CN102988299B - Formation method of drug coating and drug coating prepared by same - Google Patents

Abstract

The invention provides a formation method of a drug coating. The formation method comprises the following steps in sequence: providing at least one dried solid particle, wherein the dried solid particle comprises polymers and drug molecules; spraying a dried solid particle mixture formed by the dried solid particles on a moist surface, wherein the polymers are swelled on the moist surface, so that the physical crosslinking can be carried out between the solid particles so as to form the drug coating; or spraying the dried solid particle mixture formed by the dried solid particles on a dried surface, and then spraying atomized water drops on the surface of the dried solid particle mixture, wherein the polymers are swelled to result in physical crosslinking between the solid particles so as to form the drug coating. The drug coasting provided by the invention has the advantages that the slow release time can be controlled to reach 1 to 90 days, and preferably 3 to 30 days, so that the drug coating can be kept on the surface of a lesion part for a long time in order to come into play for a long time, and as a result, the nasal diseases such as nasosinusitis and allergic rhinitis can be treated better.

Description

A kind of formation method of medication coat and medication coat thereof

Technical field

The present invention relates to field of medicaments, be specifically related to a kind of formation method and medication coat thereof of medication coat.

Background technology

Sinusitis and allergic rhinitis are otorhinolaryngology commonly encountered diseases and frequently-occurring disease, betide between 5 ~ 79 years old.Hygiene department's investigation display: the sickness rate of current global allergic rhinitis is up to 10% to 14%, and sinusitis sickness rate accounts for about 15% of population, and the whole world has 600,000,000 people nearly enduring to the fullest extent " harassing and wrecking " of rhinitis, and be progressively ascendant trend.

Wherein the asthmatic patient of 66% is the victim of allergic rhinitis.According to expert introduction, allergic rhinitis is as correctly treated, and the patient more than 1/3 finally develops into asthma.

Nasal sinuses is also known as paranasal sinuses, paranasal sinus, and be the sclerotin chamber of gassiness multiple around nasal cavity, they all communicate with nasal cavity with tubule.They are hidden on nasal cavity side, and as shown in Figure 1, maxillary sinus 11 is positioned at the upper jaw bone above nasal cavity both sides, eye socket; Sinus frontalis 12 is in frontal bone; Sieve hole 13 is positioned at the both sides on nasal cavity top, is made up of gassiness loculuses many in screen casing; Sphenoid sinus 14 is talked endlessly in bone nasal cavity rear.

Epidermal mucosa cell in the nasal cavity of normal person and nasal sinuses continues there is limpid liquid secretion out, have the pulsation of rule rate again via the cilium above mucosa cells, by these secretions from nasal sinuses, flow to cavum nasopharyngeum, throat via nasal cavity backward and swallow again esophagus and stomach.General adult about secretes the mucus of 1 liter every day, maintains the humidity of nasal cavity and nasal sinuses inside by these mucus, and the dust simultaneously in absorbed air and foreign body, to protect the health of respiratory tract.Once because the invasion of virus, antibacterial, or the stimulation of foreign body, cause limpid mucilage secretion to become pus thick, or the pulsation having rule rate lost by cilium, capital produces the sensation of the thick nasal mucus of pus or nasal mucus refluence, and causes rhinitis or the swelling of nose film, all can make these tubular occultation.When these tubular occultation, nasal cavity mucus will be had influence on and remain in a standstill in nasal sinuses, impact discharge.If not diagnosis and treatment early, will develop and become sinusitis, allergic rhinitis or other rhinitis.

Headache, nasal obstruction, rhinorrhea, temporary olfactory disorder, fear of cold, heating, inappetence, constipation, whole body discomfort etc. can be caused when nasal sinuses inflammation.Comparatively small children child can vomit, suffer from diarrhoea, the symptom such as cough.Pus nasal mucus stimulates throat can also cause throat discomfort, pharyngolaryngitis etc.

And allergic rhinitis, usual patient contact or after sucking sensitinogen, the IgE(IgE in body) can cause and mastocyte release histamine cause anaphylaxis.Allergen is inducing specific IgE antibody and the antigen reacted with it.Their multi-sources are in animal, plant, insecticide, fungus or occupational material.Allergen is mainly divided into inhalant allergen and food-consuming structure.Inhalant allergen is the main cause of allergic rhinitis.Patient's main manifestations of allergic rhinitis is telangiectasis, permeability increases and glandular secretion increase and eosinophilic granulocyte infiltration etc.If above-mentioned disease recurrent exerbation, mucosal epithelium layer proliferative can be caused to change, cause mucosa plumpness and Polypoid changes.Its symptom is similar to flu, mainly the disease such as rhinocnesmus, nasal obstruction, rhinorrhea, sneeze and stream clear water shape nasal mucus (runny nose), intermittent recurrent exerbation, nasal mucosa pale edema during outbreak.Seriously also likely can develop into sinusitis, asthma or ear infection.

Functional nasal endoscope Minimally Invasive Surgery has especially significantly therapeutic effect to acute sinusitis and chronic sinusitis.Pathological tissues and bone can be removed accurately, make nasal sinuses enlarged open, recover the normal physiological function of nasal sinuses.Findings in endoscopic sinus surgery has traditional sinusitis and to perform the operation incomparable invasive.But nasal endoscopic surgery is expensive, treatment is not thorough, and very easily recur, the expense of repetitive therapy causes patient mental's financial burden overweight.

The operative therapy for the treatment of of allergic rhinitis mainly contains the treatment of nerve block art, the operation of low-temperature plasma art, concha nasalis inferior mucosa, reduces the operation of parasympathetic nervous irritability, and other operative therapy, and the relapse rate of above-mentioned operation is high, costly.

For the application of Drug therapy in nose diseases, adopt collunarium or spray to the mode of nasal cavity spraying medicine traditionally.Research shows, due to blocking of tissue, under traditional therapeutic modality, drug molecule can not reach diseased region smoothly, uneven for the medicinal liquid being no more than 30% can only be sent to diseased region, greatly reduce medication effect.

Existing nasal cavity flushing device at present, can with normal saline or containing the medicine liquid washing nasal cavity of medicine, but of short duration drug effect is almost only limitted in concha nasalis position, sinus frontalis 12 and maxillary sinus 11 hole body inside can not be arrived, can not to inflammation nasal sinuses direct effect, and most nasal sinuses generation pathological changes can relate to nearly all hole body.In fact, even if medicinal liquid can enter hole body cavity inside, and for the hole body of sinus frontalis opening in bottom, after cleaning or spray medicine complete, nearly all medicinal liquid all can be flowed out by Dou Kou, and medicine is also had no chance to store and carried out permanently effective treatment therein.

