CN1720024A - Therapeutic compositions for drug delivery to and through covering epithelia - Google Patents
Therapeutic compositions for drug delivery to and through covering epithelia Download PDFInfo
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- CN1720024A CN1720024A CN 200380104617 CN200380104617A CN1720024A CN 1720024 A CN1720024 A CN 1720024A CN 200380104617 CN200380104617 CN 200380104617 CN 200380104617 A CN200380104617 A CN 200380104617A CN 1720024 A CN1720024 A CN 1720024A
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Abstract
The present invention provides a polymer foams and films for delivery of therapeutic agents to and through nasal, oral or vaginal mucosa and cornified or non-cornified epithelium of labia and scrotum. Polymer foams or absorbable or non-absorbable films containing a therapeutic agent incorporated therein wherein said agent is released from said foams or films upon placement of said foam or film on the surface epithelium of nasal, oral, or vaginal labia or scrotum. The foam or the film has a controllable rate of gelling, swelling and degradation and is preformed into a device or is applied as a coating to a surface of a more complex drug delivery system.
Description
Background of invention
Invention field
The present invention relates to be suitable for delivering therapeutic agents to and therapeutic combination by nasal cavity, oral cavity or vaginal canal and the epithelium delivering therapeutic agents by labia and scrotum.Especially, the present invention relates to comprise the compositions of following material: therapeutic agent and polymer, further optionally in conjunction with mucoadhesive, penetration enhancer, release improver and/or other additive and excipient.These compositionss can be prepared as solid structure or semisolid biodegradation or non-biodegradation foam or film or comprise the liquid preparation of introducing therapeutic agent wherein, discharge this medicament from said composition during when wherein placing on its nasal cavity, oral cavity, vagina, labia or scrotum epithelial surface or closely near nasal cavity, oral cavity, vagina, labia or scrotum epithelium.Depend on the existence of concrete component in the said composition, compositions of the present invention works to the protective epithelium part or is transported to the body circulation by such epithelium.Compositions of the present invention has controlled gelatine, swelling and degradation rate.Compositions can form in advance as foam tampon, tampon shape cylinder, bar, pad, bolster, pipe, sheet, ball, tablet, ring or beadlet or the diaphragm-operated apparatus of single or double (device); or being applied to the surface of more complicated delivery system as a kind of component, this delivery system comprises the apparatus of making as the conventional tampon, tampon shape apparatus, pessulum, ring, bar, pad, bolster, sheet, pipe, ball, tablet or the beadlet that are covered by said composition as second component, by different materials.With fluid composition as can the spray system supplying and store, this system on spraying epithelial surface the time fast gelation change into froth bed.Film can be formed in advance the sheet of required form and size or spray on mucosa, labia or the scrotum epithelial surface, wherein its gelatine and form foam, film or gel or be applied to the surface and the surface of covering and coating vagina, nasal cavity, oral cavity, scrotum or labia apparatus.
Background of invention is with relevant open
Skin, scrotum and labia epithelium and mucosa be as those of lining vagina or nasal cavity and oral cavity, as the protective barrier of anti-external environment condition antibacterial and virus are got rid of and are prevented that them from entering in the body by this approach.Except that getting rid of noxious bacteria and virus, above-mentioned barrier is also very effective when eliminating is applied to the chemicals, medicine of skin, labia, scrotum or mucosa and pharmacological agent.This barrier is formed by several layers.
In skin, horny layer is represented the keratinization layer, and epidermis is formed by the pavement epithelium cells layer, and corium is by forming with the staggered cell thin of epidermis, and the basement membrane covering causes body circulation capillary tube clump.
The protective epithelium of nasal cavity, vagina or oral cavity, labia and scrotum, similar to skin, by a plurality of layers of lining of stratified squamous epithelium, this stratified squamous epithelium is formed for getting rid of the protective barrier of antibacterial and other foreign substance.The epithelium in lining nasal cavity, vagina or oral cavity is represented muciparous mucomembranous surface.Therefore mucosa is the mucous secretion film in lining body cavity and road.Labia is formed by non-mucosa non-keratinocyte epithelium.Scrotum is formed by the slight cornified epithelium of non-mucosa, and this epithelium is different with the keratinization layer of skin.
Owing to prevent the existence of the barrier that antibacterial, virus and various chemicals enter, encounter problems when attempting carrying pharmacological agent by these tissues.Therefore, the therapeutic effect of nasal cavity, oral cavity or vaginal medication mainly is limited to outside or inner local the use up to now.Therefore advantageously provide convenience, effective and pratical and feasible the permission locally carry medicine or carry medicine to body circulation compositions by nasal cavity, oral cavity, vagina, labia or scrotum epithelium.
For making pharmacological agent pass through skin barrier, attempted developing and/or find to promote it to pass through the chemical compound of these barriers.The most known these penetration enhancers are dimethyl sulfoxine (DMSO).DMSO have quick change cell membrane characteristic with allow material between cell by, enter cell and the ability by cell.These unique characteristics make this chemical compound be used for laboratory as penetration enhancer with as the cryoprotective agent of cell freezing.Be that DMSO is dangerous for the human body use lamentedly, forbid being used for the human body purposes by Food and Drug Administration.
Second kind of dermal osmosis accelerator, ethoxydiglycol is with its trade name TRANSCUTOL
Known, be developed recently and introduce and be used for topical use and be mainly used in the conveying that promotes that the skin tanning agent enters epidermis and enters ectoderma cutis.
The in-vitro evaluation that ethoxydiglycol is worn the penetration enhancer of skin administration as clonazepam (clonazepam) is described in
Eur.J.Pharm.Sci.,9:365-372 (2000).This open source literature is estimated ethoxydiglycol and is combined separately or with propylene glycol, to the infiltration facilitation effect of clonazepam by the artificial membrane is made up of the carbopol hydrogel and the infiltration by stripped (in vitro) rabbit ear skin.The increase that article has been described as the percutaneous infiltration of preparaton Chinese medicine is the function of ethoxydiglycol content, infer when combining with propylene glycol with infiltration and carrier property, ethoxydiglycol is the good enhancing carrier that is used for clonazepam, increases the flux that medicine enters skin and process skin.
Yet up to recently, ethoxydiglycol is not used in or is shown as and promotes medicine process nasal cavity, oral cavity and vaginal mucosa or enter the body circulation by labia or scrotum to wear the mucosa conveying or be described as having such performance.The ethoxydiglycol that is used to promote transvaginal to carry was before used by the inventor openly, and such purposes is described in patent 6,086,909,6,197,327 B1,6,416,779 B1,6,572, the pending application Ser.Nos.:10/226 that 874 B1 and on August 21st, 2002 submit to, the pending application Ser.Nos.:10/349 that on January 22nd, 667 and 2003 submitted to, 029, be incorporated herein all documents as a reference.
Although these patents and application have been described mucosa and have been worn mucosal drug and carry, they do not describe the conveying of using biodegradation or non-biodegradation compositions in detail, although when when preparation these compositionss can provide effectively, make things convenient for, actual, simply, the advantage of practicality, soft easy complications and Noninvasive, in the time can spraying, provide meet scrotum, labia, vagina, oral cavity or or the advantage of nasal cavity epithelial surface, maybe drying and forming-film when being prepared as foam and film meets the advantage of separating materialization and non-keratinocyte epithelial surface easily.
Therefore, advantageously obtain therapeutic combination, they can promote pharmacological agent to the conveying of the keratinization in labia, scrotum, vagina, nasal cavity or oral cavity or non-keratinocyte epithelium with promote these pharmacological activity medicament parts to enter or carry out the circulation of whole body body by these tissues.
Be used for carrying medicine to develop and be described in patent 6,086 recently to the transvaginal compositions in uterus, 909,6,416,779 B1,6,572,874 B1 and 6,197,327 B1 by vaginal mucosa.These compositionss typically be prepared as wear the mucosa preparaton or, preferred for preparation is worn the apparatus of mucosa preparaton for introducing this.
Have been found that concrete composition prepared now; those that particularly are formulated as solid, semisolid or liquid foam or film can overcome the observed general considerations that is caused by above-mentioned protection barrier, and this barrier effectively prevents to enter the body circulation through labia, through the drug conveying of scrotum or through mucous membrane by nasal cavity, oral cavity, vagina, labia or scrotum epithelium.
Therefore the purpose of this invention is to provide delivering therapeutic agents to and by the keratinization of lining nasal cavity, oral cavity or vaginal canal and labia and scrotum and the therapeutic composition of non-keratinocyte epithelium.Such conveying comprises and is configured as biodegradation or non-biodegradation foam and film preparaton, this preparaton when preparation be soft, can tortuous, Noninvasive, adapt to the surface of scrotum, labia, nasal cavity, oral cavity or vaginal canal at an easy rate.
Be incorporated herein by reference through this at this all patents, patent application and open source literature of quoting.
Summary of the invention
One aspect of the present invention is that the treatment that contains at least a matrix polymer chemical compound or its mixture and treatment effective agent has compositions, and this medicament is to be mixed with the different-stiffness of solid, semisolid or liquid and biodegradation or the nonbiodegradable foam or the film of viscosity.
Another aspect of the present invention is the therapeutic combination that contains the matrix polymer of the biodegradation that is mixed with solid, semisolid or liquid or nonbiodegradable foam or film, and said composition comprises mucoadhesive in addition, discharge improver, penetration enhancer, absorption enhancer and/or another kind of pharmacology can accept excipient and additive.
Another aspect of the present invention is foam of polymers or film composition, and said composition is particularly suitable for the effective agent transvaginal of treatment, nasal cavity, oral cavity, labia, scrotum is local or carry or be transported to the body circulation through the epithelium part.
Another aspect of the present invention is foam of polymers or the film composition that contains the effective agent of wherein introducing of treatment, this is treated effective agent and is selected from antiinflammatory, local anesthetic, calcium channel antagonist, potassium channel blocker, beta-adrenergic excitomotor, vasodilation, cyclooxygenase-2 inhibitors, antibacterial, antiviral agent, antifungal, antipsychotic, osteoporosis agent, migraine agent, anti-hiv agent, Anti-epileptics, antitumor agent, chemotherapeutics, antipsychotic, anti-neural degeneration agent, OPIOIDS analgesic or biotechnology-derived medicament, as protein and peptide.
Another aspect of the present invention is to use polymeric biological degraded or nonbiodegradable foam or film composition to be used for part or system's delivering therapeutic agents to the sanguimotor method of body, wherein said composition contains and is selected from the effective agent of following treatment: antiinflammatory, local anesthetic, calcium channel antagonist, potassium channel blocker, the beta-adrenergic excitomotor, vasodilation, cyclooxygenase-2 inhibitors, antibacterial, antiviral agent, antifungal, antipsychotic, the osteoporosis agent, Anti-epileptics, antipsychotic and anti-neural degeneration agent, the migraine agent, anti-hiv agent, the pharmacological agent of antitumor agent and chemotherapeutics or biotechnology-derived is as protein and peptide.
Another aspect of the present invention is biodegradation or nonbiodegradable mucosa, through mucous membrane, labia, through labia, scrotum and through the foam or the film composition of scrotum, said composition be used for delivering therapeutic agents to and/or pass through nasal cavity, the oral cavity, vagina, labia or scrotum epithelium, said composition is made up of following material: about 1-about 95% is selected from following polymer: avicel cellulose, polyacrylic acid, Polyethylene Glycol, polypropylene glycol, the divinyl glycol, poly(ethylene oxide), poly(propylene oxide), carboxymethyl cellulose, hydroxyethyl-cellulose, polyactide, poly-ethanol ester lactide, polymethylacrylic acid, poly--γ-benzyl-L-glutamate, poly-fumaric acid propylene glycol ester, poly--∈-caprolactone, polybutylene terephthalate (PBT), polyvinyl alcohol, polyvingl ether, poly--l-vinyl-2-pyrrolidone, 2,5-dimethyl-1, the 5-hexadiene, divinylbenzene, polystyrene-divinylbenzene, the polyacid acid anhydride is as gathering-two (to carboxyl-phenoxypropanes)-altogether-decanedioic acid, polyhydroxyalkanoatefrom, poly-beta-hydroxy-butyrate, poly--beta-butyrolactone, the silica gel that alkyl replaces, positive tetraethyl orthosilicate, dimethyldiethoxysilane, baregin, collagen, or its mixture, wherein said composition is prepared into foam, this foam forms in advance as tampon, tampon shape cylinder, bar, pad, bolster, pipe, film, sheet, ball, tablet, the apparatus of ring or beadlet, or be prepared as film, or introduce or be applied to the surface of complicated delivery system as a kind of component, this induction system comprise as second component by different materials, as the conventional tampon that partially or completely covers by this foam or film, tampon shape apparatus, pessulum, ring, bar, pad, bolster, sheet, pipe, ball, the apparatus that tablet or beadlet are made, wherein said composition is as solid, semisolid or liquid preparation are supplied and are stored, and said preparation is contacting with epithelial tissue or keeping on the apparatus surface time or change anatomy and the treatment needs of physical appearance to adapt to medicine-feeding part fast.
Another aspect of the present invention is foam tablet or dissolvable tablets, and this tablet is used for the individually dosed of pharmacology's effective agent or introduces apparatus, and this apparatus inserts nasal cavity, oral cavity or vaginal canal, or is placed on and labia or the close contact position of scrotum.
Another aspect of the present invention is to contain pharmacology's effective agent, be suitable for being placed on biodegradation or non-biodegradation film on nasal cavity, oral cavity, vagina, labia or the scrotum epithelial surface.
Definition
As used herein
The stratified tissue of " protective epithelium " expression cell structure, wherein this layer covers outer surface or lining bodily cavity.On the histology, epithelial tissue can be divided into protective epithelium and glandular epithelium.The present invention relates to cover the mucous secretion epithelium,, but also cover labia and scrotum keratinization epithelium as nasal cavity, oral cavity and vagina.
" mucosa " expression medicine is to the conveying of vagina, nasal cavity or mouth mucus secretory epithelium.
" through mucous membrane " expression enters body circulation drug system by vagina, nasal cavity or mouth mucus secretory epithelium and carries.
" oral cavity " expression physiology medicament is to the conveying of the mucosa in lining oral cavity.
" labia " expression pharmacological agent is carried to the part of labia.
" through labia " expression is carried by the system of non-mucosa non-keratinocyte labia epithelium to body circulation pharmacological agent.
" scrotum " expression medicine is carried to the part of scrotum.
" through scrotum " expression medicine enters body circulation system by the slight keratinization epithelium of the non-mucosa of scrotum and carries.
" cornified " expression keratinized tissue.
" medicament ", " pharmacology's effective agent ", " pharmacology can accept medicament ", the natural or synthetic compound of " active drug Neo-Confucianism can be accepted medicament " or " medicine " expression, this chemical compound is when be administered into generation biology effect or curative effect when comprising human mammal by mucosa or labia or scrotum epithelium.
" pharmacy medicament " or " medicinal medicament " expression excipient, pharmacology's non-activity typically.
The chemical compound that " release improver " or " carrier " expression can help medicine to discharge from compositions.
" alginic acid " expression alginic acid or its salt are as snow algin.
The conjugate of synthetic or non-natural conjugate or aliphatic diol and aliphatic series or the aromatic alcohol or the ester of " not ionizable diol, derivatives " expression aliphatic diol is as the trade name TRANSCUTOL with it
Known ethoxydiglycol, or its mixture.
" TRANSCUTOL
" expression is also with the known ethoxydiglycol of the title diethyl single ethylether of alcohol.
" AVICEL
" 50 microns of nominal dimensions of expression, available from the avicel cellulose of FMC Biopolymers.
" NOVEON
" expression polycarbophil or by the polyacrylic acid of divinyl two alcohol and cross linkings.
" poloxamer " represents ethylene oxide-propylene oxide block copolymer family, is also referred to as the copolymer of polyoxyethylene and polyoxypropylene.
" carbopol " expression is by the slight crosslinked acrylic acid polymer of polyalkenyl polyether, available from B.F.Goodrich.
Brief Description Of Drawings
Fig. 1 illustrates the release that ketorolac tromethamine enters the pH4.2 phosphate buffer from alginic acid hydroxypropyl emthylcellulose foam.
Fig. 2 shows that ketorolac enters the release of the synthetic vaginal fluid of pH 4.2 from the alginic acid film.
Fig. 3 shows that hydroxypropyl emthylcellulose absorbs and dissolving with the water of hydroxypropyl emthylcellulose-Avicel foam under different percentile mixture.
Detailed Description Of The Invention
The invention describes useful biodegradation of treatment or non-biodegradation foam or film composition and local epithelium or through the epithelium delivering therapeutic agents to and pass through nasal cavity, oral cavity, vagina, labia or scrotum epithelium and enter whole body body circulation method.
Foam of the present invention or film composition allow pharmacological activity medicament part directly effectively to carry to vagina, nasal cavity or oral epithelium or by the whole body body circulation that penetrates into of vagina, nasal cavity, oral cavity, labia or scrotum epithelium.Avoided the problem relevant with the bonded new compositions of new transport way with the oral administration that causes the medicine inactivation, or the problem relevant: require medicine invasive intravenous, intramuscular, intraperitoneal, Intradermal, epidermis or the subcutaneous delivery approach of injection, visit doctor's office and/or medical worker's assistance with following aspect.
