylcellulose and 14mg PEG600

Described device is placed on before coating dry ice upper 15 minute.The reservoir of described irradiation unit With the upper described solution of brush coating, then by described device lyophilizing.After freeze drying, obtained following Material:

36a: rigid homogeneous thin film.Mechanically stable.

36b: rigid homogeneous thin film.Mechanically stable.

Embodiment 37

By 100mg HAL HCl, 40mg hydroxypropyl methylcellulose and 30mg PEG are dissolved in 4ml water prepares liquid.Described device is placed on before coating dry ice upper 15 minute.Described The upper described solution of reservoir brush coating of irradiation unit, then by described device lyophilizing.Freezing After Gan, obtain uniform, soft, the thin film of mechanically stable.

Embodiment 38

By by 100mg HAL HCl, 40mg hydroxypropyl methylcellulose and 30mg PEG 950-1050 is dissolved in 2ml water and prepares liquid.Described device is placed on dry ice before coating 15 minutes.The upper described solution of reservoir brush coating of described irradiation unit, then by described dress Put lyophilizing.After freeze drying, uniform, hard, the thin film of mechanically stable has been obtained.

Embodiment 39

The stability of some dry compositions according to the present invention is carried out following evaluation: at round bottom glass After dry compositions prepared by glass flask, at 37 DEG C, described compositions is stayed in glass flask Many 4 weeks.Adding 5ml water in described dry compositions, compositions is dissolved.Extract 1ml sample out Product, and filtered by the injection filter of 0.45 μm.The filtered sample HPLC(of 25 μ l pacifies Prompt human relations 1100, pump rate 1ml/min) it is analyzed, use 4.4x250mm ZORBAX to extend C₁₈Post (Agilent), and using methanol/water (70:30v/v) as eluent.At 210 nm Carry out UV detection.For determining the percentage composition of ALA ester in sample, calculate relative standard product Peak area.Following dry compositions all shows the best stability, i.e. ALA-ester is protected Keep steady fixed: embodiment 20 and 21 is after 25 and 27 days, and embodiment 18 and 19 was at 8 days After.

Embodiment 40

After the reservoir of irradiation unit contacts water, the ALA-of release from some dry compositions The situation of ester is measured according to following:

The reservoir of irradiation unit encloses 5ml water (37 DEG C), described device is gently agitated for greatly About 30 minutes.Liquid is removed from described device, and by the injection filter mistake of 0.45 μm Filter.According to filtration liquid is analyzed described in embodiment 39.The release of 100% is equivalent to ALA- Ester discharges completely.Employ following abbreviations: MC: methylcellulose, HPMC: hydroxypropyl methylcellulose Element, TC: triethyl citrate.

All of dry compositions has discharged effectively with enough speed in contacting with water 30 minutes Composition (ALA-ester).

Claims (11)

1. control for the photodynamics of Cervical cancer, pre-cancerous condition and non-canceration situation for one kind The irradiation unit treated, described device contains dry medicine in the region being used for holding pharmaceutical composition Compositions, described dry pharmaceutical composition is film like,

Wherein said device be suitable to all be fixedly inserted in vagina, and when in described vagina Can independently operate, and wherein said device includes being suitable to fully-inserted and being fixed in described vagina Shell, described shell is surrounded with LED lamp system and for for described LED lamp system energy supply Power supply,

And wherein said shell includes a top housing section, it is generally conical in shape, its Front end constitute treatment surface, and shape described treatment surface so that in use cover uterine cervix and Cervical orifice, described region can be provided irradiation, described treatment surface composition to be used for accommodating institute by it State the reservoir of dry pharmaceutical composition,

Wherein said dry pharmaceutical composition includes:

A) effective ingredient, described effective ingredient is selected from 5-ALA ester and pharmaceutically acceptable salt thereof；

B) one or more polymer, described polymer is cellulose ether；And

C) optional other pharmaceutically acceptable excipient.

Irradiation unit the most according to claim 1, it is characterised in that described dry medicine Compositions passes through Film coating, solvent evaporate or prepared by lyophilizing.

Irradiation unit the most according to claim 2, it is characterised in that described Film coating For dip-coating or spraying.

4. according to the irradiation unit described in aforementioned any one claim, it is characterised in that described dry Dry pharmaceutical composition includes 5-ALA ester or its pharmaceutically acceptable salt of Formulas I:

R² ₂N-CH₂COCH₂-CH₂CO-OR¹ (I)

Wherein

R¹Represent substituted or unsubstituted alkyl；And

R²Each expression hydrogen atom or R independently¹Group.

5. according to the irradiation unit described in any one of claim 1-3, it is characterised in that described dry Dry pharmaceutical composition is made up of described effective ingredient and one or more polymer described.

Irradiation unit the most according to claim 1 and 2, it is characterised in that described dry Pharmaceutical composition is prepared by lyophilizing.

Irradiation unit the most according to claim 6, it is characterised in that described dry medicine Compositions is by preparing liquid lyophilizing, and described liquid is by by described effective ingredient and described one Or multiple polymers and other pharmaceutically acceptable excipient optional dissolve or are suspended in suitably Solvent prepares.

Irradiation unit the most according to claim 7, it is characterised in that described suitable solvent For water or the mixture of solvent.

Irradiation unit the most according to claim 8, it is characterised in that described suitable solvent is Water and the mixture of alcohols.

10. according to the irradiation unit according to any one of claim 1-3 and 7-9, it is characterised in that Described dry pharmaceutical composition farther includes one or more other pharmaceutically acceptable figurations Agent.

11. irradiation units according to claim 10, it is characterised in that described one or many Kind of other pharmaceutically acceptable excipient selected from plasticizer, coloring agent, thickening agent, disintegrating agent, Mucoadhesive, surface penetration reinforcing agent and/or chelating agen.