Drug releasing stent DES(Durg Eluting Stent) be widely used in coronary stricture disease and approve, DES support is coated with the medicine of promising treatment vascular restenosis or anti-neointimal hyperplasia, i.e. medication coat, can according to design requirement for patient provides long-time slow release for medicine after implantation diseased region.The long-time uninterrupted disease therapy of other needs such as this slow release chemical supply machine reason is nasal cavity provide new direction and foundation, although nasal sinuses stenostomy and angiostenosis can lean on supporter (such as, support) strut and reach unimpeded object, but because nasal cavity structure exists much different from blood circulation from physiology and pathogenic mechanism, the pattern of DES support can not be indiscriminately imitated completely in the long-term controlled release treatment of nasal cavity (in nasal sinuses).Blood circulation is closed-system, Restenosis is a segment length occurs narrowly even to block, the drug effect be coated in outside intravascular stent only needs contain or be diffused into perilesional, and under enough blood flows wash away, the medicine in DES bracket coating is very natural can spread and bring to perilesional and bring good therapeutic effect.For blood circulation, nasal cavity, comprise the cavity that nasal sinuses is all opening, and the individual variation of nasal cavity structure is more much bigger than blood vessel difference.Even if by operation by Dou Kou narrow for the stenter to implant of band medication coat, after its drug release, diffusivity also can not ensure.If the drug main that support discharges needs the flowing of liquid to spread, the help that air motion brings is very little; And as mentioned above, patient is because of the ill ciliary movement lost or almost lost nasal cavity.Even if ciliary movement still exists, in nasal sinuses, the direction of fibre swing is all towards nasal sinuses mouth, and the fibre swing of nasal cavity is then backward, so nasal cavity mucus first flows to nasopharynx part backward, then to be gulped down in stomach and point to take off.So after being in the band medicine coating stent drug release of nasal sinuses mouth, the chance be diffused in nasal sinuses is very little, can not arrive to inflammation treatment in nasal sinuses, and inflammation severity highest point and source exactly in nasal sinuses.Thus this medication coat to be given on apparatus, and the effect of being treated inflammation in the nasal sinuses such as sinusitis by the drug release in coating is unsatisfactory.

About recent studies on and the progress of Implantable Medical Device band medicine coating structure and function, existing a lot of similar article and patent both at home and abroad.Number of patent application CN201734994U discloses " a kind of with the medicine carrying arteria coronaria coating bracket of gradient concentration style carrying medicament ", number of patent application CN1628863A discloses " a kind of preparation of polymer drug-laden coating on cardiovascular stent ", number of patent application CN1391886A discloses one " medicine releasing control method of implantable medical devices ", has set forth different structure coating to the benefit improved product quality and disease therapy aspect and bring from different aspect.But these technology are all carried out based on improvement or the coating changed on the surface of medical apparatus and instruments own, no matter apparatus is used for where, and coating and apparatus are inseparable entirety, and coating is mechanical contact to implant site.As mentioned above, the coating with medicine on apparatus can not bring innovation to improve to nose diseases treatment.Therefore, we need to find a kind of technology, medicine is enable directly, fully to penetrate into disease sites in nasal sinuses, instead of spread by means of the release of the coating on apparatus, medicine is made directly to form the coating being tightly adhered to body surface (as nasal sinuses inner surface) at diseased region, and slow releasing medicine.

Existing spraying or coating generation technique are all by medicine and slow release dissolution of polymer in solvent, make it at adhesion or carry at apparatus outer surface, then by heating, solvent volatilization is formed band medicine coating on apparatus by being coated with or flooding.Under normal circumstances, the solvent of medicine and polymer is all strong solvent, harmful or even fatal, and the solvent residual amount on apparatus in coating needs strict control.Therefore, the solution containing polymer and medicine is directly sprayed make it form coating to diseased region can not to realize.And nasal cavity narrow space, even if non-irritating solvent also can not smoothly volatilization, only leave active drug and controlled release polymer forms good coating, and only can along nasal cavity flow out the same with existing nasal wash and can not get rational delay.Therefore, must, by dry for the polymer of solvent-free medicine and controlled release particle transport to nasal cavity, then be that these granules form the firm coating that can be bonded to lesion surface.This is the problem to be solved in the present invention just.

By simple Minimally Invasive Surgery, while reduction operation wound, herbal sprinkling is inner to nasal sinuses, can realize for the long-term site-directed quantitative administration of diseased region, could the effect of more effective performance Drug therapy.

Summary of the invention

The object of this invention is to provide a kind of formation method of medication coat, the coating formed itself does not rely on or is attached to any entity apparatus, directly generate at diseased region, the surface making this medication coat reside in diseased region for a long time plays a role, and plays therapeutical effect thoroughly to nasal cavity diseases such as Drug therapy sinusitis, allergic rhinitises.

The invention provides a kind of formation method of medication coat, described method comprises: the solid particle providing at least one drying, and described solid particle comprises polymer and drug molecule; When described polymer is a kind of polymer, this polymer is degradable hydrophilic/water-soluble polymer; When described polymer is at least two kinds of polymer, this polymer at least comprises degradable polymer and hydrophilic/water-soluble polymer; Be sprayed onto on wetted surface by the solid particle mixture that the solid particle of described drying is formed, described polymer makes, between solid particle, physical crosslinking occurs in wetting surface generation swelling and forms medication coat.

Described drug molecule and described polymer are dissolved jointly or is dispersed in easy volatile solvent, form described solid particle by atomization ejection, electrostatic spinning or grinding, described solid particle is the microgranule that described drug molecule is dispersed in described polymer.

By the spray solution of wherein a kind of polymer formation to the another kind of polymer surfaces forming microgranule, thus form the described solid particle of skin-core structure.

In described solid particle, outside, degradable polymer and drug molecule Homogeneous phase mixing are core to hydrophilic/water-soluble polymer; Or degradable polymer outside, hydrophilic/water-soluble polymer and drug molecule Homogeneous phase mixing are core; Or hydrophilic/water-soluble polymer and drug molecule Homogeneous phase mixing are outside, degradable polymer is core; Or degradable polymer and drug molecule Homogeneous phase mixing are outside, hydrophilic/water-soluble polymer is core.

The present invention also provides a kind of formation method of medication coat, and described method comprises: the solid particle providing at least one drying, and described solid particle comprises polymer and drug molecule; When described polymer is a kind of polymer, this polymer is degradable hydrophilic/water-soluble polymer; When described polymer is at least two kinds of polymer, this polymer at least comprises degradable polymer and hydrophilic/water-soluble polymer; Be sprayed onto on desiccated surface by the solid particle mixture that the solid particle of described drying is formed, then in described solid particle mixture surface sprinkling water droplets, described polymer generation swelling makes between solid particle, physical crosslinking occur and form medication coat.

Described drug molecule and described polymer are dissolved jointly or is dispersed in easy volatile solvent, form described solid particle by atomization ejection, electrostatic spinning or grinding, described solid particle is the microgranule that described drug molecule is dispersed in described polymer.

By the spray solution of wherein a kind of polymer formation to the another kind of polymer surfaces forming microgranule, thus form the described solid particle of skin-core structure.

In described solid particle, outside, degradable polymer and drug molecule Homogeneous phase mixing are core to hydrophilic/water-soluble polymer; Or degradable polymer outside, hydrophilic/water-soluble polymer and drug molecule Homogeneous phase mixing are core; Or hydrophilic/water-soluble polymer and drug molecule Homogeneous phase mixing are outside, degradable polymer is core; Or degradable polymer and drug molecule Homogeneous phase mixing are outside, hydrophilic/water-soluble polymer is core.

The present invention provides again a kind of medication coat, and described medication coat is that the solid particle mixture swelling formed by the solid particle of drying is cross-linked the rear thin film formed.

The average particle size distribution of described solid particle between 50 nanometers to 500 micron, preferably between 700 nanometers to 200 micron.

By technique scheme, slow-release time can control at 1 day to 90 days by medication coat provided by the present invention, preferably controls this slow-release time at 3 to 30 days.Thus the surface residing in diseased region for a long time plays a role, treat the nasal cavity such as sinusitis, allergic rhinitis disease better.By the degradation rate regulating the ratio of degradable polymer and water-soluble polymer to carry out regulating drug coating, and then the slow release speed of regulating drug coating.