Newfound local epithelium or invasive through epithelium nasal cavity, oral cavity, vagina, labia or scrotum route of administration right and wrong, do not require medical worker's assistance or visit doctor's office, the needs of the excess dose drug administration that the elimination oral delivery needs, more convenient, practical and economical.Medicine according to the present invention is walked around gastrointestinal absorption, hepatic metabolism and kidney deactivation through carrying through epithelium of vagina, nasal cavity, oral cavity, labia or scrotum epithelium, directly carries the medicine part or directly arrives the systemic blood circulation.In addition, because their softnesses, flexible and adapt to tissue surface easily, all foams or film composition are obvious more practical, Noninvasives and comfortable.
Foam compositions can form structural foam in advance, and this foam is biodegradation or nonbiodegradable, the form of acceptant tissue surface.Film composition can be used alone as single or multiple lift single or double nasal cavity, oral cavity, vagina or labia film insert or placement easily or be sprayed at labia and other tissue surface on or as the coating on the non-film apparatus, even as the coating on the film apparatus.
In addition, compositions of the present invention, because with bonded their chemical property of component of its processing, promote and allow to have different chemical property-as different pharmaceutical stability, dissolubility with enter the conveying of medicine of the absorption of tissue, with because by the mucoadhesive of compositions, medicine bonding and that permeance property is assisted is local or be delivered directly to blood circulation, can eliminate more observed side effect during these medicines of high dose of administration.These different chemical properties depend on the chemical compound as mucoadhesive or release improver, typically be hydrophilic or hydrophobic polymer, combine separately or with another kind of polymer, and/or further with suitable penetration enhancer or absorption enhancer and/or discharge improver and combine, this depends on medicine.
I.
Therapeutic combination
Substantially comprise and bonded hydrophilic of pharmacology's effective agent or hydrophobic polymer component according to therapeutic combination of the present invention, the preferred hydrophilic polymer, foam of polymers or film are processed in described combination.Find the effective delivering therapeutic agents of this conjugate to and by nasal cavity, oral cavity or vagina epithelium and non-keratinocyteization or slight keratinization epithelium by labia and scrotum.When said composition is placed on vagina, nasal cavity or oral mucous epithelia and labia and the scrotum epithelial surface, discharge the therapeutic agent of introducing foam or film from said composition, work or permeate by tissue in this therapeutic agent part, or both worked also by the tissue infiltration in the part.Foam of the present invention or film have controlled gelatine, swelling and degradation rate.
Foam of the present invention or film composition comprise at least two kinds of components, it is polymer, preferred hydrophilic polymer or its mixture, they typically have mucosa adhesion or carrier property, with therapeutic agent or its mixture, but can comprise another kind of mucoadhesive, release improver, penetration enhancer, absorption enhancer and/or another kind of pharmaceutical excipient and additive in addition.
Foam of the present invention or film composition are particularly suitable for the part and carry delivering therapeutic agents or be transported to the body circulation through epithelium vagina, nasal cavity, oral cavity, labia and scrotum.The representative therapy agent is antiinflammatory, local anesthetic, calcium channel antagonist, potassium channel blocker, beta-adrenergic excitomotor, vasodilation, cyclooxygenase-2 inhibitors, antibacterial, antiviral agent, antifungal, antipsychotic, osteoporosis agent, migraine agent, anti-hiv agent, antitumor agent, Anti-epileptics, anti-neural degeneration agent and chemotherapeutics, with the pharmacological agent of biotechnology-derived, as protein and peptide.
Compositions of the present invention preferably is formulated as solid, semisolid or liquid foam or film.
A.
The foam preparaton
Be suitable for foam preparaton that pharmacological agent carries and comprise the solid structure that forms concrete shape in advance or the foam of semisolid or liquid preparation, it is the formation froth bed when contact with epithelial tissue or apparatus surface.Can or apply the endoporus of preproduction foam of polymers support or coating or the surface introducing pharmacology effective agent of foam or film before foam forms.
Can medicine and other additive be joined in the foam of polymers support of preproduction by adopting medicine or the weak solution spraying foam of additive in dichloromethane or ethanol.The quantity of preferred solution, temperature and surrounding air speed make just goes in the foam or solvent evaporation after the absorption on the surface at it in solution absorption.This similar process is in the process of using when pill is applied coating.
The liquor capacity of selecting every gram foam to apply makes that foamy basic major part is all coated.After determining suitable liquor capacity, select drug level to obtain the required drug dose of per unit weight or per unit volume.
Perhaps, medicine and additive can be introduced by emulsion coating, wherein force foam stand by preproduction by apply Water-In-Oil that vacuum will prepare or O/w emulsion in polymer solution.After solvent evaporation, the polymeric film that comprises medicine and additive is deposited on the porous support surface.The machined parameters of this emulsion coating is well known by persons skilled in the art, requires to optimize any kind technology, additive and equipment stable and that pharmacological agent discharges and think within the scope of the invention from supporting structure.
1.
Foamy manufacturing
The present invention relates to be fit to therapeutic agent is transported to and passes through the foam compositions of nasal cavity, oral cavity, vagina, labia and scrotum keratinization and the conveying of non-keratinocyte epithelium.This biodegradation or non-biodegradation foam compositions with solid, semisolid or liquid structure can be by prepared known in the art, this technology is introduced hole in polymeric matrix, promptly by lyophilization, ventilation, lyophilization, hydrocarbon template, salt or microgranule leaches, polymerization and the free form manufacturing technology such as the three-dimensional polymer printing of gel or solvent cast, gas expansion, sintering, High Internal Phase Emulsion.Making foamy most preferred process is lyophilization, below describes this technology in detail.The previous example that can be used for making the foamy process application that comprises among the present invention of having described.Referring to, for example
Proc. Natl.Acad.Sci.USA, 97,1970-1975 (2000);
Polymer, 35,1068-1077 (1994);
J.Biomat.Sci.Polym.Ed., 7,23-28 (1995);
Biomaterials, 17,1417-1422 (1996);
J.Biomed.Mat.Res., 30,449-461 (1996);
J.Controlled Rel., 40,77-87 (1996);
Biomaterials, 24,3133-3137 (2003) and
J.Controlled Rel., 87,57-68 (2003)).
Freeze dried foam is perforate, high surface, biodegradation or nonbiodegradable structure, and this structure can be from various polymer, preferably from the hydrophilic polymer manufacturing.Foamed materials be characterized as controlled chemistry and physical property, it can be used according to their hope and regulate.
Adjustable performance comprises hydrophilic, absorption of fluids speed, degraded situation and rate of dissolution, and melting speed is the needed time of foam complete obiteration.The water of release, foam or the film of explanation medicine absorbs and dissolving in Fig. 1-3.
Therefore the present invention can be foam, and this foam hydration and the quick gel that forms can distribute in big relatively zone.The present invention also can be a foam, and this foam hydration is gentle to form gel slowly so that therapeutic agent continues to discharge in a few hours or a couple of days.Can advantageously improve these performances to the ratio of medicine and/or additive by ratio or the polymer that changes between polymer, the polymer, as shown in figs. 1 and 3.
Typically, adopt the quantity that needs preparation 1-10% (w/w) solution, by at moisture or non-aqueous solvent, as methanol, ethanol, glycerol, dichloromethane, propylene glycol, Allyl carbonate, sugared furan alcohol, spermol, Difluoroethane and isopropyl alcohol, dissolving is as host material, the suitable polymer as shown in following portion C in preferably purifying waste water, the preferred hydrophilic polymer, or its mixture prepares freeze dried foam.Perhaps, can in acetic acid, cyclohexane extraction, acetonitrile, the tert-butyl alcohol, ethanol and isopropyl alcohol or in the mixture of water and nonaqueous solvent, prepare the polymer solution that contains medicine and additive.
Compositions is prepared by following mode: at suitable solvent, the pharmacological agent of about 2000mg of about 0.01-that dissolving is selected in preferably purifying waste water or more right quantity or the mixture of two or more such medicaments, this solution and polymer solution are mixed together about 10 minutes-Yue several hours, preferred about 15-60 minute, arrive under about-100 ℃ at-60 ℃, preferably freezing this mixture becomes required shape under-80 ℃, for example before freezing, by this mixture being poured into the bottle of required form, dish, plate, manage and wait or be poured in the cystosepiment, when freezing, described plate is cut into the structure of required form, use the suitable freeze dryer or the freeze-drier of any kind to come this freezing of lyophilizing.Lyophilisation condition and device and equipment are well known by persons skilled in the art, and the freeze-dry process or the equipment of any kind are thought within the scope of the invention.
Typically, with above-mentioned polymer or polymeric blends and drug solution form, at first freezing at least 15 minutes, typically at least 30 minutes for the required shape and size of the freeze dried foam of finishing.For aqueous solution, cryogenic temperature is 0 ℃ to-80 ℃ and preferably less than-10 ℃.After freezing, refrigerated sample is launched or takes out from form thing, selectively can simply heat in formation beyond the region of objective existence portion.Refrigerated sample is put into the pallet that is pre-cooling to the temperature that is lower than the solvent freezing point.Under vacuum, at 0 ℃ to-80 ℃ with preferably sample was changed into foam in about 48 hours-Yue 144 hours less than-20 ℃ of following lyophilizing (freeze-dried).May need still less or more time, this depends on the thickness and the composition of foam or film.Except that after anhydrating, foam or film are warmed up to room temperature, typically simultaneously still under vacuum.This process is wherein comprised the useful foam or the film of treatment of the medicine of introducing.
Perhaps, can be by ventilation prepared closed pore form.In this technology, polymer solution in mixer such as Oakes mixer, by high shear mixing blade rapid mixing, is injected air or another kind of gas simultaneously.The foam that obtains can be metered to mould or spray on the matrix membrane as thin layer.Can or adopt the heat drying foam under environmental condition then.
Perhaps, can and foam lyophilizing more than freezing according to process described above.
2.
Biodegradation and non-biodegradation foam
In one embodiment, the present invention relates to be mixed with foam, be used for the compositions that delivering therapeutic agents arrived or passed through nasal cavity, oral cavity, vagina, labia and scrotum epithelium.Can regulate foamy physics of the present invention and chemical property to optimize their required purposes, this is realized by following mode: the rate of release of foamy pharmacological activity medicament is introduced in control.Medicine can take place by diffusion or corrosion or by both combinations from the release of transfer tool, causes medicament to arrive or carries by immediately, the controlled or pulse of nasal cavity, oral cavity, vagina, labia or scrotum epithelium.
Rate of drug release depends on the physicochemical property of medicine, foamy composition, at the surrounding medium of administration position, wherein pH, ionic strength, temperature, buffer capacity, enzymatic activity and cytoactive only are several examples of influential variable.
From the compositions manufacturing, the foam stand that is degraded into junior unit more or polymer by various mechanism in the administration position is categorized as the biodegradation system.The decision design biological degradation polyalcohol is to allow the drug release by body or surface erosion, comprise separately or with the bonded natural and synthetic polymer of following material: the representativeness of polysaccharide but non-limitative example such as alginate, glucosan, cellulose, collagen and chemical derivative thereof, protein such as albumin gelatin and copolymer and blend, many carboxylic acids such as polyactide, poly-ethanol ester lactide and copolymer thereof, polyethylene terephthalate, poly-butanoic acid, poly-valeric acid, polyactide-be total to-caprolactone, polyanhydride, many positive esters and blend and copolymer.
Non-degraded foam system among the present invention is a kind of like this system, and wherein compositions resists the destruction at administration position delivery system 3 d function, makes to be mainly diffusion from the drug release of compositions.Can be separately or be used in combination with biological degradation polyalcohol with the representativeness of the non-biodegradation polymer of making the foam compositions that has desirable characteristics as described herein but non-limitative example comprises polyamide, polyethylene, polypropylene, polystyrene, polrvinyl chloride, polymethylacrylic acid and independent derivant thereof or as its copolymer mixture.
3.
Foamy shape
Can use suitable technology known in the art to prepare foam compositions by lyophilizing with certain size scope and different shape, this shape comprises foam film, sheet, bolster, pipe, cylinder, ball, tablet, ring, beadlet and any other required shape, this technology is introduced hole in polymeric matrix, i.e. lyophilization, ventilation, lyophilization, hydrocarbon template, salt or microgranule leaches, polymerization and the free form manufacturing technology such as the three-dimensional polymer printing of gel or solvent cast, gas expansion, sintering, High Internal Phase Emulsion.
Foam is formed apparatus as tampon, tampon shape cylinder, bar, pad, bolster, pipe, sheet, ball, tablet, ring or beadlet or required any other shape in advance; or being applied to the surface of more complicated delivery system as a kind of component, this delivery system comprises as second component, by the apparatus of different materials as being made by conventional vagina tampon, tampon shape apparatus, pessulum, ring, bar, pad, bolster, sheet, pipe, ball, tablet or the beadlet of this foam coverage.
The foam that contains medicine can be used as independent drug conveying platform, wherein medicine is introduced foam, be a foamy part, or they can be as a kind of component of more complicated delivery system, this induction system also can comprise suppository, tampon or tampon shape apparatus.Medicine is introduced before can forming at the foam of solid, semisolid or liquid structure, or it can be introduced by the endoporus or the surface that partially or completely apply preproduction foam of polymers support.
The optimization approach of deposition of medicament is to adopt to concentrate drug solution spraying foam, subsequent drying solvent.
Can medicine and other additive be joined in the freeze dried foam by adopting medicine or the weak solution spraying foam of additive in dichloromethane or ethanol.The quantity of preferred solution, temperature and surrounding air speed make solution absorption go in the foam after solvent evaporate immediately.This similar process is in the process of using when pill is applied coating.
The liquor capacity of selecting every gram foam to apply makes that foamy basic major part is coated.After determining suitable liquor capacity, select drug level to obtain the required drug dose of per unit weight or per unit volume.
Perhaps and more not preferably, can be to foam by nozzle metering medicaments solution.Compare with above-mentioned spraying method, the covering of the method is even inadequately, and solvent is removed slowly.
4.
Medicine is from foamy release
In use, with preformed foam apparatus be placed on nasal cavity, oral cavity, vaginal canal in the tight contact position of epithelium or cover labia and scrotum, or at the suitable composition in situ formation foam of required administration position use, said composition produces porous foam structure immediately after administration, can spray quinoline or gelatine compositions but for example use.Determine from the release conditions of foam compositions by required Drug therapy effect and medicament time of contact.With most preferably contacting of epithelium is to place afterwards at least two hours in the body.By instruction of the present invention, the optimum of pharmacological activity medicament discharges and can continue to many 72 hours.Can realize longer drug release by the mixture that adopts polymer and/or additive, allow the long-term drug release that continues prolongation.
By change introducing the composition sustained release situation of polymer and other additive, it influence porosity and density and the size by the change apparatus, and is such as is known to persons skilled in the art.When administration position and component interaction, biodegradable foamed system begins the unit of disintegrate Cheng Gengxiao.When the destruction of apparatus occurred, medicine discharged from foam, followed immediately, controlled or pulse release kinetics.
Preferably, active component discharges at least 8 hours continuously after contacting with epithelium.May need pulse release at first several hrs, be slower " keeping " rate of release 72 hours at the most subsequently.Can use nonbiodegradable foam system to reach similar drug conveying situation, and the pharmacological activity medicament to or transfer rate by epithelial tissue mainly by dissolving control.
Apparatus of the present invention has excellent adhesion performance to keep the tight contact to epithelium in the administration position.Bonding component that requires polymer composition in this apparatus and administration position such as water or ion interact.
Perhaps, the foam compositions among the present invention can comprise excipient, and this excipient promotes the administration intrinsic bond properties of apparatus afterwards.The bonding permission of apparatus is when the safety location of when wearing and tearing apparatus, guarantees in being of value to the certain hour of disease treatment the desired conveying to active agents.
Active component can mainly influence the epithelial surface of wherein administration, it cause the local of disease or part treatment or, perhaps, main effect occurs in the obvious therapeutic goal place that separates with the administration position, therefore, depend on system's distribution of active agents enter the transfer of body circulation through epithelial tissue after.When contacting with the rete malpighii that covers vagina epithelium, freeze dried foam is absorption fluids at first, this begins to discharge active agents by dissolving, simultaneously, support foaming structure to become the degradation process of gel, this gel has good structural integrity to carry sumatriptan (sumatriptan) in the time that prolongs before further being dissolved into liquid.This feature promotes the bonding of apparatus, helps to control the transfer rate of active component.
Apparatus of the present invention reaches is dissolved into liquid substantially and is called dissolution time up to no longer significantly putting required time when foam or film apparatus structure, can use the dissolution in vitro technical measurement.When dissolving fully, biodegradable foamedly in nasal secretion, saliva or vaginal fluid, be separated into littler polymer unit fully.Therefore, do not need to remove apparatus, finish by the Continuous Flow of physiology's vaginal secretions from the normal drainage of nasal cavity, oral cavity or vaginal canal.
See that in Fig. 3 dissolution mechanism and water absorb.Be controlled and can change from the drug release of foam of the present invention or film by design.Particularly, some polymer allows to absorb the water that enters foam or gel quickly, causes the faster release of medicine.Other polymer or mixture, those that particularly comprise hydroxypropyl emthylcellulose are of value to drug release rates that slower water absorbs and reduces.The water absorption rate is the index that foam discharges the medicine ability.For determining independent or bonded avicel cellulose (Avicel) and HPMC to be estimated from foamy water absorption rate.Preparation is used for the foam of this research according to embodiment 5-7.
B.
Film composition
In one embodiment, the present invention relates to prepare film forming, be used for the part or through the polymer of epithelium vagina, oral cavity, nasal cavity, labia or scrotum delivering therapeutic agents.Polymeric film of the present invention is the high surface sheet from various polymer solution preparations, this sheet processing film forming.
Similar in appearance to foam, the controlled chemistry that is characterized as them and the physical property of film of the present invention, it can be regulated according to the application that they are wished.Adjustable performance comprises hydrophilic, absorption of fluids speed and comprises the degraded situation of rate of dissolution.Therefore film of the present invention comes release of active ingredients by the combination of dissolving or corrosion or these mechanism, and this depends on the interaction of the component of film composition and administration position, and this component includes but not limited to fluid and ion.This can reach required film bioadhesive performance, and control is for the desired medicament rate of release of the therapeutic scheme of a few hours or a couple of days.
Typically, prepare the quantity that about 1-about 10% (w/w) solution needs with needs, at water or nonaqueous solvent, as methanol, ethanol, glycerol, dichloromethane, propylene glycol, Allyl carbonate, sugared furan alcohol, spermol, Difluoroethane and isopropyl alcohol, dissolving is as the suitable polymer of listing below the host material in preferably purifying waste water, the preferred hydrophilic polymer, or its mixture prepares film.Then at water or nonaqueous solvent, preferably purify waste water in dissolving select be about the about 2000mg right quantity of 0.01-and the more mixture of pharmacological agent or two or more such medicaments once in a while.Two kinds of solution were mixed about 10 minutes-Yue several hours, preferred about 15-60 minute, with this mixture with the about 2mm of 0.5-, preferably about 1mm layer at plane surface or plate, as glass plate on, for example use the TCL applicator to sprawl, dry under 25 ℃, evaporate fully until water.Rete typically about 148 hours of about 24-, usually about 70 hours after drying.Perhaps, can prepare film by spraying this mixture and drying.
In other embodiments, can in acetic acid, cyclohexane extraction, acetonitrile, the tert-butyl alcohol, ethanol and isopropyl alcohol or in the mixture of water and nonaqueous solvent, prepare the polymer solution that contains medicine and additive.
1.
Monofilm and multilayer film
The monofilm that comprises medicine is used in particular in the application that wherein film contacts with tissue on two sides.Therefore medicine can be gone out from two side diffusion of film.
When requiring different functions from the second layer, two membranes or be useful more than two membranes.For example, for oral application, the medicament elution layer is that anti-stick film needs most.Yet in opposite one side, the secondary shielding rete can be used for preventing that medicine from entering the loss of saliva and digestive system.Useful screened film polymer comprises polyethylene terephthalate, polyethylene and nylon.
Function example as multilayer film, multilayer film is by above-mentioned screened film, as the intermediate layer of medicine storage tank with comprise mucoadhesive and/or discharge the 3rd layer of improver and form, the trilamellar membrane body contact, controlling diaphragm and tissue bonding and discharge the speed of medicine from the storage tank layer.
2.
Film v. foam compositions
Polymeric film is the conforming layer of material, and is thick less than 4mm usually, is made up of the polymer that structural integrity is provided at least in part.Selectively, film can have multiple structure, and wherein each layer has different compositions.The air of carrying secretly in the normal film can be much smaller than 10% of by volume.0.5 inch thick more thick polymer layer is commonly referred to sheet at the most.
For film of the present invention, production method is the solution that produces at least a polymer.This solution can comprise other dissolving and insoluble polymer, medicine, transcutol, excipient etc.Solution can be sprawled equably or sprayed on surface (glass, paper, or another polymer sheet), can be under environmental condition or selectively, heat drying.After solvent evaporation, stay the film that to peel off.Film is because the good comfort that their thinness provides the patient to use for nasal cavity, oral cavity, vagina, labia or scrotum.
On the contrary, foam of polymers can be made up of polymer composition as mentioned above, and it comprises at least 10%, usually greater than 50% the voidage of being filled by air or another kind of gas.For freeze dried foam, from the solution of polymer and additive.Normally at least a polymer is water miscible.After solution was poured into the mould of required form, solution was frozen into solid.Refrigerated solution selectively, after mould removal, at low temperature, is reduced to low-level with lyophilizing under low pressure down as-40 ℃ up to water content.Under drying condition, after the intensification sample, obtain freeze dried foam with mold shape.Foam is soft three-dimensional apparatus, and it is especially easily for vagina and labia treatment.
C.
Be used to produce the host material of foam or film composition
The host material that is used for the preparation of foam of the present invention or film composition is hydrophilic or hydrophobic polymer, the preferred hydrophilic polymer.These polymer can be used alone or in conjunction with each other.When using two or more mixture of polymers, it can have different concentration and ratio each other.
The non-exclusive list of matrix polymer comprises cellulose and cellulose derivative, avicel cellulose, polyacrylic acid, Polyethylene Glycol, polypropylene glycol, divinyl glycol, poly(ethylene oxide), poly(propylene oxide).Other possible polymer comprises cellulose derivative such as carboxymethyl cellulose, hydroxyethyl-cellulose, polyactide, poly-ethanol ester lactide, polymethylacrylic acid, poly--γ-benzyl-L-glutamate, poly-fumaric acid propylene glycol ester, poly--∈-caprolactone, poly--mutual-phenenyl two acid bromide two alcohol ester, polyvinyl alcohol, polyvingl ether, poly--l-vinyl-2-pyrrolidone, 2,5-dimethyl-1, the 5-hexadiene, divinylbenzene, polystyrene-divinylbenzene, polyanhydride is as poly-biconjugate carboxyl-phenoxypropane-common-decanedioic acid, polyhydroxyalkanoatefrom such as poly-beta-hydroxy-butyrate or poly--beta-butyrolactone, silica gel such as positive tetraethyl orthosilicate and dimethyldiethoxysilane with the alkyl replacement.
1.
Hydrophilic polymer
The example that is suitable for the hydrophilic polymer of foam or film manufacturing comprises hydroxypropyl emthylcellulose (HPMC), sodium carboxymethyl cellulose, Polyethylene Glycol (PEG), alginic acid, snow algin, baregin, gelatin, collagen, polyvinyl pyrrolidone, poloxamer (poloxamer), acrylic acid based polymer, as carbopol, noveon, polyurethane, polyvinyl alcohol, chitosan, hydroxypropyl cellulose, poly(ethylene oxide), fibronectin, hyaluronic acid, polysaccharide glue such as gum karaya, polyacrylamide, polycarbophil, glucosan, xanthan gum, polyacrylamide, polyacrylamide, crosslinked polymethyl vinyl ether-altogether-maleic anhydride, commercially available is Gentrez
TM, gelatin, corn starch and composition thereof.
2.
Hydrophobic polymer
Be suitable for forming foam and or the example of the hydrophobic polymer of film especially poly(propylene oxide), polyamide, polystyrene and polymethylacrylic acid.
In table 1, list suitable and preferred host material that is used for foam and film preparation and composition thereof.
Table 1
| Polymer | Form in (% polymer) | Foam |
| HPMC | 1.0 | Film |
| 2.5 | Film | |
| 5.0 | Film | |
| Gelatin | 1.0 | Film |
| 2.5 | Film, rod | |
| 5.0 | Film, rod | |
| 10.0 | Film, rod | |
| Gelatin/HPMC (50/50) | 1.0 | Film |
| 2.5 | Film | |
| 5.0 | Film | |
| 10.0 | Film | |
| Alginic acid | 1.0 | Film |
| 2.5 | Film, rod | |
| 5.0 | Film, rod | |
| 10.0 | Film | |
| Alginic acid/HPMC (50/50) | 1.0 | Film |
| 2.5 | Film | |
| 5.0 | Film | |
| Alginic acid/PEG 400 (25/75) | 5.0 | Film, rod |
| Alginic acid/PEG 1400 (25/75) | 5.0 | Film, rod |
| Alginic acid/PEG 4000 (25/75) | 5.0 | Film, rod |
| Alginic acid/PEG 400w/ ketoconazole (25/75) | 5.0 | Rod |
| Carbopol | 0.5 | Film |
| 1.0 | Film | |
| 2.5 | Film | |
| Noveon | 0.5 | Film |
| 1.0 | Film | |
| 2.5 | Film | |
| Baregin | 1.0 | Film |
| 2.5 | Film, rod | |
| 5.0 | Film, rod | |
| 10.0 | Rod | |
| Baregin/HPMC (50/50) | 1.0 | Film |
| 2.5 | Film | |
| 5.0 | Film | |
| Collagen | 0.5 | Film |
| 1.0 | Film | |
| 2.5 | Film |
The alginic acid that uses is a snow algin.
3.
Additive
Foam and film preparaton can only comprise two kinds of components, it is above-mentioned polymer and following at therapeutic agent described in the part D, or they can comprise other component, this other component comprises various excipient and additive, as discharge improver, mucoadhesive and/or penetration enhancer/absorption enhancer, filler, dyestuff etc., or other pharmaceutical excipient and additive.
A.
Mucoadhesive
As mentioned above, foam of the present invention or film composition comprise polymer, and it can have or can not have the mucoadhesive energy.In many cases, polymer, particularly hydrophilic polymer have the mucoadhesive energy of some degree.Such performance advantageously supports compositions of the present invention to be adhered to the ability of mucosa, labia or scrotum epithelium, yet, it may be enough to maybe may to be not enough to reach for compositions to the local adherent complete mucoadhesive of tissue or provide pharmacological agent through epithelium, through labia or through enough supports of scrotum conveying.Under these circumstances, compositions can comprise easily another kind of mucoadhesive with reach with the prolongation of tissue and closely contact, compositions is to the interaction on bonding and medicine and mucosa, labia or the scrotum surface of organizing.
Be used to increase film or foam apparatus to the adherent mucoadhesive of mucosa preferably polymer such as hydroxypropyl emthylcellulose, carboxymethyl cellulose, polyactide-altogether-glycollide, chitosan, chitosan ester or propylidene chloride chitosan, sodium alginate, poloxamer, carbopol, baregin or another kind of cellulose derivative.Because it is a kind of substrate of foam or film preparation, hydroxypropyl emthylcellulose (HPMC) is particularly preferred for the present invention.Other example of mucoadhesive comprises polyacrylic acid, hyaluronic acid, polyvinyl alcohol, polyvinyl pyrrolidone, polycarbophil (polycarbophil) and carbopol (carbopol).
Mucoadhesive typically exists with about 0.5-about 10%.
B.
Penetration enhancer/absorption enhancer
For using through mucous membrane, conducting drugs to the body circulation through labia or through the scrotum compositions, compositions comprises absorption enhancer or penetration enhancer in addition.
Absorption enhancer or penetration enhancer are ionizable or can not ionized molecules that their change the physics and/or the biochemistry shielding properties of epithelium, have strengthened the pharmacological activity medicament and have entered the body circulation and shift.
Ionizable penetration enhancer comprises cation, anion and amphion excipient, and they are suitable for improving the transfer through the protective epithelium on vagina, nasal cavity, oral cavity and labia or scrotum surface of hydrophilic and lipophilic drugs molecule.
The preferred anionic surfactants penetration enhancer comprises derivant, bile acid, phosphate ester, carboxylate and the sulfates/sulfonates of fatty acid.For the purpose of simple example, show the sodium gegenion for anion-permeable membrane promoter, it is not restrictive, comprises the gegenion of any other bio-compatibility of the known at present or following discovery of those skilled in the art.
Particularly; the preferred anionic surfactants penetration enhancer comprises Sodium caproate; sodium caprylate; Capric acid sodium salt; sodium laurate; Sodium myristate; sodium palmitate; palmitoleic acid sodium; enuatrol; sodium ricinoleate; linoleic acid sodium; sodium stearate; sodium lauryl sulfate; sodium tetradecyl sulfate; sodium lauryl sarcosinate; aerosol OT; natrii tauroglycocholas; sodium cholate; NaGC; sodium deoxycholate; sodium taurodeoxycholate; glycodesoxycholic acid sodium; ursodesoxycholic acid sodium; chenodeoxy cholic acid sodium; cattle sulphur chenodeoxy cholic acid sodium; glycol chenodeoxy cholic acid sodium; CHOLYLSARCOSINE sodium; N-methyl sodium taurocholate; cattle sulphur-24; 25-dihydro fusidic acid (fusidate) sodium; polyoxyethylene-10 oleyl ether disodium hydrogen phosphate; the esterification products of aliphatic alcohol or with the alcohol ethoxylate of phosphoric acid or anhydride; ether carboxylate; the succinum monoglyceride; sodium stearyl fumarate; stearyl propylene glycol hydrogen succinate ester; the list of monoglyceride and diglyceride/diacetyl tartrate, the citrate of monoglyceride and diglyceride; the glyceryl of fatty acid-newborn ester; the lactyl ester of fatty acid; alginate; ethoxylated alkyl sulfates; the alkylbenzene sulfone; alpha-alkene sulfonate; acyl-hydroxyethyl sulfonate; acyl taurine salt; alkyl glyceryl ether sulfonate; the octyl group disodium sulfosuccinate; endecatylene acylamino--MEA-disodium sulfosuccinate; phosphatidic acid; phosphatidyl glycerol; polyacrylic acid; hyaluronate sodium; glycyrrhetinic acid; edetate and sodium citrate.
Cation permeability promoter comprises ammonium salt and pyridiniujm.For for simplicity, show chlorine root gegenion for cation permeability promoter, it is not restrictive, comprises the gegenion of any other bio-compatibility of the known at present or following discovery of those skilled in the art.Particularly, the preferred cation penetration enhancer comprises chitosan, N-trimethyl chitosan TMC, poly--the L-arginine chitosan, poly-L-Lysine chitosan, aminated gelatin, chlorination cetyl three ammoniums, chlorination decyl trimethyl ammonium, chlorination cetyl trimethyl ammonium, chlorination alkyl benzyl dimethyl ammonium, chlorination diisobutyl phenoxy group ethyoxyl dimethyl benzyl ammonium, tonsilon pyridine, chlorination isopropyl pyridine, N-lauryl, N, N-dimethylglycine, N-octyl group, N, N-diethyl glycine, polyoxyethylene-15 coconut palm amine, poly-L-Lysine, poly--the L-arginine.
The amphion penetration enhancer is included in the natural and synthetic compound that the administration position shows positive charge and negative charge simultaneously.Particularly; preferred amphion penetration enhancer comprises lecithin, LYSOLECITHIN SUNLECITHIN A, hydroxylated lecithin, lysophosphatidylcholine, phosphoric acid lecithin, cephalin, serinephosphatide, two capryl-L-alpha-phosphate lecithin, lauroyl carnitine, acylcarnitines, palmityl-D, L-carnitine.
The concentration of these promoter is changed significantly along with the chemical compound difference, yet they are preferably with about 0.01-about 60% and the more preferably from about concentration use of 10-about 15%.
Not ionizable glycol ethers derivant is by being selected from the polyoxyethylene alkyl ether that following chemical compound is represented, ester or with the diol, derivatives of glyceride: polyoxyethylene alkyl ether is for example, polyoxyethylene lauryl ether, polyoxyethylene list oleyl ether and ethoxydiglycol, the polyoxyethylene groups alkylphenol, for example polyoxyethylene groups nonyl phenol and polyoxyethylene octyl phenol ether, the polyoxyethylene sterol, for example polyoxyethylene cholesterol ether and polyoxyethylene soyasterol ether, and cyclodextrin, alpha-cyclodextrin for example, beta-schardinger dextrin-, gamma-cyclodextrin, DM-methylates-beta-schardinger dextrin-, 2-HP-or sorbitol.
Not ionizable diol ester derivant is a polyoxyethylene glycol ester; the polyoxyethylene fatty acid glyceride; the polyoxyethylene fatty acid glyceride; polyoxyethylene glyceride or polyoxyethylene vegetable oil or hydrogenated oil and fat; this derivant is represented by being selected from following chemical compound: polyoxyethylene glycol ester; polyoxyethylene monooleate for example; the polyoxyethylene dilaurate; polyoxyethylene list and dioleate; the polyoxyethylene fatty acid glyceride; for example polyoxyethylene glyceryl laurate and polyoxyethylene glyceryl oleate; the polypropylene glycol fatty acid ester; for example oleic acid propylene glycol ester and propylene glycol stearate; polyoxyethylene glyceride; for example polyoxyethylene sorbitan monooleate dehydration and polyoxyethylene tristearate; polyoxyethylene vegetable oil or hydrogenated oil and fat, for example polyoxyethylene hydrogenated Oleum Ricini; polyoxyethylene almond oil (almond oil); polyoxyethylene almond oil (apricot kernel oil); polyoxyethylene sad or caprin or LABRASOL.