Accompanying drawing explanation

Fig. 1 shows the position of human body nasal sinuses;

Fig. 2 shows the structure of the solid particle according to a preferred embodiment of the present invention;

Fig. 3 shows the partial enlarged drawing at the position be shown by the dashed box in Fig. 2;

Fig. 4 A shows the solid particle mixture of two solid particles before occurring to be cross-linked according to a preferred embodiment of the present invention;

Fig. 4 B shows the solid particle mixture be cross-linked to form according to two solid particles of a preferred embodiment of the present invention;

Fig. 5 shows the solid particle mixture be cross-linked to form according to multiple solid particles of a preferred embodiment of the present invention, is formed shown in it by 6 solid particles;

Fig. 6 shows the electromicroscopic photograph of the medication coat formed according to a preferred embodiment of the present invention, shows drug molecule and is distributed in equably in polymer;

Fig. 7 A shows the solid particle mixture of two solid particles before occurring to be cross-linked according to another preferred embodiment of the present invention;

Fig. 7 B shows the solid particle mixture be cross-linked to form according to two solid particles of another preferred embodiment of the present invention;

Fig. 8 shows the solid particle mixture be cross-linked to form according to multiple solid particles of another preferred embodiment of the present invention, is formed shown in it by 6 solid particles;

Fig. 9 shows the solid particle mixture of multiple solid particles between generation is crosslinked according to another preferred implementation of the present invention, and wherein, this solid particle is depicted as two kinds of solid particles;

Figure 10 shows the solid particle mixture be cross-linked to form according to multiple solid particles of another preferred implementation of the present invention, and wherein, this solid particle is depicted as two kinds of solid particles.

Detailed description of the invention

In this article, " solid particle " has two kinds of forms of expression, and a kind of is the microgranule of dispersed form, and another kind is the microgranule of core-skin form.

In this article, " solid particle mixture " refers to the mixture formed by above-mentioned " solid particle ".In this solid particle mixture, this solid particle is at least two, and meanwhile, this solid particle can be the solid particle that the form of expression is identical, also can be the solid particle that the form of expression is different.

In this article, " medication coat " refers to and is cross-linked the rear thin film formed by above-mentioned " solid particle mixture " swelling, is also referred to as " band medicine thin film " simultaneously.

In this article, " hydrophilic/water-soluble polymer " refers to hydrophilic or water-soluble polymer, i.e. this polymer or possess hydrophilic (hydrophilicity, namely large affinity is had to water, can hydrone be attracted, or be dissolved in water), or possess water solublity (water solubility, the i.e. dissolution properties of material in water), otherwise both have concurrently.

Described solid particle of the present invention is dry solid particle, is preferably micron order or nano_scale particle, and the modes such as grinding, atomization, spraying, electrostatic spinning can be adopted to obtain.

Described solid particle at least comprises drug molecule and polymer.Described polymer can be a kind of polymer, be such as degradable hydrophilic/water-soluble polymer, namely this polymer possesses degradability and hydrophilic/water solublity simultaneously, now, this polymer can be called as degradable polymer, also can be called as hydrophilic/water-soluble polymer.Certainly, described polymer also can comprise multiple polymers, such as, at least comprise a kind of degradable polymer and a kind of hydrophilic/water-soluble polymer.

Degradable polymer in described solid particle can constantly be degraded, and is progressively discharged by the drug molecule playing therapeutical effect of its inside, reaches the effect of slow release simultaneously.Can there is swelling, volume swell in this hydrophilic/water-soluble polymer, make solid particle mutually fused crosslinked, now, this hydrophilic/water-soluble polymer plays the effect of physical crosslinking agent under wetting surface or the prerequisite having moisture to exist.

In the dry state, described solid particle is stored by enclosed moisture-resistant.In high humility or when having aqueous water to exist, hydrophilic/water-soluble polymer can absorb water swelling.Solid particle after swell is overlapped and fused, and each solid particle of hydrophilic/water-soluble polymer that contains is connected with the solid particle of surrounding, forms fine and close entirety.

The formation method of medication coat of the present invention comprises at least two kinds: the solid particle mixture that the solid particle by drying is formed by (1) is sprayed at any wetted surface with moisture, and the hydrophilic in solid particle/water-soluble polymer generation swelling makes, between solid particle, physical crosslinking occurs and forms described medication coat; (2) first the solid particle mixture of drying is evenly sprayed at any desiccated surface, then in the surface sprinkling water droplets of solid particle mixture, makes solid particle mutually fused on this surface, physical crosslinking occurs, forms medication coat.

Usual solid particle mixture will complete swelling and crosslinked film forming needs considerable water quantities to realize, and therefore, should is at least moistening or the relative humidity surface that is greater than more than 80% by sprayed surface.

Under normal circumstances; (1) the kind method of employing makes the coating of acquisition more even in moistening or prior surface sprinkling solid particle mixing physical ability of spraying moisture, adopts (2) kind method then can obtain more fine and close medication coat in the surface sprinkling water droplets of solid particle mixture.When employing (2) kind method, this water droplets can dispense on the outer surface of solid particle mixture of irregularity equably, makes the surface comprising microscopic folds can obtain enough moistenings equally.After solid particle arrives surperficial any position, be easy to the coating forming excipient at the outer surface of the solid particle mixture of irregularity.

embodiment 1 is according to the solid particle mixture of an embodiment of the invention

According to first embodiment of the invention, the medication coat formed by solid particle mixture can produce physical crosslinking by single solid particle and be formed under moisture state.Now, " single solid particle " should represent the solid particle that the form of expression is identical, in the present embodiment, this solid granulates is the microgranule 2 of dispersed form, as shown in Figure 2.

Usually, this solid particle at least comprises drug molecule and polymer, and described polymer can be a kind of degradable hydrophilic/water-soluble polymer, also can be the mixture of degradable polymer and hydrophilic/water-soluble polymer.Wherein, this drug molecule is in the polymer dispersed.Such as in figs. 2 and 3, numeral 21 represents degradable polymer, and numeral 22 represents hydrophilic/water-soluble polymer, and numeral 23 represents drug molecule.

The formation method of the microgranule of this dispersed form comprises: drug molecule and polymer jointly dissolved or be dispersed in a kind of easy volatile solvent.Preferably, polymer is dissolved completely in solvent, forms homogeneous solution; And drug molecule dissolves completely or be dispersed in suspended state and be dissolved with in the solution of polymer.

The formation method of the microgranule of this dispersed form also comprises: by the atomization ejection in the atmosphere of room temperature or heating of above-mentioned solution, the solvent in microlayer model volatilizees in the process of being scattered, the solid particle 2 of atomized pelletize.

Should be appreciated that, the solid particle of this dispersed form also can by electrospinning process, and by polymeric Hydrostatic electrospray, the fine droplet of atomization is solidified into microgranule when arriving collecting board.

In the solid particle formed by said method, drug molecule is generally uniformly dispersed in polymer, and the electromicroscopic photograph shown in Fig. 6 can illustrate that drug molecule is distributed in polymer equably well, even the phenomenons such as reunion does not occur.

In the present embodiment, this kind of effumability solvent includes but are not limited to hydrofluoroalkane based compound (HFA, as HFA134 and HFA227ea), acetone etc.