With the not ionizable diol, derivatives of glyceride by representing with the diol, derivatives of glyceride, for example polyoxyethylene oleate and polyoxyethylene glyceryl stearate.
In the polymer composition that is used to form foam of the present invention or film, change or not ionogenic promoter with the about 60wt% of about 0.01-, the about 25wt% of preferably about 5-, the most preferably from about quantity of the about 15wt% of 10-existence.
Most preferred not ionizable diol, derivatives is an ethoxydiglycol, also is known as TRANSCUTOL
, available from Gattefosse, Westwood, N.J.
C.
Discharge improver
For reaching from mucosa, through mucous membrane, labia, through labia, scrotum or through the required drug release of scrotum foam or film composition, pharmacological agent is optionally introduced carrier, medicine has low-affinity for this carrier, and this carrier promotes can improve such rate of release from drug release or this carrier of foam or film.Therefore, lipophilic drugs is introduced hydrophilic modifier and lipophilic drugs introduced hydrophilic carrier.
Hydrophilic modifier comprises Macrogol 200, Polyethylene Glycol 8000, poloxamer, polyoxyethylene glyceryl coconut palm acid esters and carbopol.
Hydrophobic modified dose comprises Suppocire AS2, Suppocire AS2X, suppocire CM, WitepsolH15, Witepsol W25, mineral oil, Semen Maydis oil, paraffin oil, Semen Brassicae Campestris oil, Oleum Ricini, Oleum Gossypii semen, lecithin, Oleum Arachidis hypogaeae semen, Oleum sesami, soybean oil and hydrogenated vegetable oil.
Discharging improver can the quantity with the about 70wt% of about 5%-exist in compositions.
D.
Other excipient and additive
1.
Solubilizing agent
Solubilizing agent be used for the production period of apparatus increase medicament the dissolubility of preparaton or, perhaps, between the operating period of apparatus, increase the dissolubility of medicament in tissue fluid.
Can use any medicinal solubilizing agent.Preferred solubilizing agent is Polyethylene Glycol (PEG), ring glucosan, sugared furan alcohol, propylene glycol, Allyl carbonate and surfactant.
Typically the quantity with about 5%-about 30% adds solubilizing agent.
2.
Buffer agent
Buffer agent is used to control the release of the pH of the middle environment of apparatus with control or raising medicament.Any medicinal buffer or its mixture can be used for purpose of the present invention.Illustrative buffer agent is potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium carbonate, sodium bicarbonate, boric acid, tartaric acid, tromethane citrate (tris citrate) and triethanolamine.
Typically the quantity with about 1%-about 10% adds buffer agent.
3.
Filler
Filler is the inert fraction that is used to increase size or improves the apparatus usability.Any medicinal filler can be advantageously used in purpose of the present invention.Illustrative filler is calcium carbonate, silicon dioxide, titanium dioxide, paraffin, stearic acid, Talcum, wax and zinc stearate.
Typically the quantity with about 5%-about 15% adds filler.
4.
Antiseptic
Antiseptic is used to prevent at the duration of storage microbial growth.Can use the suitable antiseptic of all pharmacy.Preferred antiseptic is benzalkonium chloride, propyl p-hydroxybenzoate, benzyl alcohol, sorbic acid, phenol, phenethanol, BHA and BHT.
Typically the quantity with about 0.01%-about 5% adds antiseptic.
5.
Plasticizer
Plasticizer is to be used for softening film or foamy chemical compound.Illustrative plasticizer is glycerol, water, Polyethylene Glycol, propylene glycol, sorbitol and triacetin, to mention.
Typically the quantity with about 5%-about 25% adds plasticizer.
6.
Surfactant
Surfactant as Tween 80, sodium lauryl sulfate and Brij, can advantageously adopt the quantity of 0.01%-about 5% to add as needs.
7.
Antioxidant
The antioxidant that is applicable to foam and film is selected from ascorbic acid, BHA, BHT, sodium sulfite, vitamin E, sodium metabisulfite and propyl gallate, can adopt the quantity of 0.1%-about 3% to add.
D.
Pharmacological agent
Foam of the present invention or film composition are suitable for the mixture of any pharmacological agent or two or more medicaments is carried through epithelium, and it helps therapeutic effect maybe can be transported to the body circulation by vagina, nasal cavity, oral cavity, labia or scrotum epithelium when the part is transported to vagina, nasal cavity, oral cavity, labia or scrotum epithelium.
A.
Representative pharmacological agent
The representativeness of using foam of the present invention or film to carry easily
Pharmacology's medicine AgentBe the pharmacological agent of antiinflammatory, calcium or potassium channel antagonist, beta-adrenergic excitomotor, vasodilation, local anesthetic, cyclooxygenase-2 inhibitors, antibacterial, antiviral agent, antipsychotic, Anti-epileptics, antifungal, osteoporosis agent, migraine agent, anti-hiv agent, anti-neural degeneration agent, anticarcinogen, OPIOIDS analgesic and biotechnology-derived, as protein and peptide.The non-limiting representative example of these medicines is non-steroidal anti-inflammatory agents, and it comprises aspirin, ibuprofen, indomethacin, diclofenac, bute, bromfenac, fragrant that ester, sulindac, Nabumetone, ketorolac and naproxen.
The example of calcium channel antagonist comprises diltiazem, isradipine, nimodipine, felodipine, verapamil, nifedipine, nicardipine and bepridil.
The example of potassium channel blocker comprises dofetilide, almokalant, sematilide, ambasilide, azimilide, tedisamil, sotalol, piroxicam and ibutilide.
The example of beta-adrenergic excitomotor comprises terbutaline, albuterol, orciprenaline and ritodrine.
Vasodilation comprises nitroglycerin, sorbide nitrate and isosorbide mononitrate.
The example of cyclooxygenase (COX) inhibitor is aspirin, naproxen, ketoprofen, ketorolac, indomethacin, fragrant that ester, ibuprofen, diclofenac, tenoxicam, bromfenal, celecoxib, Nabumetone, bute, rofecoxib, sulindac, meloxicam and flosulide.
The example of local anesthetic comprises lignocaine, mepivacaine, etidocaine, bupivacaine, 2-chloroprocaine hydrochlorate, procaine and tetracaine hydrochloride.
The example of anti-osteoporotic is to be selected from following diphosphate: alendronate, clodronate, 1-hydroxyl-ethyl-1,1-di 2 ethylhexyl phosphonic acid (etidronate), Pamidronate, Tiludronate, ibandronate, olpadronate, Risedronate, neridronic acid salt and zoledronic acid salt.
The example of antifungal, antibacterial is miconazole, terconazole (triaconazole), isoconazole, fenticonazole, fluconazol, nystatin, ketoconazole, clotrimazole, butoconazole, econazole, metronidazole, clindamycin, 5-fluorouracil, acyclovir, AZT, famciclovir, penicillin, tetracycline, erythromycin, amprenavir, amividine, ganciclovir, indivaris, lapinavis, nelfinavir, rifonavir and saguinar.
The example of migraine agent is Almogran, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, Zomitriptan, Ergotamine, dihydroergotamine, bosentan and draws naphthalene smooth.
The example of anti-tumor (neoplastin) or chemotherapeutics is vincristine, cisplatin, doxorubicin, daunorubicin, actinomycin D, colchicine, digoxin, etoposide, holder Bo Xikang, irinotecan, paclitaxel, docetaxel, cyclophosphamide, methotrexate, gemcitabine, mitoxantrone, holder Bo Xikang, moors glycosides, vinblastine and ametycin for mud.
The example of anti-hiv agent is Saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, Lopinavir and ganciclovir.
The example of antinauseant is aprepitant, cyclizine, dolasetron, domperidone, dronabinol, levonantradol, metoclopramide, nabilone, ondansetron, prochlorperazine, promethazine and tropisetron.
The example of OPIOIDS analgesic is buprenorphine, dynorphin A, fentanyl, metenkephalin, morphine, naloxone, pentazocine and spiradoline.
The example of Anti-epileptics is carbamazepine, clonazepam, phenobarbital, phenytoin, primidone and valproate.
The example that is used for the antipsychotic of neurodegenerative disease treatment is bromocriptine, carbidopa, galantamine, memantine, pergolide, selegiline, tacrine and benzhexol.
The example that is used for the treatment of the medicine of mental illness is alprazolam, amitriptyline, amoxapine, BUP, buspirone, chlordiazepoxide, chlorpromazine, clozapine, diazepam, fluoxetine, fluphenazine, haloperidol, imipramine, loxapine, metrotiline, oxazepam, paroxetine, perphenazine, phenelzine, pimozide, prazepam, protriptyline, risperidone, selegiline, Sertraline, thoridazine and trazodone.
The example of antinanseant is aprepitant, cyclizine, dolasetron, domperidone, dronabinol, levonantradol, metoclopramide, nabilone, ondansetron, prochlorperazine, promethazine and tropisetron.
The example of biotechnology-derived medicine is insulin, calcitonin, somatostatin, vassopressin, leuprorelin acetate (luprolide), oxytocin, bivalirudin, eptifibatide (integrilin), brain natriuretic peptide, 1: PN: WO02056903 PAGE: 25 claimed protein, proglumide G17 peptide, ziconotide, the U.S. logical sequence (cereport) of triphen, interleukin, humanized antibodies and growth hormone.
B.
The dosage of pharmacological agent
Add pharmacological agent with part or the effective quantity of whole body therapeutic.Typically, with the quantity adding medicine of the about 2000mg of about 0.01-, as follows.By accident, dosage can surpass the 2000mg scope up to 20, and 000mg is particularly when existing repeat administration.
Calcium channel antagonist: bepridil (50-1600mg), diltiazem (30-1500mg), felodipine (1-50mg), isradipine (1-20mg), nicardipine (30-600mg), nifedipine (15-650mg), nimodipine (100-1400mg), verapamil (100-1500mg).
Potassium channel blocker: almokalant, ambasilide, azimilide, dofetilide (0.2-5mg), ibutilide (0.3-5mg), sematilide, sotalol, (80-1300mg), tedisamil.
Beta-adrenergic excitomotor: orciprenaline (20-240mg), ritodrine (100-2000mg), albuterol (0.1-5mg), terbutaline (1-60mg).
Vasodilation: sorbide nitrate (10-500mg), isosorbide mononitrate (10-250mg), nitroglycerin (2-150mg).
Cyclooxygenase-2 inhibitors: aspirin (5-8000mg), bromfenac, celecoxib (100-2400mg), diclofenac (50-800mg), fragrant that ester, flosulide, ibuprofen (600-6,000mg), indomethacin (30-600mg), ketoprofen (50-1200mg), ketorolac (5-200mg), meloxicam (2-60mg), Nabumetone (500-4,000mg), naproxen (100-3000mg), phylbutazone, rofecoxib (5-200mg), sulindac, tenoxicam.
Local anesthetic: 2-chloroprocaine (50-2400mg), bupivacaine (50-1600mg), etidocaine, lignocaine (10-150mg), mepivacaine (25-1600mg), procaine (150-3,000mg), tetracaine.
Anti-osteoporotic: alendronate (2-160mg), olpadronate, clodronate (1-3200mg), 1-hydroxyl-ethyl-1,1-di 2 ethylhexyl phosphonic acid (2-1400mg), ibandronate (0.01-100mg), neridronic acid salt (0.1-200mg), Pamidronate (1-3,000mg), Risedronate (0.05-50mg), Tiludronate (0.02-400mg), zoledronic acid (0.05-150mg).
Antibacterial: acyclovir (100-4,000mg), amprenavir (150-7,200mg), amivudine (10-1200mg), butoconazole, clindamycin (75-20,000mg), clotrimazole (5-200mg), econazole (2-100mg), and erythromycin (100-16,000mg), famciclovir, fenticonazole, fluconazol (50-1600mg), ganciclovir (250-12,000mg), indinavir (400-9,600mg), isoconazole, ketoconazole (1-6400mg), Lopinavir (50-2000mg), and metronidazole (100-10,000mg), miconazole (600-15,000mg), nelfinavir (300-10,000mg), Nystatin (0.5-12 Mio U), penicillin V K (100-8000mg), ritonavir (150-4800mg), and Saquinavir (300-15,000mg), terconazole (triaconazole) (2-400mg), and tetracycline (300-16,000mg).
Migraine agent: Almogran (2-100mg), bosentan (50-1000mg), dihydroergotamine (1-20mg), eletriptan (1-400mg), Ergotamine, frovatriptan, draw naphthalene smooth, naratriptan (0.5-20mg), rizatriptan (2-120mg), sumatriptan (10-800mg), Zomitriptan (0.5-40mg).
Antitumor agent/chemotherapeutics: actinomycin D, cisplatin (5-400mg/m
2), colchicine (0.1-50mg), cyclophosphamide (50-800mg), daunorubicin, docetaxel, doxorubicin (50-2,500mg/m
2), etoposide, gemcitabine (70-4,000mg/m
2), irinotecan, methotrexate (0.2-40mg), mitoxantrone (0.05-2mg/m
2), ametycin, paclitaxel is for mud pool glycosides, holder Bo Xikang, vinblastine, vincristine (1-200mg).
The biotechnology-derived medicine: 1: PN: WO02056903 PAGE: 25 claimed protein, bivalirudin (0.5-1000mg), calcitonin (100-20,000IU), cereport, proglumide G17 peptide, growth hormone, the humanized antibodies, insulin, integrilin (0.1-1400mg), interleukin, luprolide, brain natriuretic peptide (0.001-2mg), oxytocin (0.01-10,000U), somatostatin, vassopressin (0.1-40,000U), ziconotide.
Antinauseant: aprepitant (40-600mg), cyclizine, dolasetron (25-400mg), domperidone, dronabinol (1-60mg/m
2), levonantradol, metoclopramide (10-200mg), nabilone, ondansetron (4-75mg), prochlorperazine (5-600mg), promethazine (5-200mg), tropisetron.
OPIOIDS analgesic: buprenorphine (0.5-2000mg), dynorphin A, fentanyl (0.1-10mg), metenkephalin, morphine (30-1000mg), naloxone (0.1-3000mg), pentazocine (50-1500mg), spiradoline.
Anti-epileptics: carbamazepine (100-9,600mg), clonazepam (3-60mg), phenobarbital (15-800mg), phenytoin (150-1200mg), primidone (5-3000mg), valproate (350-12,000mg)
Medicine in the neurodegenerative disease: bromocriptine (0.5-400mg), carbidopa (5-400mg), galantamine (4-100mg), memantine, pergolide (0.02-20mg), selegiline (2-40mg), tacrine (20-650mg), benzhexol (0.5-40mg)
Medicine in the mental illness: alprazolam (0.2-40mg), amitriptyline (5-400mg), amoxapine (25-1200mg), BUP (25-1800mg), buspirone (5-250mg), chlordiazepoxide (5-1200mg), chlorpromazine (10-3200mg), clozapine (5-1200mg), diazepam (1-200mg), fluoxetine (5-350mg), fluphenazine (0.2-40mg), haloperidol (0.5-400mg), imipramine (10-1200mg), loxapine (10-1000mg), maprotiline (10-1000mg), oxazepam (20-600mg), paroxetine (5-250mg), perphenazine (10-300mg), phenelzine (20-400mg), pimozide (0.5-40mg), prazepam, protriptyline (10-300mg), risperidone (0.1-20mg), department unlucky blue (2-40mg), Sertraline (10-800mg), thoridazine, trazodone (50-1200mg.
C.
Pharmacological agent is from the uniformity and the release of foam or film composition
For determining that whether foam of the present invention or film are effective to drug conveying and whether therefore are applicable to therapeutic purposes, measure medicine from the release of foam or film and its uniformity.
The freeze dried foam rod mensuration that use contains the ketorolac tromethamine in snow algin is expressed as the uniformity of pharmacological agent from foamy recovery and release %.
Ketorolac is being measured by UV absorbance method according to the distributing homogeneity in the foam of embodiment 5 preparations.Set up the standard curve of ketorolac in deionized water by under 322.5nm (path length 12.31mm), measuring the UV absorbance: independent alginic acid for following material, the ketorolac solution that contains ketorolac (7.4%) and snow algin (92.6%), with comprise ketorolac (3.8%), the ketorolac solution of alginic acid (48.1%) and hydroxypropyl emthylcellulose (48.1%) mixture.The alginic acid solution that does not contain medicine is used alone as tester, has insignificant absorbance.
For this research, select from three foam rods A of the mixture preparation that comprises 7.4% ketorolac and 92.6% alginic acid, B and C are used for analyzing.The irregular material of about 2mm is removed from the two ends of foam rods.Use razor blade, each foam rods is divided into 5 shorter cylindrical section of length 9mm.Write down the weight of each section.Use high intensity mixer that each section is dispensed into the 200ml deionized water.Write down each solution at the UV of 322.5nm absorbance.