Certainly, also the methods such as evaporate to dryness, extraction, filtration can be adopted the removal of solvents in solution, obtain dry polymer and the mixed uniformly solid mixture of drug molecule, then by means such as grindings, the making of this mixture is become micron or nano level solid particle 2.

In the present embodiment, drug molecule and polymer can be dissolved in two kinds of different solvents respectively, and these two kinds of different solvents can be partially or completely mutually miscible.By by two kinds of solution mix homogeneously, to be then atomized, electrostatic spinning or grinding pelletize, can obtain equally containing solid particle 2, wherein, drug molecule is uniformly distributed in polymer.

Fig. 4 A shows the solid particle mixture of two solid particles 2 before occurring to be cross-linked according to this preferred implementation; wherein; solid particle 2 is depicted as the individuality independently disperseed; when this solid particle mixture is sprayed to after on wetted surface; polymer wherein makes, between solid particle, physical crosslinking occurs in this wetting surface generation swelling, as shown in Figure 4 B.Only being depicted as two solid particles in the diagram occurs crosslinked, and Fig. 5 shows six solid particles and occurs crosslinked.

Those skilled in the art is known, and drug particles conveying technology is one of current important development direction, by current understanding, has new drug more than half to there is the problem of dissolving and absorbing.After drug particles reduces, effective contact area of drug molecule and human body will increase, so the absorbed speed of medicine improves along with reducing of drug particles yardstick.Therefore, the yardstick reducing drug particles becomes the feasible method improving utilization ratio of drug.

Inventor finds: after the granule of 1mm particle diameter is ground into the microgranule of 1 μm of particle diameter, and doubly, the particle surface area of equal in quality is increased to original 1000 times to 9 powers of individual particle volume decline 10.And due in fact less microparticle surfaces be not definitely spherical, therefore diameter of particle less after its surface area increase ground even more.Larger surface area provides higher touch opportunity, makes the utilization rate of drug molecule more efficient, makes the microscopic dimensions of the coating formed more even simultaneously.Meanwhile, the microgranule that particle diameter is less can under relatively low humidity good filming.

But the particle diameter of microgranule is less, the microgranule producing this size is more difficult, and in preparation and storing process, the anti-coagulation problems that will solve is also more outstanding.After particle size is down to nanoscale, surface has been covered with step structure, and the representative of this structure has the unease atom of high surface energy.This kind of atom active is very large, very easily adsorbs bond with foreign atom.Easily cause the phase inter coagulation because of Van der Waals force between microgranule, form unstable large microgranule before the use, make coating forming procedure or instability after being formed.

Therefore, as far as possible fully cover surface to make solid particle 2 and form firmly binding film, the selection of the particle diameter of this solid particle is very crucial.Shown by a large amount of experiments, the average particle size distribution of solid particle 2 should between 50 nanometers to 500 micron, or particle size distribution is narrower, between 700 nanometers to 200 micron.

The concrete operations example of solid particle 2 according to the present embodiment can with reference to example 1-6.Wherein, the polymer contained by the solid particle in example 1-5 is a kind of degradable water-soluble polymer, and the polymer contained by solid particle in example 6 comprises degradable polymer and water-soluble polymer.

embodiment 2 solid particle mixture according to another implementation of the invention

Second embodiment of the invention, the medication coat formed by solid particle mixture can produce physical crosslinking by single solid particle and be formed under moisture state.Now, " single solid particle " should represent the solid particle that the form of expression is identical, in the present embodiment, this solid granulates is the microgranule 3 of core-skin form, as shown in Figure 7.

Usually, this solid particle at least comprises drug molecule and polymer, and described polymer can be a kind of degradable hydrophilic/water-soluble polymer, also can be the mixture of degradable polymer and hydrophilic/water-soluble polymer.Wherein, this drug molecule is in the polymer dispersed.Such as in the figure 7, numeral 31 represents degradable polymer, and numeral 32 represents hydrophilic/water-soluble polymer, and numeral 33 represents drug molecule.

The formation method of the microgranule of this core-skin form comprises: be sprayed onto by a kind of polymer solution and form the another kind of polymeric particle surface of microgranule, and the solvent in polymer solution can not dissolve polymer microgranule, and the two forms the microsphere microgranule of skin-core structure.Usually, contained by sprinkling polymer solution, polymer is hydrophilic/water-soluble polymer, and the polymer particles be sprayed contains the homogeneous mixture (polymer particles now can be the solid particle formed by above-described embodiment 1) of at least one degradable polymer and at least one drug molecule.Inter-adhesive and fused during in order to as far as possible reduce spraying between microgranule, in spraying process, the device that can shake is placed on (such as by sprayed-on polymer microgranule, ebullated bed) above also can apply dry heat air-flow, all microparticle outer surface to be sprayed can be made to greatest extent not lumpd by evenly spraying.Namely obtain a kind of hydrophilic/water-soluble polymer after drying outside, degradable polymer and drug molecule are at interior core-skin type microgranule.Now, the outer field hydrophilic/water-soluble polymer in the skin-core structure given by Fig. 6 wraps up inner degradable polymer and drug molecule completely, but in fact, should be appreciated that, the microsphere microgranule of portion envelops also within the scope of the invention.

Equally, contained by sprinkling polymer solution, polymer can be also degradable polymer, and the polymer particles be sprayed contains at least one hydrophilic/water-soluble polymer and at least one drug molecule.Correspondingly, can obtain a kind of degradable polymer outside after drying, hydrophilic/water-soluble polymer and drug molecule are at the core-skin type microgranule of interior portion envelops.Now, because the hydrophilic/water-soluble polymer of inside is not wrapped up completely by the degradable polymer of outside, thus ensure being cross-linked between each solid particle.

In certain embodiments, be used for also can comprising at least one drug molecule in the polymer solution that sprays, and by sprayed-on polymer microgranule containing or not drug containing composition, form outer band medicine, sandwich layer band medicine or the core-skin type microgranule not with medicine; If top layer and sandwich layer are with medicine simultaneously, two class medicines can be of the same race or homology medicine, or inhomogeneity medicine not of the same race, but can not play any chemical reaction after two class medicament contacts or combined effect causes adverse consequences.

Fig. 7 A shows the solid particle mixture of two solid particles 3 before occurring to be cross-linked according to this preferred implementation; wherein; solid particle 3 is depicted as the individuality independently disperseed; when this solid particle mixture is sprayed to after on wetted surface; polymer wherein makes, between solid particle, physical crosslinking occurs in this wetting surface generation swelling, as shown in Figure 7 B.Only being depicted as two solid particles in the figure 7 occurs crosslinked, and Fig. 8 shows six solid particles and occurs crosslinked.

The concrete operations example of solid particle 3 according to the present embodiment can with reference to example 7-8.

embodiment 3 is according to the solid particle mixture of another embodiment of the present invention

According to the 3rd embodiment of the present invention, the medication coat formed by solid particle mixture can produce physical crosslinking by non-single solid particle and be formed under moisture state.Now, " non-single solid particle " solid particle that the form of expression is not identical and diverse solid particle should be represented.

Typically, this non-single solid particle is two kinds of different solid particles, and wherein a kind of solid particle 4 comprises degradable polymer, and another kind of solid particle 5 comprises hydrophilic/water-soluble polymer.Wherein, seldom, namely in formed solid particle mixture, the content of two kinds of solid particles is approximately equal for the relative mass of described two kinds of solid particles or volume differences.Should be appreciated that, the ratio between a kind of solid particle 4 and another kind of solid particle 5 is preferably between 30:70-50:50.When cross-linking reaction occurs the solid particle 4 containing hydrophilic/water-soluble polymer, the solid particle 5 containing degradable polymer can be wrapped in the inner, common formation medication coat of the present invention, as Figure 8-9.

Preferably, at least one in above-mentioned two kinds of solid particles contains a kind of drug molecule.

The concrete operations example of solid particle mixture according to the present embodiment can with reference to example 9.

In above-mentioned three embodiments; according to the kind of degradable polymer contained in solid particle mixture of the present invention and hydrophilic/water-soluble polymer; and composition is very large to the quality influence of formed medication coat; such as shown in example 9; powerful and durability degree after simultaneously also affecting film forming, such as, shown in example 8.In certain embodiments, the mass percent of degradable polymer or degradable polymer mixture can be 1-80,10-80,10-70,10-60,10-50,10-40,10-30,20-80,30-70, or 40-60.In certain embodiments, the mass percent of hydrophilic/water-soluble polymer can be 10-90,20-90,30-90,40-90,50-90,60-90,70-90,10-80,10-70,10-60,10-50,10-40,10-30,20-80,30-70, or 40-60.

The above degradable polymer comprises synthesis and the natural polymer that hydrolytic degradation can occur.Synthesis hydrolysis degradable polymer comprises and comprises Poly(D,L-lactide-co-glycolide (poly (L-lactide-co-glycolide), PLGA) at interior hydrolysis degradable polyester.Typical natural degradable polymer comprises chitosan.Typical water-soluble polymer comprises Polyethylene Glycol (PEG), polyethyleneglycol block copolymer (such as with the PEG/PLGA of Polyethylene Glycol unit for macromolecular chain tail end, PEG/PLA diblock or triblock copolymer, or PEG/PLGA, PEG/PLA diblock or three block random copolymerizations, alternate copolymer), sucrose, starch, Algin, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA).Polyvinyl alcohol (PVA) is a kind of typical easily hygroscopic polymer, under the state having water, swelling and chemical degradation can occur.The above polymer, except sucrose, all has the feature of easy moisture absorption.

Poly(D,L-lactide-co-glycolide (poly (L-lactide-co-glycolide), PLGA) is the degradable polymer of a quasi-representative, is widely used in human body.The performance of microgranule film forming caudacoria, particularly along with degraded deepens continuously, film can be adhered to maintaining the time that time of film forming brute force and film be etched completely and can be controlled by the ratio adjusting lactide (LA) and Acetic acid, hydroxy-, bimol. cyclic ester (GA) in copolymer.Film forming is powerful, and namely after microgranule generates crosslinked coated film, this thin film maintains and is in continuous state, the bursting of opposing external force, the ability of tearing, rubbing, stretching.When the mol ratio of lactide (LA) to decline gradually by 100% or when rising gradually by 0%, the degree of crystallinity of copolymer is tending towards declining, cause powerful decline.In addition, when lactide (LA) mol ratio by 100% gradually decline or when rising gradually by 0%, the degradation time in vitro of PLGA can reduce.Therefore, different degradation rates and degree of crystallinity can be obtained by regulating the monomer mole ratio in copolymer, thus realize different treatment cycle.Usually, in Poly(D,L-lactide-co-glycolide (PLGA) strand, the mol ratio of lactide (LA) and Acetic acid, hydroxy-, bimol. cyclic ester (GA) controls between 10%LA:90%GA to 85%LA:15%GA.Typical PLGA proportion of composing is ratio 10:90,50:50,70:30,85:15 of lactide (LA) and Acetic acid, hydroxy-, bimol. cyclic ester (GA), and the polymer molar percentage ratio fluctuation of all these proportional components 3%, all can be able to use through qualified commercially available prod.The PLGA of lactide and Acetic acid, hydroxy-, bimol. cyclic ester 50:50 molar ratio can make film strength keep for 1 to 2 week, and the PLGA of lactide and Acetic acid, hydroxy-, bimol. cyclic ester 70:30 molar ratio can make film strength keep 30 to 60 days.

For obtaining desirable degraded and bond properties, various water-soluble polymer and degradable polymer compositions may be applied to.Above-mentioned one or more degradable polymers mentioned and one or more water-soluble polymers can be comprised in formula.The present invention comprises likely combining of water-soluble polymer.The combination of polymers of following form can be comprised in formula:

Degradable polymer and hygroscopicity or non-hygroscopic water solublity non-chemically degradation polymer

Degradable polymer and water-soluble chemical degradable polymer

Degradable polymer, hygroscopicity water solublity be degradation polymer and non-hygroscopic water-soluble polymer non-chemically

Degradable polymer, hygroscopicity or non-hygroscopic water solublity be degradation polymer and water-soluble chemical degradable polymer non-chemically

In combinations thereof, water-soluble polymer can be hygroscopicity or non-hygroscopic; Described degradable polymer can be hydrophilic/water-soluble polymer, also can non-hydrophilic and non-soluble polymer; Described hydrophilic/water-soluble polymer can be degradable polymer, also can be non-degradable polymer.

In some implementation, formula can comprise above-mentioned any one PLGA and one or more above-mentioned water-soluble polymers mentioned mentioned.Usually, formula can comprise any compositions of PLGA and above-mentioned all water-soluble polymers.Typical combination comprises PLGA and PVA, PEG, starch, Algin, PVP and their compositions.In formula, the mass percent of PLGA is 100% to 1%, and water-soluble polymer or water-soluble polymer composition mass percent are 99% to 1%.Preferred PLGA percent mass hundred ratio is 10-15%, 15-25%, 25-35%, 55-70% or 70-90%.Such as, in a kind of formula, comprise the PLGA of 50% mass percent, the PVA of 25% mass percent and the starch of 25% mass percent.

In other implementations, formula can comprise above-mentioned PLGA and another degradable polymer (such as, chitosan) of mentioning any one proportioning, and one or more water-soluble polymers.

The formula combination of polymers of typical formation coating comprises 70/30PLGA/PVA; Chitosan/PVA; 70/30PLGA/ chitosan/PVP; Chitosan/PVP; 70/30PLGA/PEG; 70/30PLGA/ starch; 70/30PLGA, PEG copolymer/PEG; 70/30(PLGA/PEG copolymer)/(PLGA/PVA); 70/30(PLGA/PEG copolymer)/(PEG/(70/30PLGA)); PLGA/ sucrose/PEG; Chitosan/PVA; Chitosan/PVP; PLGA/PVP; With PLGA/ Algin.Weight average molecular weight (Mw) scope of the PLGA applied in formula is 600 to 300000, and the more excellent range of choice is 6000 to 200000.Or the intrinsic viscosity of PLGA (IV) value scope is 0.2 to 4.0, and the more excellent range of choice is 0.8 to 1.2.Weight average molecular weight (Mw) scope of PEG is 1000 to 100000.Weight average molecular weight (Mw) scope of chitosan is 10000 to 300000.Weight average molecular weight (Mw) scope of PVP is 6000 to 3000000.