From standard curve, calculate in the following relationship in the ketorolac solution concentration of μ g/ml: absorbance=0.051 * concentration+0.0001.
For each foam section, the concentration that multiply by 200ml obtains the weight (μ g) of ketorolac in this solution.For each section, ketorolac weight is obtained each section ketorolac weight in every mg foam μ g ketorolac divided by the weight of foam section.At last, the result who obtains is obtained from the % ketorolac of each foam section recovery divided by the desired quantity (73.4 μ g/mg foam) from preparaton.The results are shown in Table 2.
Table 2
The ketorolac response rate (%)
| Foam rods A | Foam rods B | Foam rods C | |
| Foam section # | |||
| 1 | 99.7 | 98.6 | 96 |
| 2 | 100 | 97.3 | 97.3 |
| 3 | 92.1 | 96.7 | 95.8 |
| 4 | 91.8 | 99.5 | 99 |
| 5 | 96 | 94.7 | 97.7 |
| Meansigma methods | 95.9 | 97.4 | 97.2 |
| Standard deviation | 3.95 | 1.85 | 1.31 |
| High/low ratio | 1.09 | 1.04 | 1.03 |
| High/low ratio, all data | 1.09 |
The ideal 100% ketorolac response rate is every 1mg foam 73.4 μ g ketorolacs.
Snow algin (AA) solution concentration is that every 100g water comprises the 2.5g alginic acid.
The concentration of ketorolac tromethamine is represented 7.43% of foam wt.The ratio of ketorolac: AA is 2: 25.
As shown in table 2, for the average recovery rate of all three rods very near 100%, promptly respectively 95.7,97.4 and 97.7%.The result show when medicine with medicine to polymer ratio existed in 2: 25 the time, ketorolac release almost can reach 100% from the foam of snow algin preparation.
Above research further is deployed in pH 4.22 phosphate buffers ketorolac tromethamine from the foamy release of snow algin/HPMC.For this research, ketorolac concentration is 7.4%, is normalized to the 120mg foam.Foam is from snow algin/HPMC mixture preparation.
The result who is presented among Fig. 1 shows: with only compare from the foam of ketorolac and alginic acid preparation, have slower ketorolac controlled release speed from the foam of the mixture preparation of ketorolac, alginic acid and HPMC.
In Fig. 1, as can be seen, and only compare, have slower ketorolac controlled release speed from the foam of the mixture preparation of ketorolac, snow algin and HPMC from the foam of ketorolac and snow algin preparation.
As shown in Figure 1, about 93% ketorolac discharges at 2 hours from the alginic acid foam, and about 54% medicine is simultaneously from 50: 50AA: the HPMC foam discharges.
These presentation of results medicines are from foamy slow point to rapid release.Can be by changing substrate or by the binding matrix material with change their relative to each other or with respect to the ratio of medicine and easily control and adjustment release speed.
Data show that further the distribution of ketorolac in lyophilizing alginic acid or alginic acid/HPMC mixture is even especially.
As shown in Figure 1, about 93% ketorolac discharges at 2 hours from the alginic acid foam, and about 54% medicine discharges from alginic acid/HPMC foam (50: 50) simultaneously.
These presentation of results medicines are from foamy slow point to rapid release.Can be by changing substrate or by the binding matrix material with change their relative to each other or with respect to the ratio of medicine and easily control and adjustment release speed.
Data show that further the distribution of ketorolac in lyophilizing alginic acid or alginic acid/HPMC mixture is even especially.
Carry out the test of same type for film composition, wherein measure ketorolac enters the synthetic vaginal fluid of pH 4.2 from the alginic acid film release.
As shown in Figure 2, two hours at interval under, about 55% ketorolac is from the film release of the formulations prepared from solutions be made up of 96.2% alginic acid (sodium salt) and 3.8% ketorolac.Film is according to embodiment 7 preparations.
Carry out the test of same type for film composition, wherein measure ketorolac enters the synthetic vaginal fluid of pH 4.2 from the alginic acid film release.As shown in Figure 2, after two hours, about 55% ketorolac discharges from the film of the formulations prepared from solutions be made up of 96.2% snow algin and 3.8% ketorolac.Film is according to embodiment 7 preparations.
D.
Medicine is from foamy release
Be controlled and can change from the drug release of foam of the present invention or film by design.Particularly, some polymer allows faster absorption to enter the water of foam or gel, cause the faster release of medicine, other polymer or mixture, those that particularly comprise hydroxypropyl emthylcellulose are of value to drug release rates that slower water absorbs and reduces.
For determining to absorb and drug release, to testing separately or with the bonded avicel cellulose of various concentration (Avicel), HPMC from foamy water.Preparation is used for the foam of this research according to embodiment 4-6.
The result who in Fig. 3, shows this research.Fig. 3 clearly illustrate with from comprise every kind of material of equal number (foam of 50%/%50%) AVICEL/HPMC mixture preparation or only compare from the foam of HPMC preparation, faster and absorb water from the foam of AVICEL/HPMC mixture (95.2%/4.8%) preparation with bigger quantity.
Fig. 3 shows that for the foam from the preparation of AVICEL/HPMC mixture, water absorbs the ratio that depends on avicel cellulose (AVICEL).Observing faster when higher with respect to the ratio of HPMC, water absorbs.HPMC slows down water and absorbs.
E.
Improve drug release
For manufacturing has the foam or the rete of rapid release pharmacological activity powder performance, selective polymer or mixture of polymers are to improve the dissolubility of medicine in the hydrated polymer layer.For high solubility agents, hygroscopic polymer such as cellulose derivative are used in combination separately or with the excipient, for example surfactant that reduce viscosity.Perhaps, can pass through the dissolving of hydrophobic polymer such as polyethylene or polypropylene and the use solubility enhancing agent and/or the surfactant promotion low solubility drug of introducing small part.
Improve the polymer of viscosity when being introduced in hydration or reduce the polymer of drug solubility, reach controlled and lasting release.Introduce different physical form such as amorphously also can postpone the release of medicine from foam or film apparatus to crystalline drug particle.Comprise fast can reaching pulse release with the bonded balance scheme of lasting releasing layer, this pulse release is of value to treatment of diseases.
Local foam, film and spray typically comprise mucoadhesive, about 1%-about 10% penetration enhancer and about 1%-about 10% buffer agent of quantity for the about 10wt% concentration of about 0.5wt%-, and its Chinese medicine is to about 85-99 from about 1-15 to polymer ratio.
Through mucous membrane, typically comprise mucoadhesive, about 5%-about 25% penetration enhancer and about 1%-about 10% buffer agent of quantity for the about 25wt% concentration of about 0.5wt%-through labia or through scrotum foam and film, its Chinese medicine is that about 1-15 arrives about 85-99 to polymer ratio.
Local foam of the present invention or film comprise hydrophilic or hydrophobic polymer at least, preferably have the polymer and the pharmacological agent of mucoadhesive energy.If if the mucoadhesive of polymer can be very slight or polymer do not have the mucoadhesive energy, then add mucoadhesive.
The drug conveying of through mucous membrane allows medicine directly to enter the body circulation by nasal cavity, oral cavity, vagina, labia or the transmission of scrotum epithelium, therefore avoids invasive intravenously administrable or more not effective oral administration.
II.
Therapeutic combination
Therapeutic combination of the present invention is local nasal cavity, oral cavity, vagina, labia or scrotum compositions or through last peel composition, and it carries medicine to circulate to body by nasal cavity, oral cavity or vaginal mucosa or by labia or scrotum epithelium.
D.
Local nasal cavity, oral cavity, vagina, labia or scrotum foam or film
Local foam of the present invention or film comprise hydrophilic or hydrophobic polymer at least, preferably have the polymer and the pharmacological agent of mucoadhesive energy.If if the mucoadhesive of polymer can be slightly or polymer do not have the mucoadhesive energy, then add mucoadhesive.
B.
Through last peel composition
Allow medicine directly to enter the body circulation through the epithelium drug conveying, therefore avoid invasive intravenous pharmacy or more effective oral administration by nasal cavity, oral cavity, vaginal mucosa or by labia or the transmission of scrotum epithelium.
Through mucous membrane of the present invention or typically comprise hydrophilic or hydrophobic polymer substrate at least through last foams or film, preferably have mucoadhesive can polymer, penetration enhancer or absorption enhancer and and pharmacological agent.If if the mucoadhesive of polymer can be slightly or polymeric matrix do not have the mucoadhesive energy, then add mucoadhesive.
C.
Concrete illustration foam or film composition
Be to comprise that polymer, the preferred preparation are used for the mucosa adhesive polymer of quick or slow drug conveying or the compositions of polymeric blends specifically with preferred part with through last foams or film composition.These compositionss also comprise cavity foam or film, and it can introduce drug solution or powder easily.Also comprise wherein foam or film is used to cover conventional apparatus, as the compositions of tampon, this depends on the polymer of from this apparatus drug release being regulated (s), depends on their purposes.
Therefore, discharge for topical use for quick medicament, compositions mainly comprises and the suitable bonded AVICEL base polymer of mucoadhesive, and for slow release, compositions mainly comprises the HPMC base polymer, and it can have the mucoadhesive energy but mainly regulate the release of medicine.
Foam of the present invention or film composition are made up of the conjugate of following material substantially: about 2000mg of about 0.01mg-and higher once in a while effective dose pharmacological agent, this medicament be selected from above in part D illustrative medicament or be suitable for any other medicines that through mucous membrane is carried, introducing is from the foam or the film of the preparation of polymer or its mixture, preferably comprises at least a or several penetration enhancers and/or discharges improver and/or other mucoadhesive and/or other non-toxicity pharmacology can accept the biocompatibility excipient.
Said composition typically is formulated as foam or the film that is suitable for inserting nasal cavity, oral cavity or vaginal canal or to be suitable for being placed on the shape preparation on labia or the scrotum, said composition is further optionally introduced nasal cavity, oral cavity, vagina, labia or scrotum apparatus or covered such apparatus.
In table 3, list concrete representative compositions.
Table 3
Foam and film preparaton
| Ex.A Wt/g | Wt％ | Ex.B Wt/g | Wt％ | Ex.C Wt/g | Wt％ | Ex.D Wt/g | Wt％ | Ex.E Wt/g | Wt％ | Ex.F Wt/g | Wt％ | Ex.F-1 Wt/g | Wt％ | |
| Material | ||||||||||||||
| AA | 1.2503 | 46.3 | 2.5023 | 92.6 | 2.5 | 96.2 | ||||||||
| HPMC | 1.2507 | 46.3 | 1 | 4.8 | 5.0014 | 50 | 5.0002 | 100 | 5.0044 | 20 | ||||
| Ktr | 0.2015 | 7.46 | 0.2002 | 7.41 | 0.1 | 3.8 | ||||||||
| Avicel | 20.192 | 95.2 | 5.005 | 50 | 20.0017 | 80 | ||||||||
| | 100 | 100 | 50 | 79 | 90 | 95 | 75 | |||||||
| Form | Foam | Foam | Film | Foam | Foam | Foam | ||||||||
| Ex.5 | Ex.6 | Ex.7 | Ex.8 | Ex.9 | Ex.10 | |||||||||
The AA=alginic acid, sodium salt (Sigma)
HPMC=hydroxypropyl emthylcellulose USP (Dow Chemical)
Ktr=ketorolac tromethamine USP (Quimica Sintetica)
Avicel=Avicel NF, Ph-101 (FMC Biopolymer), 50 microns of nominal granularities
The weight % of Wt%=dried ingredients in foam
Preparation through mucous membrane of the present invention or through in the universal method of peel composition, the essence that depends on medicine, water-soluble or the nonaqueous solvent with the 0.01-2000mg medicine, combine with polymer that is used for foam or film preparation or polymeric blends, experience suitable technology as mentioned above to make foam and film, preferred above-mentioned lyophilizing, ventilation, spray drying or drying.Can add or not add described other additive.Foam that generates or film can be shaped as independent apparatus or introduce apparatus, as intravaginal tampon, foam suppository, foam tablet, foam pessulum etc., but or be molded as the dissolved tablet in oral cavity, bar or pad or introduce foam capsule, gel capsule or be suitable for the another kind of form that nasal cavity, oral cavity inserted and be suitable for these application, or as mentioned above, can introduce or be used for to cover independently non-foam, non-film apparatus.
Typically, for carrying through epithelium vagina, labia and scrotum, because the shielding properties of nasal cavity and buccal mucosa is restricted less, blood supply is compared in vaginal mucosa more near mucomembranous surface, compare with being used for the conveying of nasal cavity or oral transmucosal, compositions comprises more a high proportion of mucoadhesive and penetration enhancer.For labia or scrotum purposes, because these compositionss must pass through non-keratinocyteization or the non-mucous epithelium of keratinization, the quantity that foam or film comprise the mucoadhesive of higher quantity and penetration enhancer is generally higher.
The foam of thing combined according to the invention or film are used for by the infiltration by vagina, nasal cavity, oral cavity, labia or scrotum epithelium medicine being delivered directly to the body circulation.Mucosa adhesive polymer enhancing foam or film are bonding to protective epithelium, the best diol, derivatives that exists strengthens the infiltration by mucosa in these compositionss, the particularly infiltration of medicine, this medicine otherwise can not pass through nasal cavity, oral cavity, vagina, labia or scrotum epithelium barrier.
In addition, by allowing prolongations that contact of medicine and mucomembranous surface, the transfer efficiency of therefore further enhancing chemical compound with the medical compounds of the bonded diol, derivatives solubilising of suitable mucoadhesive.
III.
Preparaton and apparatus
Every kind of foam of the present invention or film composition are prepared according to its concrete purposes, promptly for as local or through epithelium vagina, nasal cavity, oral cavity or labia, through labia, scrotum or through the purposes of scrotum foam or film.
A.
Preparaton
Preparaton is prepared particularly according to the transport way that it may use.
Therefore, through the epithelium administration, compositions is formulated as foam or film for nasal cavity, but but preferred spraying foam or gelatine film.
Carry through epithelium for the oral cavity, compositions is formulated as the apparatus that foam tablet or capsule or gel foam or spray or little introducing can insert oral cavity space, as buccal bioadhesive tablet, bar, permeable pad or bag etc.
Carry for the vagina through mucous membrane, compositions is formulated as foam tampon, foam ring, foam pessulum, foam suppository or foam sponge.In these each can be introduced the intravaginal apparatus easily, for example conventional tampon, pessary, pessulum, suppository or vaginal sponge.
Carry through epithelium for labia, foam or film adopt the structure that can conveniently be connected to labia, as bar, bolster, pad, butterfly binder etc.
Carry through epithelium for scrotum, compositions preferably is formulated as liquid or semisolid, they are sprayed or are applied in addition scrotum easily.
For carrying, but foam or film are formulated as bar, can connect or spray in the above as the gelatine film through the epithelium scrotum.
Discharge for low, bioadhesive foam tablet, bar, pad or film are made up of hydroxypropyl cellulose and polyacrylic acid substantially.In case they are placed near labia or scrotum epithelium on labia or scrotum epithelium or closely, and these foams or film discharge medicine five days at the most.
For all these mucosals, also medicine at first can be formulated as solution, suspension, emulsifiable paste, lotion, paste, ointment or gel, they can be introduced foam or film and be applied to nasal cavity or oral cavity or vagina, labia or scrotum.
The accurate essence of specific through mucous membrane transport way and the form of wherein carrying medicine are depended in the additive that other are suitable and the selection of excipient.Therefore, actual preparaton depends on whether the performance of pharmacological agent and active component will be formulated as foam or film or be formulated as emulsifiable paste, lotion, foam, paste, solution or the gel of introducing foam or film subsequently indirectly, and the characteristic that depends on active component.
2.
Apparatus
According to treatment foam of the present invention or film can be that independent apparatus or it can be the parts of complex combination body more, and this assembly comprises as a kind of foam of component or film and apparatus or the preparaton formed as the material by different with said foam or film of second component.The form of this other apparatus can be for for example, structure apparatus such as bar, pad, ball, bolster, tampon, tampon shape apparatus, pessary, sponge or pessulum, or its form can be preparaton, as tablet, paste, suppository, bioadhesive tablet, bioadhesive micropartical, emulsifiable paste, lotion, ointment or gel.
Structure apparatus such as tampon can be wholly or in part can be adopted by foam or film coating or covering or foam or film anyly arranges easily that to insert apparatus inner or insert certain part of apparatus.
Perhaps, medicine can be introduced the apparatus that non-foam, non-film apparatus and cavity foam or film composition can be used for coating or cover the purpose that only is used for rate of release control.
IV.
Transport way
The present invention relates to be used for delivering therapeutic agents to and by nasal cavity, oral cavity or vaginal mucosa epithelium and by the keratinization of labia and scrotum or the foam of polymers or the film of non-keratinocyte epithelium.Especially, the present invention relates to wherein to contain solid, semisolid or the liquid polymers foam or the film of the therapeutic agent of introducing, wherein when this foam or film were placed on nasal cavity, oral cavity or vaginal mucosa, labia or scrotum surface, this medicament discharged from this foam or film.Foam of the present invention has controlled gelatine, swelling and degradation rate.