Water-soluble polymer and degradable polymer combined effect form suitable coating, i.e. thin film.Water-soluble polymer provides the bonding strength between microgranule and the pull-out capacity between film forming caudacoria and film formation surface.In addition, water insoluble polymer particle is easy to swelling occurs, and therefore, microgranule, at the mutual additive fusion of swelling state, forms a complete densification on when injected organism tissue surface, do not have the homogeneous thin film of hole and defect.Degradable polymer provides necessary brute force and mechanical property for thin film, and extends the degradation time of thin film.Suitable coating, i.e. thin film, should possess zero defect in homogeneity, film, and maintain enough brute forces and mechanical property within the desirable time, and this time is determined jointly by the ratio of base polymer each in formula in solid particle mixture.Such as, lower brute force and degradation time are than expecting that short film may be because water-soluble polymer is too much in formula, and degradable polymer deficiency causes.

The water absorption rate measuring microgranule is one of method measuring polymer swelling effect.Water absorption rate can be 1% to 80% mass percent, may be narrower, is 20% to 30% mass percent.The definition of water absorption rate is, when microgranule is fully exposed under dampness, the maximum amount of water that microgranule can be drawn accounts for the percentage ratio of the two gross mass.In the present invention, when microgranule water absorption rate is in 10% to 30% scope, suitable coated film can be formed.Should be appreciated that, swelling effect needs to control in suitable scope, to ensure performance after coating film forming.Lower water absorption rate swelling is poorer, may be not enough to make each microgranule to be cross-linked with each other formation film; And too high water absorption rate causes swelling excessive, single microgranule water content is too many, powerful not enough after causing film forming.

As mentioned above, in other implementation, the block copolymer that the polymer being made into microgranule can be made up of degradable polymer segment and Water-soluble polymer segments or random copolymer.The physical state of this base polymer depends on the weight ratio of degradable polymer and water-soluble polymer in copolymer and the molecular size range of segment.In some implementation, and chain segment molecular weight can be selected to decide the copolymer being used for making microgranule generated by both adjustment mass ratio, make it be rendered as under room temperature or ambient temperature solid-state, and nonfluid, gel, paste or liquid state.Room temperature or ambient temperature refer to 20-30 ° of C, or narrower 23-27 ° C, or are more than or equal to 25 ° of C.Block copolymer can be diblock, three blocks, starblock, or under normal circumstances, graft block copolymer.

Typical implementation, block copolymer comprises PLGA segment and PEG chain segment.The solid block thing making microgranule can be diblock copolymer, and the mass ratio of PLGA and PEG is 99:1 to 50:50.The weight average molecular weight of PLGA be 6000 to 500000, PEG weight average molecular weight be 1000 to 10000.The solid block thing making microgranule can be triblock copolymer, and PLGA segment is copolymer end, and the mass ratio of PLGA and PEG is 99:1 to 50:50.The weight average molecular weight of PLGA be 6000 to 500000, PEG weight average molecular weight be 1000 to 10000.The solid block thing making microgranule can be triblock copolymer, and PEG chain segment is copolymer end, and the mass ratio of PLGA and PEG is 99:1 to 50:50.The weight average molecular weight of PLGA be 6000 to 500000, PEG weight average molecular weight be 1000 to 10000.

In some implementation, degradable polymer can be offered help for the bonding force between coated film and film formation surface.Such as, chitosan is known with the good polymer of biological tissue's cohesive.In other implementation, water-soluble polymer may have faint internal action, thus, can have faint pull-out capacity with film formation surface.Such as, Algin end group can form relative micro-effect with some film formation surface, and thus, the formula comprising chitosan and Algin can have good bonding force to film formation surface.

Because this coated film was exist with solid-state micron order or nano_scale particle form before formation, by gas propagation, after touching body surface, dense coating could be formed under moisture existence condition.In principle, even if film formation surface exists complicated structure, gas also can carry microgranule and arrive these folds, hole, corner etc. and block or cover irregular surface.And then form continuous print firmly controlled-release coating on surface wetted in advance.

Therefore, utilize this principle, this type coating can be applied to any human tissue surface, particularly the common spray medicine surface that not easily arrives or retain.Such as, in nasal cavity hole body, particularly in sinus frontalis 12.

Form coating in nasal sinuses after, under the combined effect of degradable polymer and water-soluble polymer, medicine gradually by slow release out.Can by regulating composition and the molecular size range of slow release degradable polymer, and regulate the ratio of degradable polymer and water-soluble polymer to regulate degradation rate, and then regulate slow release speed.Slow-release time controls at 1 day to 90 days, and preferred slow-release time is 3 to 30 days.

The granular recipe of a kind of controlled-release coating of formation as above can comprise with degradable polymer but be not limited only to following polymer: chitosan, Algin, cellulose esters, glucosan, elastin laminin, fibrin, hyaluronic acid, polyacetals, polyarylate (TYR derivant or fatty acid), poly-α hydroxy ester, poly-β hydroxy ester, polyamide, polyamino acid, polyalkanoate, polyalkylene compound, polyethoxylate, polyalkylene succinic acid, condensing model, condensing model ester, poly-aspartate, poly butylene succinate, polycaprolactone, polycaprolactone/polyethyleneglycol ester copolymer, Merlon, TYR derives Merlon, polycyanoacrylate, poly-dihydropyran, PPDO, poly-6-caprolactone, poly-6-caprolactone-dimethyltrimethylene carbonate, polyesteramide, polyester, aliphatic polyester, polyether ester, Polyethylene Glycol/poe copolymer, poly-1,3-propanedicarboxylic acid, polyglycolic acid, PGA, PGA/polyglycol ester interpolymer, PGA-trimethylene carbonate, polyhydroxyalkanoate, poly butyric ester, PHBV, poly-iminocarbonic ester, polyketals, Poly-L-lactic acid, Poly-L-lactic acid-glycolic, Poly-L-lactic acid-glycolic/ethylene glycol copolymer, poly-L lactide, poly-L lactide caprolactone, poly-DL lactide glycolide, poly-L lactide glycolide/polyglycol ester interpolymer, poly-L lactide/ethylene glycol copolymer, poly-L lactide/PGA copolymer, poe, polyoxyethylene/polyoxypropylene copolymer, polypeptide, polyphosphazene, poly phosphate, APP ester, polypropylene fumaric acid ethylene glycol, PTMC, polytyrosinecarbonates, polyurethane, fimbrin, spider silk, Tephaflex, (Acetic acid, hydroxy-, bimol. cyclic ester, lactide and neopentyl glycol carbonic ester) terpolymer, viscose glue, cellulose, cellulose acetate, cellulose butyrate, butyl acetate cellulose, cellophane, celluloid, cellulose propionate, cellulose ether, carboxymethyl cellulose, and the combination of above-mentioned polymer, mixture or copolymer.

Medicine in this medication coat can be selected but be not limited only to following listed medicine: long-acting steroids hormone, anti-inflammatory drug, anti-allergic drug, parasympatholytic, antihistaminic medicine, anti-infective, antiplatelet drug, anticoagulation, antithrombotic, anti-cicatrix medicine, antiproliferative pharmaceutical, chemotherapeutic, antineoplastic agent, the congested agent of solution, accelerator for concrescence, vitamin (as: tretinoin, vitamin A, vitamin B, and spin-off), immuno modulating agent, immunosuppressant, and the compositions of above-mentioned medicament or mixture.

Optional infection medicament generally includes antibacterial, antifungal, antiparasitic, antiviral agent, antiseptic.Anti-inflammatory agents generally includes steroid or nonsteroid anti-inflammatory drugs.