Use the various diseases of method of the present invention, comprise that as the treatment of osteoporosis, inflammation, pain, carcinoma of prostate and other tumor growth, fungus, antibacterial, virus or parasitic infection and other medical patient's condition the therapeutic agent with the patient's condition treatment with being suitable for of nasal cavity, oral cavity, vagina, labia or scrotum epithelium directly contacts.Direct contact like this allows immediately, the continuously and effectively treatment of the various diseases or the medical patient's condition.Use is carried through the systemic drug of epithelium approach and is eliminated by gastrointestinal tract or by the medicament inactivation of hepatic metabolism.Direct treatment so also allows only to use the affected medicament of organizing desired dosage of treatment.
For each treatment, as described with the diverse ways compounding pharmaceutical.Simply, the preparation active medicine is to be adhered to mucosa, labia or scrotum epithelium and directly to pass through mucosa, labia or scrotum epithelium or pass through mucosa, labia or the transmission of scrotum epithelium.For carrying through epithelium to the body circulation, if be essential and suitable, add additive for the performance of medicine, this additive promotes to the infiltration of the bonding and medicine that transmits by nasal cavity, oral cavity, vagina, labia or scrotum epithelium.
A.
Vagina is carried
The intravaginal drug delivery system provides the lasting conveying of medicine to vagina epithelium, is used for the treatment of the various patient's condition that comprise following disease: dysmenorrhea, osteoporosis, tumor growth, migraine, neurodegenerative disease, vagina or systemic infection.
Can be undertaken that vagina is carried or it can be solid matter delivery system such as conventional vagina tampon, ring, pessulum, tablet or suppository by the foam apparatus of the medicine that wherein contains introducing or film, for example, by foam or film coating or comprise foam or film.Perhaps, it can be incorporated into have adequate thickness with keep that the vagina epithelium contact prolongs foam or the paste or the gel of film.Perhaps, foam or film for example can provide coating on suppository wall or sponge or other absorbent material by the suspension impregnation of the solution that comprises liquid medicine, lotion or bioadhesive particle.Effectively delivering therapeutic agents comprises within the scope of the invention to any type of drug delivery system of vagina epithelium.
Intravaginal is local carries and comprises contacting of vagina epithelium and mucosa and foam or film composition, said composition comprise the effective agent of independent treatment or with the mixture of following material in the effective agent of treatment: carrier, mucoadhesive, absorption enhancer or penetration enhancer.
Intravaginal is carried and to be reached by following mode: directly carry foam of the present invention or film composition to vagina or carry the vagina of compositions of the present invention to introducing vagina apparatus, as mentioned above.Be placed on the tight contact position of vagina epithelium or be placed on closely position with foam or film composition or by the apparatus of its coating or introducing near vagina epithelium, wherein medicament discharges or discharges from foam or film apparatus from compositions or apparatus, directly or the effect by mucosa adhesion chemical compound, it contacts or is adhered to vagina epithelium and mucosa with vagina epithelium, wherein its permeates vaginal wall and is transported to the uterus and/or is transported to blood circulation by vaginal mucosa absorption or transmission.
Using foam of the present invention or film that medicine is carried by vaginal mucosa has significantly improved systemic bioavailability and has greatly increased the concentration of these medicines in blood plasma.
B.
Carry in the oral cavity
What be used for the conveying of medicine oral cavity allows medicine directly to enter the body circulation by the nasal membrane transmission through last foams or film, therefore avoids invasive intravenously administrable or more effective oral administration.
In one embodiment, the present invention relates to the oral cavity delivery system, designing this system interacts with the epithelium with the lining oral cavity, wherein the medicine that discharges from these apparatus can be local works or successfully through the shielding of oral epithelium with reach mucosa and the tela submucosa zone, wherein they reach the body circulation to be distributed to obviously and the target of administration position separating to buccal mucosa.
Because it is non-invasive and be provided to the easy path of administration position, can be applicable to the patient of two kinds of sexes by the drug conveying of oral cavity route, reach highly conforming properties.Buccal mucosa is rich in blood vessel, promotes to body circulation path.In addition, the medicine that absorbs from buccal mucosa can be avoided the liver first pass metabolism similar in appearance to vaginal approach.
C.
Nasal cavity is carried
In another embodiment, the present invention also relates to the administration of foam and film drug conveying apparatus to nasal membrane, wherein the medicine of Yin Ruing can be discharged into nasal cavity epithelium or infiltration epithelium barrier to reach darker mucosal tissue, and wherein it can reach the body circulation and distributes.The advantage of nasal provides fast Absorption and less drug degradation or does not have drug degradation, and this medicine has the whole body target, and this is to cross (first-pass) metabolism owing to also walk around liver head from the blood drain of nasal cavity.This approach is accepted extensively by the patient because the nasal cavity preparation administration is easy.Interested especially is to be used for biotechnology-derived medicine such as proteinic nasal cavity transportation scheme, and this medicine and health immune system and adjuvant immune defence measure (being vaccine) interact.Only in the following cellular layer of epithelium, provide to the form of immune path by nose with nasal cavity associated lymphoid tissue (NALT).
D.
Labia is carried
The present invention relates to conveying by outside non-keratinocyte mucosa labia epithelium.
Foam of the present invention or film contain therapeutic agent and/or the antiinflammatory that takes stopgap measures, analgesic, chemotherapeutics, antitumor agent, osteoporosis agent, antifungal, antibacterial, antiviral agent or parasiticide to non-keratinocyte labia epithelium or the administration by this barrier, circulate with body with direct conveying pharmacological activity medicament.
With foam or film composition or the pastille apparatus applies once on demand every day, twice or several times, or apply according to therapy.Apparatus, or its active part for example comprise the pad of foam or film composition or are typically provided with drying or wet form or can moistening before inserting by the pad that foam or film composition cover.
Be used for the foam of the drug conveying by the labia epithelium or the lady's apparatus of film insert typically, as band, little bolster, miniature pad, the combinations of preferred little rectangular pad or two bands that connect with the butterfly formula or pad or be connected to one or two such insert of labia, it is in place that it can keep the vagina insert to put.The advantage of labia administration is two apparatus and/or with having both sides, no matter apparatus is pad or band, can pastille, and also these two inserts can be simultaneously apply along each side of clitoris.
One embodiment of the invention are lady's foam or the film apparatus with following design: labia butterfly pad, a pair of Labial pad or Labial pad combine to keep the labia apparatus in place with the vagina insert.Improving above two kinds of apparatus is used to comprise or receives, comprises pharmacological agent or by pharmacological agent dipping, this pharmacological agent of introducing apparatus is formulated as into emulsifiable paste, lotion, foam, ointment, micropartical, nanoparticle, microemulsion, solution or gel.
Perhaps, medicine can be introduced in the coating on foam pad or the sponge, or is included in the foam pad as suppository, sponge, tablet or other absorbent material and can be configured as pad by the suspension dipping of the solution that contains medicine, lotion or the bioadhesive particle of liquid.
The device for vaginal cleaning and hygiene of the drug conveying by labia generally is any structure that can connect or be applied to labia.Apparatus can be independent or be connected to some structural support things, as slide plate.
Typically, except above-mentioned apparatus, device for vaginal cleaning and hygiene can be foam band, adhesive tape, binder, pad, pouch or sack, and they can be directly connected to labia or be fit into some structural support things, as slide plate or clamp ring etc.
Apparatus can comprise optionally that the heating appliances of battery power is to strengthen blood flow and/or to promote drug release and conveying.Battery is connected to the belt that pad maybe can be connected to slide plate or clamp ring.
E.
Scrotum is carried
Foam of the present invention or film allow treatment antiinflammatory, analgesic, chemotherapeutics, osteoporosis agent, antitumor agent, antifungal, antibacterial, antiviral agent or parasiticide pharmacology medicament to keratinization scrotum epithelium or the administration by this barrier, to carry the pharmacological activity medicament to prostate, testis or directly circulate to body and be used for the systemic drug conveying.
The present invention relates to following discovery: can concentrate the conveying of Drug therapy directly to overcome the many problems that adopt the whole body conveying to cause by using topical composition or containing the apparatus of the therapeutic agent of special preparation to non-mucosa scrotum epithelium.The foam of special preparation or film composition promote the medicine that discharges from apparatus to carry through scrotum to bonding being used for of scrotum.Optionally, such compositions contains the enhancing medicine by the infiltration of scrotum epithelium and other components of absorption.
Method through the scrotum treatment comprises typical topical therapeutic, this topical therapeutic comprises by local foam or film composition being provided or comprising the apparatus of topical composition, this topical composition contain combine with at least a mucoadhesive with promote medicine to the bonding of scrotum epithelium with, the medicine that combines with penetration enhancer necessarily and prepare, slight cornified scrotum epithelium is directly contacted with medicine or with the apparatus that comprises medicine, and the time of contact can prolong as required.
One embodiment of the invention relate to by foam or film and form or by male's apparatus of foam or film coating, be used for carrying pharmacological agent by the slight keratinization scrotum of non-mucosa tissue.Apparatus provides the Continuous Contact with the scrotum epithelium, has therefore guaranteed to introduce the therapeutic effect of compositions of the present invention wherein.
Typically, male's apparatus is foam or film band, adhesive tape, binder, pad or band, binder or pad assembly, pouch or sack, they can be directly connected to scrotum or be fit into some structural support things, as clamp ring, athletic supporter, suspender belt etc., but it also can be foam or the film gel that sprays on scrotum.
With the apparatus administration on demand of foam or film composition or foam or film coating be applied to nasal cavity, oral cavity or vaginal canal or to labia or scrotum once a day, twice or repeatedly, or according to the therapy administration or apply.After can using once, it stayed on the protective epithelium several hours or a couple of days or it can repeat to apply with various intervals.Apparatus, or its active part, for example independent foam or film coating pad or the pad that comprises compositions typically provide with drying or wet form or can moistenings before putting into nasal cavity, oral cavity or vaginal canal or labia or scrotum.
Embodiment 1
The ketoconazole foam
This embodiment explanation contains the foamy preparation of ketoconazole.
Obtain PEG400 from Fluka Chemika, obtain snow algin, obtain ketoconazole (USP 24, and is micronized) from Quimica Sintetica S.A from Sigma-Aldrich.
Ketoconazole is dissolved in Polyethylene Glycol (PEG) 400 to form uniform 10mg/mL solution.Snow algin is dissolved in distilled water to produce 5.0w/w% solution.45 milliliters of (45.0mL) alginic acid solution are combined with 5.0mL ketoconazole/PEG 400 solution, these solution are mixed together 15 minutes under 70 ℃.With the aliquot impouring 5.0mL plastic injector of five milliliters of (5.0mL) these solution and freezing down at-80 ℃.Refrigerated cylindrical shape sample is taken out from the syringe mould subsequently, use the lyophilizing of Virtis Unitop 1000L posture lyophilizer.Obtain the foam of polymers that cylindrical shape contains ketoconazole.
Vagina is carried with the foamy preparation that contains medicine
This embodiment describes and is used for the foamy preparation method that local vagina is carried ketoconazole.
Obtain ketoconazole (USP 24, and is micronized) from Quimica Sintetica S.A.From DowChemical, Midland, Michigan obtains hydroxypropyl emthylcellulose (Methocel@K, HPMC K15M).From Spectrum Chemical Manufacturing Corp., Gardena, California obtains polyoxyethylene sorbitan monoleate (Tu Wen @80).
In the 100.0mL distilled water, prepare foam by the Tween 80 that in beaker, adds 1.0gm.Solution is heated to 80 ℃ and add the Methocel of 2.5gm subsequently.Mechanical agitation is used to prepare homogeneous solution.Solution is cooled to 60 ℃ and adding 2.0gm ketoconazole.Mechanical agitation is to mix the preparaton that obtains fully.
18 5.0mL plastic injectors are filled and are put into-80 ℃ refrigerator one hour by the solution that contains medicine.Then VirtisUnitop 1000L lyophilizer is discharged and put into to the freezing cylinder of solution from syringe.The lyophilizing cylinder is to obtain the foam sample that cylindrical shape contains ketoconazole subsequently.
Be used for the foamy preparation that contains medicine that local vagina is carried
This embodiment describes and is used for the foamy preparation method that transvaginal is carried ketoconazole.
Obtain ketoconazole (USP 24, and is micronized) from Quimica Sintetica S.A.From DowChemical, Midland, Michigan obtains hydroxypropyl emthylcellulose (Methocel@K, HPMC K15M).From Spectrum Chemical Manufacturing Corporation, Gardena, California obtains polyoxyethylene sorbitan monoleate (Tu Wen @80).All other chemicals are from Sigma Aldrich, St.Louis, and Missouri obtains.
Use 0.1 mole of citric acid solution and 0.2 mole of phosphoric acid disodium hydrogen formulations prepared from solutions citric acid/phosphate-buffered liquor (pH=5.0).Prepare 100 ml solns by adding the 49.0mL citric acid solution to the 51.0mL disodium phosphate soln.
In 100.0mL citric acid/phosphate-buffered liquor, prepare foam by the Tween 80 that in beaker, adds 1.0gm.Solution is heated to 80 ℃ and add the Methocel of 2.5gm subsequently.Mechanical agitation is to prepare uniform solution.Solution is cooled to 60 ℃ and adding 2.000mg ketoconazole.Mechanical agitation is to mix the preparaton that obtains fully.
18 5.0mL plastic injectors are filled and are put into-80 ℃ refrigerator one hour by the solution that contains medicine.Then Virtis Unitop1000L lyophilizer is discharged and put into to the freezing cylinder of solution from penetrating.The foam sample that contains ketoconazole with the postlyophilization cylinder with the production cylindrical shape.
Be used for the foamy preparation that contains medicine that transvaginal is carried
This embodiment describes and is used for the foamy preparation method that transvaginal is carried ketoconazole.
Be heated to 80 ℃ of preparation foams by the Methocel that in beaker, adds 2.5gm to the neutralization of 100.0mL distilled water.Mechanical agitation is with the preparation homogeneous solution.Solution is cooled to 60 ℃, adds the 2.0gm ketoconazole.
18 5.0mL plastic injectors are filled and are put into-80 ℃ refrigerator one hour by the solution that contains medicine.Then VirtisUnitop 1000L lyophilizer is discharged and put into to the freezing cylinder of solution from syringe.The lyophilizing cylinder contains the foam sample of ketoconazole with the production cylindrical shape subsequently.
Embodiment 5
The foam that contains ketorolac
This embodiment describes the foamy preparation that contains ketorolac of use alginic acid/hydroxypropyl methylcellulose matrix.
Solution is prepared by following mode: adopt down at 70-80 ℃ to mix 0.2015g ketorolac tromethamine and 100.0ml deionized water, add the 1.2507g hydroxypropyl emthylcellulose subsequently, adopt continuous stirring to add the 1.2503g alginic acid subsequently.Warm solution is dispensed into the 10ml plastic injector with the 10ml aliquot.With sample freezing 18hr under-80 ℃.After at room temperature simple the intensification, sample is injected to from syringe on the metal dish that is pre-cooling to-40 ℃.Sample at-20 ℃ of following lyophilization 117hr, is warmed up to room temperature 5hr subsequently under vacuum under vacuum, change into foam.Under drying condition, store the foam that obtains.
Embodiment 6
The alginic acid foam that contains ketorolac
This embodiment describes the foamy preparation of alginic acid that contains ketorolac tromethamine.
Solution is prepared by following mode: adopt down at 70-80 ℃ to mix 0.2002g ketorolac tromethamine and 100.0ml deionized water, adopt continuous stirring to add the 2.5023g alginic acid subsequently.
Warm solution is dispensed into the 10ml plastic injector with the 10ml aliquot.With sample freezing 18hr under-80 ℃.After at room temperature simple the intensification, sample is injected to from syringe on the metal dish that is pre-cooling to-40 ℃.Sample at-20 ℃ of following lyophilization 117hr, is warmed up to room temperature 5hr subsequently under vacuum under vacuum, change into foam.Under drying condition, store the foam that obtains.
Embodiment 7
The alginic acid film that contains ketorolac
This embodiment describes the preparation of the alginic acid film that contains ketorolac tromethamine.
Mix the 2.5g alginic acid and the 50.0ml deionized water prepares solution by adopting down at 80 ℃.After cool to room temperature, add the 100mg ketorolac and stir 1hr.With solution impouring diameter is the mould of 4-inch, at room temperature dry 70hr.Under drying condition, store the film that obtains.
Embodiment 8
Hydroxypropyl emthylcellulose-Avicel foam
This embodiment describes and uses hydroxypropyl emthylcellulose and the avicel cellulose derivant foam preparation as substrate.
By adopting the Avicel PH-101 avicel cellulose and the 79.0g deionized water that mix 1.0046 hydroxypropyl emthylcelluloses and 20.0192g to prepare solution down at about 70 ℃.Warm solution is dispensed into the 5ml plastic injector with the 5ml aliquot.After cool to room temperature, with sample freezing 2hr under-80 ℃.After at room temperature simple the intensification, sample is injected to from syringe on the metal dish that is pre-cooling to-20 ℃.Sample changes into foam at-20 ℃ of following lyophilization 90hr with at-10 ℃ of following lyophilization 2hr.Under vacuum, sample is warmed up to ambient temperature 22hr then.Under drying condition, store the foam rods that obtains.
Embodiment 9
The hydroxypropyl emthylcellulose foam
This embodiment describes and uses hydroxypropyl emthylcellulose and the avicel cellulose derivant foam preparation as substrate.
By adopting the Avicel PH-101 avicel cellulose and the 90.0g deionized water that mix 5.0014 hydroxypropyl emthylcelluloses and 5.0050g to prepare solution down at about 70 ℃.Warm solution is dispensed into the 5ml plastic injector with the 5ml aliquot.After cool to room temperature, with sample freezing 2hr under-80 ℃.After at room temperature simple the intensification, sample is injected to from syringe on the metal dish that is pre-cooling to-20 ℃.Sample changes into foam at-20 ℃ of following lyophilization 90hr with at-10 ℃ of following lyophilization 2hr.Under vacuum, sample is warmed up to ambient temperature 22hr then.Under drying condition, store the foam rods that obtains.
The hydroxypropyl emthylcellulose foam
This embodiment describes and uses hydroxypropyl emthylcellulose and the avicel cellulose derivant foam preparation as substrate.
By adopting the Avicel PH-101 avicel cellulose and the 75.0g deionized water that mix 5.0044 hydroxypropyl emthylcelluloses and 20.0017g to prepare solution down at about 70 ℃.Warm solution is dispensed into the 5ml plastic injector with the 5ml aliquot.After cool to room temperature, with sample freezing 2hr under-80 ℃.After at room temperature simple the intensification, sample is injected to from syringe on the metal dish that is pre-cooling to-20 ℃.Sample changes into foam at-20 ℃ of following lyophilization 90hr with at-10 ℃ of following lyophilization 2hr.Under vacuum, sample is warmed up to ambient temperature 22hr then.Under drying condition, store the foam rods that obtains.
Embodiment 11
Alginic acid-HPMC the foam that contains Transcutol and ketorolac tromethamine
This embodiment describes the foamy preparation of alginic acid/HPMC that contains penetration enhancer transcutol and ketorolac tromethamine.
Solution is prepared by following mode: adopt down at 70-80 ℃ to mix 0.20g ketorolac tromethamine and 100.0ml deionized water, add the 1.25g hydroxypropyl emthylcellulose subsequently, adopt continuous stirring to add the 1.25g alginic acid subsequently.Warm solution is dispensed into the 10ml plastic injector with the 10ml aliquot.With sample freezing 18hr under-80 ℃.After at room temperature simple the intensification, sample is injected to from syringe on the metal dish that is pre-cooling to-40 ℃.Sample at 20 ℃ of following lyophilization 117hr, is warmed up to room temperature 5hr subsequently and changes into foam under vacuum under vacuum.Adopt the 1.6%transcutol trometamol of about 1.0ml in dichloromethane to spray with cutting to about 4cm foam rods long and heavily about 160mg.Use slight heat of vaporization dichloromethane, in foam rods, stay the transcutol trometamol of about 16mg.Under drying condition, store the foam that obtains.
Embodiment 12
The HPMC foam that contains cyclodextrin B
This embodiment describes the foamy preparation of HPMC that contains cyclodextrin B.
Compositions:
| Foam #1 | | | |
| HPMC | 2.4992g (95.21％) | 2.5100g (91.0％) | 2.4906g (83.2％) |
| Beta-schardinger dextrin- | 0.1258g | 0.2940g | 0.5015g |
| (4.79％) | (9.02％) | (16.8％) | |
| Water | 97.5g | 97.5g | |
| BCD: HPMC ratio | 1∶20 | 1∶10 | 1∶5 |
Mix hydroxypropyl emthylcellulose, beta-schardinger dextrin-and deionized water by employing under 70 ℃ and prepare solution.Warm solution is dispensed into the 5ml plastic injector with the 5ml aliquot.After cool to room temperature, with sample freezing 35min under-80 ℃.After at room temperature simple the intensification, sample is injected to from syringe on the metal dish that is pre-cooling to-20 ℃.Sample changes into foam at-20 ℃ of following lyophilization 17hr with at-10 ℃ of following lyophilization 49hr.Under vacuum, sample is warmed up to ambient temperature 4.5hr then.Produce soft white foam rod in all cases.Under drying condition, store foam rods.
Embodiment 13
The alginic acid film
This embodiment describes the preparation of alginic acid film.
To be dissolved in distilled water from the snow algin that Sigma-Aldrich obtains to produce 5.0w/w% solution.Use magnetic stirring bar to mix at least 2 hours down at 80 ℃ alginic acid and water to form homogeneous solution.The layer that with thickness is this cohesive alginic acid solution of 300mm-2.0mm uses manual thin layer chromatography (TLC) plate coater (CAMAG, Switzerland) to be coated to glass plate (20 * 20cm
2) on.Allow solution layer to descend dry 24 hours, the polymeric film that obtains is removed from glass plate at 25 ℃.Obtain limpid, soft, hydrophilic alginic acid film.
Embodiment 14
Alginic acid Alendronic acid sodium salt film
This embodiment describes the preparation of the alginic acid film that contains alendronate.
Use said method will be dissolved in distilled water from the snow algin that Sigma-Aldrich obtains to produce 5.0w/w% solution.Alendronic acid sodium salt (Lot#ASFPG004) is from AlbanyMolecular Research, Albany, and New York obtains, and 50.6mg is joined in the 25.0mL alginic acid solution.In 50mL plastics conical pipe, using wrist effect agitator to stir at least one hour, homogeneous solution limpid under 25 ℃ solution to form.Use manual thin layer chromatography (TLC) plate coater (CAMAG, Switzerland) to be coated to glass plate (20 * 20cm with the thick layer of about 1.0mm cohesive alginic acid Alendronic acid sodium salt solution
2) on.Allow solution layer to descend dry 24 hours, the polymeric film that obtains is removed from glass plate at 25 ℃.Obtain limpid, soft, hydrophilic alginic acid Alendronic acid sodium salt film.
Embodiment 15
Alginic acid metoclopramide film
This embodiment describes the preparation of the alginic acid film that contains metoclopramide.
Use said method will be dissolved in distilled water from the snow algin that Sigma-Aldrich obtains to produce 5.0w/w% solution.Metoclopramide is from ICN Biomedicals, Inc., and Aurora, the Ohio obtains, and 51.6mg is joined in the 25.0mL alginic acid solution.In plastics 50mL conical pipe, using wrist effect agitator to stir at least one hour, homogeneous solution limpid under 25 ℃ solution to form.Use manual thin layer chromatography (TLC) plate coater (CAMAG, Switzerland) to be coated to glass plate (20 * 20cm with the thick layer of about 1.0mm cohesive alginic acid metoclopramide solution
2) on.Allow solution layer to descend dry 24 hours, the polymeric film that obtains is removed from glass plate at 25 ℃.Obtain limpid, soft, hydrophilic alginic acid/metoclopramide film.
Embodiment 16
HPMC/ Alendronic acid sodium salt film
This embodiment describes the process that is used to prepare the film that contains alendronate.
Obtain hydroxypropyl emthylcellulose (HPMC) from Dow Chemical Company (Methocel K15M), use said method that it is dissolved in distilled water to produce 2.5w/w% solution.Alendronic acid sodium salt (Lot#ASFPG004) is from Albany Molecular Research, Albany, and New York obtains and 49.0mg joins in the HPMC solution of 25.0mL.In plastics 50mL conical pipe, using wrist effect agitator to stir at least one hour, homogeneous solution limpid under 25 ℃ solution to form.Use manual thin layer chromatography (TLC) plate coater (CAMAG, Switzerland) to be coated to glass plate (20 * 20cm with the thick layer of about 1.0mm viscosity HPMC/ alendronate sodium solution
2) on.Allow solution layer to descend dry 24 hours, the polymeric film that obtains is removed from glass plate at 25 ℃.Obtain limpid, soft, hydrophilic HPMC/ Alendronic acid sodium salt film.
Embodiment 17
HPMC/ metoclopramide film
This embodiment describes the process that is used to prepare the film that contains metoclopramide.
Obtain hydroxypropyl emthylcellulose (HPMC) from Dow Chemical Company (Methocel K15M), use said method that it is dissolved in distilled water to produce 2.5w/w% solution.Metoclopramide is from ICN Biomedicals, Inc., and Aurora, the Ohio obtains, and 50.8mg is joined in the 25.0mL HPMC solution.In plastics 50mL conical pipe, using wrist effect agitator to stir at least one hour, homogeneous solution limpid under 25 ℃ solution to form.Use manual thin layer chromatography (TLC) plate coater (CAMAG, Switzerland) to be coated to glass plate (20 * 20cm with the thick layer of about 1.0mm viscosity metoclopramide solution
2) on.Allow solution layer to descend dry 24 hours, the polymeric film that obtains is removed from glass plate at 25 ℃.Obtain limpid, soft, hydrophilic HPMC/ metoclopramide film.
Embodiment 18
Comprise the preparation of the foam or the film of pharmacological agent
This embodiment describe be used for mucosa, through mucous membrane, scrotum, through scrotum, labia or through labia carry various pharmacological agent foam or the preparation of film.
Be used for following every kind of medicine at the dose indicating mucosa according to what embodiment 1-17 prepared arbitrarily, through mucous membrane, labia, through labia, scrotum or through the foam or the film of table capsule administration: aspirin (975mg), piroxicam (20mg), indomethacin (50mg), fragrant that ester (500mg), sulindac (200mg), Nabumetone (750mg), ketorolac (10mg), ibuprofen (200mg), bute (50mg), bromfenac (50mg), naproxen (550mg), lignocaine (100mg), mepivacaine (0.2mg), etidocaine (200mg), bupivacaine (100mg), 2-chloroprocaine hydrochloride (100mg), procaine (200mg), tetracaine hydrochloride (20mg), diltiazem (60mg), isradipine (10mg), nimodipine (30mg), felodipine (450mg), nifedipine (90mg), nicardipine (30mg), ritodrine (150mg), bepridil (300mg), dofetilide (1mg), almokalant (1mg), sematilide (1mg), ambasilide (1mg), azimilide (1mg), tedisamil (100mg), sotalol (240mg), ibutilide (1mg), terbutaline (5mg), albuterol (1mg), piroxicam (20mg), orciprenaline sulfate (20mg), nitroglycerin (3mg), sorbide nitrate (40mg), isosorbide mononitrate (120mg).Can adopt in a like fashion to prepare other medicines with the described quantity of top D.
Need to carry the drug dose of required dosage to depend on the concentration of active component in compositions and the quantity of penetration enhancer or mucoadhesive.The therapeutic dose scope of the vagina mucosal of the present composition changes with patient's size.
Embodiment 19
Be used for the preparation of the coating solution that contains ketorolac of through mucous membrane nasal cavity conveying
This embodiment describes the nasal cavity preparation of compositions that through mucous membrane contains ethoxydiglycol.
Use high-shear mixer, 1g ketorolac tromethamine, 1.5g Tween 80,1.0g polycarbophil, 0.05g sodium chloride and 2.5g sorbitol are disperseed in the 44g deionized water.This solution is carried out disinfection by 0.2 micron Millipore filter.The translucent mixture that obtains is suitable for spray or spreads into the nose tissue.
The through mucous membrane frothy gel preparation of compositions that contains ketorolac
This embodiment describes the preparation of the through mucous membrane gel combination that contains ketorolac that is used for the transvaginal conveying.
Ketorolac tromethamine (1g), Tween 80 (5g), propylene glycol (10g) and ethoxydiglycol (Transcutol P) (15g) are joined in the deionized water (44g) that is heated to 70-80 ℃ in the 200ml flask, adopt high-shear mixer to mix simultaneously.Add triacetin (20g) gradually and hydroxypropyl emthylcellulose (5g) keeps temperature and mixing simultaneously.When cooling, the viscosity increase has the denseness of gel up to mixture.
Embodiment 21
Contain the preparation of the oral cavity foam pad of Pamidronate
This embodiment describes the preparation of the mouth pad that contains Pamidronate.
Available from Sigma, St.Louis, the dosage of the no label Pamidronate of MO is the 0.2mg/kg body weight.The Pamidronate mouth pad is prepared by following mode: soaking Cotton Gossypii, hydroxypropyl emthylcellulose or foam pad in the Pamidronate solution of embodiment 4 described preparations.
Embodiment 22
Mucosa adhesion oral film
This embodiment describes containing of being used for that through mucous membrane carries preparation as the mucosa adhesion oral film of the peptide medicine salmon calcitonin of hydrophilic medicament.
Salmon calcitonin (MW=3.4kD) available from Bachem (Torrance, CA).Poly-(D, L-lactide-be total to-glycollide) obtained from Boehringer Ingelheim (Ingelheim, Germany) in 50: 50.Chitosan glutamate salt, medical grade (MW=150kD) obtains from Pronova Biochemical AS (Olso, Norway).Methanol, dichloromethane and glycerol available from Sigma Chemical (St Louis, MO).5g adopted 0.5mL 2% (w/w) salmon calcitonin and the poly-(D of 4.5mL 20% (w/w) in chloroform in methanol stirring under (9500rpm) under 15 ℃, the solution of L-lactide-be total to-glycollide preparation, splash into chitosan aqueous solution (2%, w/w) Yu in 0.5% (w/w) glycerol form O/w emulsion.Mixture was stirred 20 minutes, use CAMAG TLC plate coater to spread on the glass plate, under 30 ℃, carry out solvent evaporation as thin layer.
Claims (28)
1. the local pharmacology's effective agent of carrying enters body circulation foam of polymers or film composition to nasal cavity, oral cavity, vagina, labia or scrotum epithelium or by nasal cavity, oral cavity, vagina, labia or scrotum epithelium, and described compositions contains the mixture of at least a matrix polymer or matrix polymer and pharmacology's effective agent.
2. compositions according to claim 1, wherein said matrix polymer are hydroaropic substance, lyophobic dust or both mixture.
3. compositions according to claim 3, wherein said matrix polymer is selected from hydroxypropyl emthylcellulose, gelatin, alginic acid, snow algin, Polyethylene Glycol, baregin, collagen, poloxamer, carbopol, avicel cellulose, polyacrylic acid, Polyethylene Glycol, polypropylene glycol, the divinyl glycol, poly(ethylene oxide), poly(propylene oxide), carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, polyactide, poly-ethanol ester lactide, polymethylacrylic acid, poly--γ-benzyl-L-glutamate, poly-fumaric acid propylene glycol ester, poly--∈-caprolactone, poly--mutual-phenenyl two acid bromide two alcohol ester, polyvinyl alcohol, polyvingl ether, poly--l-vinyl-2-pyrrolidone, 2,5-dimethyl-1, the 5-hexadiene, divinylbenzene, polystyrene-divinylbenzene, poly-biconjugate carboxyl-phenoxypropane-altogether-decanedioic acid, poly-beta-hydroxy-butyrate, poly--beta-butyrolactone, positive tetraethyl orthosilicate or dimethyldiethoxysilane.
4. compositions according to claim 2, wherein polymer is hydroxypropyl emthylcellulose, gelatin, alginic acid, snow algin, Polyethylene Glycol, baregin, collagen, poloxamer, carbopol or avicel cellulose.
5. compositions according to claim 4 further contains penetration enhancer, absorption enhancer, mucoadhesive, hydrophilic or hydrophobicity and discharges improver or its mixture.