May be used for antiallergic medicament of the present invention to include but are not limited to: Pemirolast Potassiu ( santen, Inc.), cetirizine hydrochloride, levo-cetirizine hydrochloride, and any prodrug, metabolite, derivant, homologue, congener, derivatives, salt, and their compositions.The medicament of anti-malignant cell proliferation includes but are not limited to, actinomycin D, D actinomycin D IV, D actinomycin D I1, D actinomycin D X1, Dactinomycin, dactinomycin ( merck & Co., Inc.).Antiplatelet drug, anticoagulant, antifibrin and antithrombase include but are not limited to, heparin sodium, low molecular weight heparin, heparinoid, hirudin, argatroban, Forskolin, vapiprost, ring prostatitis element, class ring prostatitis element, glucosan, D-Phe-Pro-arginine-chloromethane keto hydrochloride (chemosynthesis antithrombase), dipyridamole, glycoprotein I I b/III a platelet membrane receptor antagonist antibody, lepirudin 023 ludon, thrombin inhibitor ( biogen, Inc.), and any medicine precursor, metabolite, derivant, homologue, congener, derivatives, salt and their compositions.

May be used for cytostatics of the present invention and anti-cell proliferation includes but are not limited to: angiopeptin; Angiotensin converting enzyme inhibitor, as captopril ( bristol-Myers Squibb Co.), cilazapril, lisinopril ( merck & Co., Inc.); Calcium channel blocker, as nifedipine, colchicine; Fibroblast growth factor (FGF) antagonist, cod-liver oil (omega-fatty acid); Histamine antagonist; Lovastatin ( merck & Co., Inc.); Monoclonal antibody, includes but are not limited to, platelet derived growth factor (PDGF) receptor specific antibody; Sodium nitroprusside; Phosphodiesterase inhibitor; Prostaglandin inhibitor; Suramin; Serotonin blocker; Steroid; Sulfo-protease inhibitor; Platelet derived growth factor (PDGF) antagonist, includes but are not limited to, triazolo pyrimidine; Nitric oxide; And any prodrug, metabolite, derivant, homologue, congener, derivatives, salt, and their compositions.

May be used for antimicrobial agent of the present invention to include but are not limited to: aminoglycoside, amphenicols, ansamycins, beta-lactam antibiotic, such as penicillins, lincomycin class, Macrolide, itrofurans, quinolones class, sulfonamides, sulfone class, Tetracyclines, vancomycin, and their derivant and compositions.The type agents that may be used for the support of the application includes but are not limited to: Amdinocillin, pivmecillinam, amoxicillin, ampicillin, aspoxicillin, azidocillin, bacampicillin, benzyl penicillinic acid, penicillin sodium, carbenicillin, carindacillin, clometocillin, cloxacillin, ciclacillin, dicloxacillin, epicillin, fenbenicillin, flucloxacillin, hetacillin, lenampicillin, metampicillin, Staphcillin sodium, mezlocillin, sodium nafcillin, oxazacillin, penamecillin, penethacillin hydriodate, benethamine penicillin, benzathine penicillin G, penicillin G benzhydrylamine, calcium benzylpenicillinate, hydrabamine penicillin G, scotcil, neoproc, penicillin N, penicillin, penicillin V, penicillin V benzathine, hydrabamine penicillin V, penimepicycline, penicillin-152, piperacillin, pivampicillin, propicillin, quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin, ticarcillin.

May be used for antifungal medicine of the present invention to include but are not limited to: propylamine, imidazoles, polyenoid class, Thiocarbamates, triazole type, and derivative medicament.Antiparasitic includes but are not limited to, atovaquone, clindamycin, dapsone, two electric quinoline, metronidazole, pentamidine, primaquine, pyrimethamine, sulfadiazine, trimethoprim/sulfamethoxazole, trimetrexate, and composition thereof.

May be used for antiviral agent of the present invention to include but are not limited to: acyclovir, famciclovir, valacyclovir, edoxudine, ganciclovir, FOSCARNET, cidofovir, Fomivirsen, HPMPA(9-(3-hydroxyl-2-phosphate methoxy propyl group)-adenine), PMEA(9-(2-phosphate methoxy propyl group)-adenine), HPMPG(9-(3-hydroxyl-2-phosphate methoxy propyl group)-guanine), PMEG(9-[2-phosphate methoxy propyl group] guanine), HPMPC(1-(2-phosphate methoxy-3-hydroxypropyl)-cytosine), ribavirin, EICAR(5-acetenyl-1-β-D-RIBOSE base-1H-imidazoles-4-Methanamide), pyrazofurin (3-[β-D-RIBOSE]-4-hydroxypyrazoles-5-Methanamide), look into Chinese holly woods 3-, GR-92938X(1-β-D-RIBOSE base-1H-pyrazoles-3,4-diformamide), LY253963(1,3,4-thiadiazoles-2-base-cyanamide), RD3-0028(1,4-dihydro-2,3-benzyl two sulfur), CL387626(4,4'-bis-[4,6-d] [3-aminobenzene-N, N-bis-(2-carbamoylethyl)-sulfonic acid acid imide]-1,3,5-triazines-2-base Amino-biphenvl-2-, 2'-sodium disulfonate), BABIM(bis-[5-amidino groups-2-benzimidazole-l]-methane) NIH351, and composition thereof.

May be used for Cidex-7 agent of the present invention to include but are not limited to: ethanol, hibitane, iodine tincture, triclosan, hexachlorophene and silver-based agents: as silver chloride, silver oxide, nano-Ag particles.

May be used for antiinflammatory class medicament of the present invention and comprise steroid and nonsteroidal anti-inflammatory agent.The steroidal anti-inflammatory drug thing be suitable for includes but are not limited to, 21-acetyl oxygen pregnenolone, alclometasone, algestone, amcinonide, beclometasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, (11BETA,16ALPHA)-16,17-[methylethylidenebis(oxy), desoximetasone, dexamethasone, diflorasone, diflucortolone, two fuprednate butyl esters, enoxolone, Fluazacort, flucloronide, flumetasone, good fortune Buddhist nun shrinkage porosite, fluocinonide, fluocinonide, Novoderm Varlane, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, good fortune prednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, Halobetasol Propionate, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, Loteprednol etabonate, depersolon, medrysone, meprednisone, methyl meticortelone, Mo Meitasong furoate, paramethasone, prednicarbate, prednisolone, 25-diethylin prednisolone acetate, Inflamase, prednisone, prednival, ripple prednylidene 21-diethylaminoacetatte, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, Triamcinolone, triamcinolone hexacetonide, and derivant and compositions.

May be used for nonsteroidal anti-inflammatory agent of the present invention to include but are not limited to, epoxidase (cox) inhibitor.This kind of epoxidase (cox) inhibitor may comprise COX-1 or COX nonspecific inhibitor, such as, and salicyclic acid derivatives, aspirin, sodium salicylate, Choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine, olsalazine; P-aminophenol derivatives, such as, acetaminophen; Indole and indeneacetic acid, such as, indomethacin and sulindac; Iso-aryl acetic acid class, such as, tolmetin, diclofenac, ketorolac; Arylprop acids, such as, ibuprofen, naproxen, flurbiprofen, ketone ibuprofen, Fino ibuprofen, oxaprozin; Anthranilic acid (that acid fragrant), such as, mefenamic acid, meloxicam; Enol acid, such as, former times health class (piroxicam, meloxicam); Aldoketones, such as, nabumetone.COX inhibitor also may comprise selectivity cyclooxygenase COX2, such as, and diaryl substituted furan ketone, rofecoxib; Diaryl substituted pyrazole class, celecoxib; Heteroauxing class, e.g., etodolac; Sulfonamides, e.g., nimesulide.