6. compositions according to claim 5, wherein said mucoadhesive is selected from hydroxypropyl emthylcellulose, carboxymethyl cellulose, polyactide-common glycollide, chitosan, chitosan ester or propylidene chloride chitosan, sodium alginate, poloxamer, carbopol, baregin, polyacrylic acid, hyaluronic acid, polyvinyl alcohol, polyvinyl pyrrolidone, polycarbophil or carbopol
Wherein said penetration enhancer is selected from Sodium caproate; sodium caprylate; Capric acid sodium salt; sodium laurate; Sodium myristate; sodium palmitate; palmitoleic acid sodium; enuatrol; sodium ricinoleate; linoleic acid sodium; sodium stearate; sodium lauryl sulfate; sodium tetradecyl sulfate; sodium lauryl sarcosinate; aerosol OT; natrii tauroglycocholas; sodium cholate; NaGC; sodium deoxycholate; sodium taurodeoxycholate; glycodesoxycholic acid sodium; ursodesoxycholic acid sodium; chenodeoxy cholic acid sodium; cattle sulphur chenodeoxy cholic acid sodium; glycol chenodeoxy cholic acid sodium; CHOLYLSARCOSINE sodium; N-methyl sodium taurocholate; cattle sulphur-24; 25-dihydro sodium fusidate; polyoxyethylene-10 oleyl ether disodium hydrogen phosphate; the esterification products of aliphatic alcohol; alcohol ethoxylate with phosphoric acid or anhydride; ether carboxylate; the succinum monoglyceride; sodium stearyl fumarate; stearyl propylene glycol hydrogen succinate ester; the list of monoglyceride and diglyceride/diacetyl tartrate; the citrate of monoglyceride and diglyceride; the glyceryl of fatty acid-newborn ester; the lactyl ester of fatty acid; alginate; ethoxylated alkyl sulfates; the alkylbenzene sulfone; alpha-alkene sulfonate; acyl-hydroxyethyl sulfonate; acyl taurine salt; alkyl glyceryl ether sulfonate; the octyl group disodium sulfosuccinate; endecatylene acylamino--MEA-disodium sulfosuccinate; phosphatidic acid; phosphatidyl glycerol; polyacrylic acid; hyaluronate sodium; the biosone; edetate; sodium citrate; chitosan; N-trimethyl chitosan TMC; poly--the L-arginine chitosan; the poly-L-Lysine chitosan; aminated gelatin; chlorination cetyl three ammoniums; chlorination decyl trimethyl ammonium; chlorination cetyl trimethyl ammonium; chlorination alkyl benzyl dimethyl ammonium; chlorination diisobutyl phenoxy group ethyoxyl dimethyl benzyl ammonium; the tonsilon pyridine; the chlorination isopropyl pyridine; the N-lauryl; N; the N-dimethylglycine; the N-octyl group; N; the N-diethyl glycine; polyoxyethylene-coconut palm amine; poly-L-Lysine; poly--the L-arginine; lecithin; LYSOLECITHIN SUNLECITHIN A; hydroxylated lecithin; lysophosphatidylcholine; phosphoric acid lecithin; cephalin; serinephosphatide; two capryl-L-alpha-phosphate lecithin; the lauroyl carnitine; acylcarnitines; palmityl-D; the L-carnitine; polyoxyethylene lauryl ether; polyoxyethylene list oleyl ether; ethoxydiglycol; the polyoxyethylene groups nonyl phenol; polyoxyethylene octyl phenol ether; polyoxyethylene cholesterol ether; polyoxyethylene soyasterol ether; alpha-cyclodextrin; beta-schardinger dextrin-; gamma-cyclodextrin; DM-; methylate-beta-schardinger dextrin-; the 2-HP-; sorbitol; polyoxyethylene glycol ester; the polyoxyethylene fatty acid glyceride; the polyoxyethylene fatty acid glyceride; polyoxyethylene glyceride; polyoxyethylene vegetable oil or hydrogenated oil and fat; polyoxyethylene monooleate; the polyoxyethylene dilaurate; polyoxyethylene list and dioleate; polyoxyethylene glyceryl laurate; polyoxyethylene glyceryl oleate; the oleic acid propylene glycol ester; propylene glycol stearate; polyoxyethylene sorbitan monooleate dehydration; the polyoxyethylene tristearate; polyoxyethylene hydrogenated Oleum Ricini; polyoxyethylene almond oil; polyoxyethylene almond oil; the polyoxyethylene caprylin; the polyoxyethylene caprin; LABRASOL and
Wherein said release improver is selected from Macrogol 200, Polyethylene Glycol 8000, poloxamer, polyoxyethylene glyceryl coconut palm acid esters, carbopol, Suppocire AS2X, Suppocire CM, Witepsol H15, Witepsol W25, mineral oil, Semen Maydis oil, paraffin oil, Semen Brassicae Campestris oil, Oleum Ricini, Oleum Gossypii semen, lecithin, Oleum Arachidis hypogaeae semen, Oleum sesami, soybean oil or hydrogenated vegetable oil.
7. compositions according to claim 6, the amount of wherein said mucoadhesive is about the about 10wt% of 0.5wt%-, the amount of wherein said penetration enhancer is about the about 60wt% of 0.1wt%-, and the amount of wherein said release improver is about the about 70wt% of 5%-.
8. compositions according to claim 7 further comprises acceptable additives or excipient.
9. compositions according to claim 8, wherein said additive or excipient are solubilizing agent, buffer agent, filler, antiseptic, plasticizer, surfactant or antioxidant.
10. compositions according to claim 9, wherein independent or bonded matrix polymer further be selected from following pharmacology's effective agent and combine: osteoporosis agent, non-steroidal anti-inflammatory agent, calcium channel antagonist, local anesthetic, potassium channel antagonist, beta-adrenergic excitomotor, vasodilation, cyclooxygenase-2 inhibitors, antifungal, antiviral agent, antibacterial, antiparasitic, Anti-epileptics, migraine agent, anti-hiv agent, anti-neural degeneration agent, antipsychotic, chemotherapeutics or antitumor agent or OPIOIDS analgesic.
11. compositions according to claim 10, wherein said non-steroidal anti-inflammatory agent are selected from aspirin, ibuprofen, indomethacin, bute, bromfenac, fragrant that ester, sulindac, Nabumetone, ketorolac or naproxen;
Wherein said calcium channel antagonist is selected from diltiazem, isradipine, nimodipine, felodipine, verapamil, nifedipine, nicardipine or bepridil;
Wherein said potassium channel blocker is selected from dofetilide, almokalant, sematilide, ambasilide, azimilide, tedisamil, sotalol, piroxicam or ibutilide;
Wherein said beta-adrenergic excitomotor is selected from terbutaline, albuterol, orciprenaline, ritodrine;
Wherein said COX-2 or COX-1 inhibitor are selected from naproxen, ketoprofen, ketorolac, indomethacin, diclofenac, tenoxicam, celecoxib, meloxicam or flosulide;
Wherein said vasodilation is selected from nitroglycerin, sorbide nitrate or isosorbide mononitrate;
Wherein said bisphosphonate is selected from alendronate, clodronate, 1-hydroxyl-ethyl-1,1-di 2 ethylhexyl phosphonic acid, Pamidronate, Tiludronate, ibandronate, zoledronic acid salt, olpadronate, Risedronate or neridronic acid salt;
Wherein said antifungal agent is selected from miconazole, terconazole (triaconazole), isoconazole, fenticonazole, tioconazole, fluconazol, nystatin, ketoconazole, clotrimazole, butoconazole, econazole, metronidazole or itraconazole;
Wherein said antibacterial is selected from metronidazole, clindamycin, tetracycline, erythromycin, doxycycline, lomefloxacin, norfloxacin, alafloxacin, ciprofloxacin, azithromycin, cefmenoxime or doxycycline;
The parasiticide of wherein said selection is metronidazole or clotrimazole;
Wherein said antiviral agent is acyclovir or AZT;
Wherein said antimigraine is Almogran, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, Zomitriptan, Ergotamine, dihydroergotamine, bosentan or lanepitant;
Wherein said antitumor agent is vincristine, cisplatin, doxorubicin, daunorubicin, etoposide, holder Bo Xikang, irinotecan, paclitaxel, docetaxel, cyclophosphamide, methotrexate or gemcitabine;
Wherein said anti-HIV medicament is Saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, Lopinavir or ganciclovir; With
Wherein said pharmacological activity protein or peptide are insulin, calcitonin, vassopressin, leuprorelin acetate, somatostatin, oxytocin, bivalirudin, eptifibatide, brain natriuretic peptide, 1: PN: WO02056903 PAGE: 25 claimed protein, proglumide G17, peptide, ziconotide, the U.S. logical sequence of triphen, interleukin, humanized antibodies or growth hormone.
12. compositions according to claim 11 is administered into the surface of nasal cavity, oral cavity, vagina, labia or scrotum apparatus.
13. compositions according to claim 12 is formulated as foam.
14. compositions according to claim 13, wherein foam has different shapes and size.
15. compositions according to claim 14 wherein forms the apparatus that is shaped as sheet, pipe, tampon, cylinder, bolster, bar, pad, ball, tablet, ring or pearl in advance with foam.
16. compositions according to claim 12 is formulated as film.
17. compositions according to claim 16, wherein foam has different thickness and size.
18. compositions according to claim 12, wherein film is as the coating of nasal cavity, oral cavity, vagina or labia apparatus.
19. compositions according to claim 18, wherein said foam or film prepare by lyophilization or by ventilation.
20. apparatus that comprises arbitrary described foam of polymers of claim 1-18 or film composition, described apparatus is suitable for the localized delivery of therapeutic efficacious agents to nasal cavity, oral cavity, vagina or labia hole, and wherein said apparatus is incorporated into described apparatus by described compositions coating or described compositions.
21. apparatus according to claim 19, wherein apparatus is tampon, tampon shape apparatus, ring, sponge, pessulum, suppository, bolster, pad, bar, cylinder, ball or pearl, and wherein compositions is foam or film coating or foam or the film of introducing described apparatus.
22. the method that part or system are transported to nasal cavity, oral cavity, vagina, labia or scrotum epithelium or carry medicine by nasal cavity, oral cavity, vagina, labia or scrotum epithelium, described method comprise the step that vagina, nasal cavity, oral cavity, labia or scrotum epithelium contact with basic foam of being made up of matrix polymer and pharmacology's effective agent or film composition.
23. method according to claim 22, wherein pharmacology's effective agent is selected from non-steroidal anti-inflammatory agent, antiprostaglandin, prostaglandin inhibitor, cyclooxygenase-2 inhibitors, calcium channel blocker, potassium channel blocker, the beta-adrenergic excitomotor, vasodilation, antibiotic, antiviral agent, antifungal agent, antimycotic agent, bisphosphonate, the nausea agent, antipsychotic, antimigraine, anti-HIV medicine, anticarcinogen and chemotherapeutic agent or pharmaceutically active protein or peptide, Anti-epileptics, the OPIOIDS analgesic
The quantity that wherein is administered into medicament described in the described compositions of mucosa is enough to carry the treatment effective dose of medicine agent of the about 2000mg of about 0.01-to the body circulation.
24. method according to claim 23, wherein said non-steroidal anti-inflammatory agent are selected from aspirin, ibuprofen, indomethacin, bute, bromfenac, fragrant that ester, sulindac, Nabumetone, ketorolac or naproxen;
Wherein said calcium channel antagonist is selected from diltiazem, isradipine, nimodipine, felodipine, verapamil, nifedipine, nicardipine or bepridil;
Wherein said potassium channel blocker is selected from dofetilide, almokalant, sematilide, ambasilide, azimilide tedisamil, sotalol, piroxicam or ibutilide;
Wherein said beta-adrenergic excitomotor is selected from terbutaline, albuterol, orciprenaline, ritodrine;
Wherein said cyclooxygenase-2 inhibitors is selected from naproxen, ketoprofen, ketorolac, indomethacin, diclofenac, tenoxicam, celecoxib, meloxicam or flosulide;
Wherein said vasodilation is selected from nitroglycerin, sorbide nitrate or isosorbide mononitrate;
Wherein said bisphosphonate is selected from alendronate, clodronate, 1-hydroxyl-ethyl-1,1-di 2 ethylhexyl phosphonic acid, Pamidronate, Tiludronate, ibandronate, zoledronic acid salt, olpadronate, Risedronate or neridronic acid salt;
Wherein said antifungal agent is selected from miconazole, terconazole (triaconazole), isoconazole, fenticonazole, tioconazole, fluconazol, nystatin, ketoconazole, clotrimazole, butoconazole, econazole, metronidazole or itraconazole;
Wherein said antibacterial is selected from metronidazole, clindamycin, tetracycline, erythromycin, doxycycline, lomefloxacin, norfloxacin, alafloxacin, ciprofloxacin, azithromycin, cefmenoxime or doxycycline;
The parasiticide of wherein said selection is metronidazole or clotrimazole;
Wherein said antiviral agent is acyclovir or AZT;
Wherein said antimigraine is Almogran, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, Zomitriptan, Ergotamine, dihydroergotamine, bosentan or lanepitant;
Wherein said antitumor agent is vincristine, cisplatin, doxorubicin, daunorubicin, etoposide, holder Bo Xikang, irinotecan, paclitaxel, docetaxel, cyclophosphamide, methotrexate or gemcitabine;
Wherein said anti-HIV medicament is Saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, Lopinavir or ganciclovir; With
Wherein said pharmacological activity protein or peptide are insulin, calcitonin, vassopressin, leuprorelin acetate, somatostatin, oxytocin, bivalirudin, eptifibatide, brain natriuretic peptide, 1: PN: WO02056903 PAGE: 25 claimed protein, proglumide G17, peptide, ziconotide, the U.S. logical sequence of triphen, interleukin, humanized antibodies or growth hormone.
25. method according to claim 24 is wherein carried described compositions by vagina epithelium.
26. method according to claim 24 is wherein carried described compositions by nasal membrane.
27. method according to claim 24 is wherein carried described compositions by buccal mucosa.
28. method according to claim 24 is wherein carried described compositions by the scrotum epithelium.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42326002P | 2002-10-31 | 2002-10-31 | |
| US60/423,260 | 2002-10-31 | ||
| US60/424,920 | 2002-11-08 | ||
| US60/425,655 | 2002-11-12 | ||
| US10/444,634 | 2003-05-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1720024A true CN1720024A (en) | 2006-01-11 |
Family
ID=35931657
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200380104617 Pending CN1720024A (en) | 2002-10-31 | 2003-10-31 | Therapeutic compositions for drug delivery to and through covering epithelia |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1720024A (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552888A (en) * | 2010-12-10 | 2012-07-11 | 上海高科联合生物技术研发有限公司 | Suppository for treating mammal endometritis |
| CN103446042A (en) * | 2012-09-05 | 2013-12-18 | 力品药业（厦门）有限公司 | Medicinal preparation having taxus canadensis marsh |
| CN104159446A (en) * | 2011-08-31 | 2014-11-19 | 系统医疗风险有限责任公司 | Transdermal venous access locking solutions |
| CN104474534A (en) * | 2014-12-22 | 2015-04-01 | 哈德逊（天津）生物技术有限责任公司 | IL-18 (interleukin-18) contained anti-virus oral spray |
| CN105535928A (en) * | 2015-12-25 | 2016-05-04 | 江苏吴中医药集团有限公司 | High-bioavailability pidotimod oral liquid preparation and preparation method thereof |
| CN106883027A (en) * | 2017-03-15 | 2017-06-23 | 合肥华创现代农业科技有限公司 | One kind emulsification shitosan organic fertilizer and preparation method thereof |
| CN110720641A (en) * | 2019-10-18 | 2020-01-24 | 广东海洋大学 | Protein freeze-dried block with fat-reducing and muscle-increasing effects and preparation method thereof |
| CN111329846A (en) * | 2020-04-24 | 2020-06-26 | 云南伦扬科技有限公司 | Vaginal sterilization adhesive film and preparation method thereof |
| CN112245406A (en) * | 2020-11-09 | 2021-01-22 | 重庆理工大学 | Multifunctional hemostatic nanoparticles with low thrombus risk, preparation method and application thereof |
| CN113398100A (en) * | 2021-07-09 | 2021-09-17 | 临沂职业学院 | Sodium oleate modified paeoniflorin chitosan nanoparticle spray film agent and preparation method thereof |
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2003
- 2003-10-31 CN CN 200380104617 patent/CN1720024A/en active Pending
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552888A (en) * | 2010-12-10 | 2012-07-11 | 上海高科联合生物技术研发有限公司 | Suppository for treating mammal endometritis |
| CN104159446B (en) * | 2011-08-31 | 2016-10-26 | 系统医疗风险有限责任公司 | Transdermal venous channel lock solution |
| CN104159446A (en) * | 2011-08-31 | 2014-11-19 | 系统医疗风险有限责任公司 | Transdermal venous access locking solutions |
| CN103446042A (en) * | 2012-09-05 | 2013-12-18 | 力品药业（厦门）有限公司 | Medicinal preparation having taxus canadensis marsh |
| CN103446042B (en) * | 2012-09-05 | 2015-06-10 | 力品药业（厦门）有限公司 | Medicinal preparation having taxanes |
| CN104474534A (en) * | 2014-12-22 | 2015-04-01 | 哈德逊（天津）生物技术有限责任公司 | IL-18 (interleukin-18) contained anti-virus oral spray |
| CN105535928A (en) * | 2015-12-25 | 2016-05-04 | 江苏吴中医药集团有限公司 | High-bioavailability pidotimod oral liquid preparation and preparation method thereof |
| CN105535928B (en) * | 2015-12-25 | 2019-03-22 | 江苏吴中医药集团有限公司 | A kind of oral liquid and preparation method thereof of high bioavilability Pidotimod |
| CN106883027A (en) * | 2017-03-15 | 2017-06-23 | 合肥华创现代农业科技有限公司 | One kind emulsification shitosan organic fertilizer and preparation method thereof |
| CN110720641A (en) * | 2019-10-18 | 2020-01-24 | 广东海洋大学 | Protein freeze-dried block with fat-reducing and muscle-increasing effects and preparation method thereof |
| CN111329846A (en) * | 2020-04-24 | 2020-06-26 | 云南伦扬科技有限公司 | Vaginal sterilization adhesive film and preparation method thereof |
| CN112245406A (en) * | 2020-11-09 | 2021-01-22 | 重庆理工大学 | Multifunctional hemostatic nanoparticles with low thrombus risk, preparation method and application thereof |
| CN113398100A (en) * | 2021-07-09 | 2021-09-17 | 临沂职业学院 | Sodium oleate modified paeoniflorin chitosan nanoparticle spray film agent and preparation method thereof |
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