May be used for chemotherapy of the present invention and anti-tumor agents includes but are not limited to: anticancer agent (e.g., chemotherapy of tumors medicine, biological response modifiers, angiogenesis inhibitor, hormone receptor blocker, low temperature therapy reagent, and other can destroy or Tumor suppression generate and growth medicament), such as, alkylating agent or other can attack by DNA medicament (e.g., the cycli phosphate amine directly killing cancerous cell, isoendoxan), nitroso ureas or other repaired by T suppression cell DNA and kill medicament (e.g., the carmustine (BCNU) of cancerous cell, lomustine (CCNU)), antimetabolite or other stop the medicament of growth of cancer cells by interference specific cells function, be generally DNA and synthesize (e.g., 6-mercaptopurine, 5 fluorodioxy pyridines (5FU), antitumor antibiotics and other can retrain or arrange DNA and to go forward side by side compound (e.g., the amycin once stoping DNA to synthesize, daunomycin, epirubicin, idarubicin, Mitomycin-C, bleomycin A5), plant (Herba Catharanthi Rosei) alkaloid and other are by anti-tumor agent comprising salmosin (e.g., the vincristine of plant extract, vincaleucoblastine), steroid hormone, hormone inhibitors, hormone receptor antagonists can affect medicament (e.g., the tamoxifen of hormone reaction growth of cancers with other, Trastuzumab, arimedex, e.g., amino different dormancy energy and Formestane, triazole inhibitor, e.g., letrozole and Anastrozole, steroid inhibitor, e.g., exemestane), anti-angiogenesis albumen, micromolecule, gene therapy and (or) other can Tumor suppression angiogenesis or angiopoietic medicament (e.g., meth-1, meth-2, Sa Li polyamines), bevacizumab (Avastin), fish shark amine, endostatin, angiostatin, Angiozyme, AE-941(neovastat), CC-5013(Revimid, a kind of thalidomide derivatives), medi-522(Vitaxin), 2ME2 (2ME2, Panzem), CAI (CAI), Kang Puruiding A4 medicine precursor (CA4P), SU6668, SU11248, BMS-275291, COL-3, EMD 121974, IMC-1C11, IM862, TNP-470, celecoxib (celecoxib Celebrex), rofecoxib (Vioxx Vioxx), interferon-ALPHA, interleukin 12 (IL-12) or any at the compound of Science Vol.289,1197-1201 page (Aug.17,2000) through qualification, these compounds are all incorporated herein by reference.Biological effect adjustment reagent (as, interferon, bacill calmette-guerin (BCG), monoclonal antibody, interleukin-22, granulocyte colony-stimulating factor (GCSF) etc.), PGDF receptor antagonist, Trastuzumab, asparaginase, busulfan, carboplatin, cisplatin, carmustine, chlorambucil, cytosine arabinoside, dacarbazine, etoposide, flucarbazonesodium, fluorouracil, gemcitabine, hydroxyurea, ifosfamide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, thioguanine, phosphinothioylidynetrisaziridine, Raltitrexed, topotecan, bent fourth sulphur ester, vincaleucoblastine, vincristine, mitoazitrone, oxaliplatin, procarbazine, streptostacin, paclitaxel, docetaxel, imuran, the homologue of docetaxel derivant, the derivatives of these compounds and compositions thereof.

Example 1: the medication coat that after being absorbed water by single microgranule, physical crosslinking is formed

The composition of solid particle: drug molecule (10wt% cetirizine hydrochloride); Degradable water-soluble polymer (90wt% sodium alginate)

Preparation method: by 50g cetirizine hydrochloride, 450g sodium alginate powder (particle diameter 120 order) stirring, mix homogeneously, be dissolved in enough distilled water, be heated to 50-60 DEG C while stirring after stirring, solvent is volatilized.After the cetirizine hydrochloride and sodium alginate mixture that become solid-state version are pulverized, at 50-60 DEG C of further dry removal moisture.Add grinder grinding, to sieve granulate with 80 order screens, bulky grain continues grinding, until obtain 80 orders (that is, 180 μm) particle diameter single microgranule once.Particulate homogenous is sprayed on the surface filming of water-wet.Painting be placed on after bone dry (37 DEG C of purified water, sodium azide, PH=7.4 ± 0.2) in the molten cup of digestion instrument, do release test, 24 Hours drug release rates are that after 65%, 3 days, release rate is 96%.

Example 2: the medication coat that after being absorbed water by single microgranule, physical crosslinking is formed

The composition of solid particle: drug molecule (10wt% cetirizine hydrochloride); Degradable water-soluble polymer (90wt% sodium alginate)

Preparation method: by 50g cetirizine hydrochloride, 450g sodium alginate powder (particle diameter 120 order) stirring, mix homogeneously, be dissolved in enough distilled water.The two aqueous solution soniclizer is dispersed into droplet, and with nitrogen (or air) by acetone volatilization in droplet, obtains particle diameter at about 50nm mist projection granulating microgranule.Continue dry particles 15min with vacuum drying oven 40-50 DEG C, obtain the single microgranule of degradable polymer of band medicine.Particulate homogenous is sprayed on the surface filming of water-wet.Painting be placed on after bone dry (37 DEG C of purified water, sodium azide, PH=7.4 ± 0.2) in the molten cup of digestion instrument, do release test, 24 Hours drug release rates are that after 60%, 3 days, release rate is 89%.

Example 3: the medication coat that after being absorbed water by single microgranule, physical crosslinking is formed

The composition of solid particle: drug molecule (10wt% cetirizine hydrochloride); Degradable water-soluble polymer (90wt% sodium alginate)

Preparation method: by 50g cetirizine hydrochloride, 450g sodium alginate powder (particle diameter 120 order) stirring, mix homogeneously, be dissolved in enough distilled water, the two aqueous solution soniclizer is dispersed into droplet, and with nitrogen (or air) by acetone volatilization in droplet, obtain particle diameter at about 50nm mist projection granulating microgranule.Continue dry particles 20min with vacuum drying oven 40-50 DEG C, obtain the single microgranule of degradable polymer of band medicine.Particulate homogenous is sprayed on the surface filming of water-wet.Painting be placed on after bone dry (37 DEG C of purified water, sodium azide, PH=7.4 ± 0.2) in the molten cup of digestion instrument, do release test, 24 Hours drug release rates are that after 64%, 3 days, release rate is 87%.

Example 4: the medication coat that after being absorbed water by single microgranule, physical crosslinking is formed

The composition of solid particle: drug molecule (10wt% cetirizine hydrochloride); Degradable water-soluble polymer (90wt% sodium alginate)

Preparation method: by 50g cetirizine hydrochloride, 450g sodium alginate powder (particle diameter 120 order) stirring, mix homogeneously, be dissolved in enough distilled water, be heated to 50-60 DEG C while stirring after stirring, solvent is volatilized.After the cetirizine hydrochloride and sodium alginate mixture that become solid-state version are pulverized, at 50-60 DEG C of further dry removal moisture.Add grinder grinding, to sieve granulate with 75 order screens, bulky grain continues grinding, until obtain 75 orders (that is, 200 μm) particle diameter single microgranule once.Particulate homogenous is sprayed on the surface filming of water-wet.Painting be placed on after bone dry (37 DEG C of purified water, sodium azide, PH=7.4 ± 0.2) in the molten cup of digestion instrument, do release test, 24 Hours drug release rates are that after 57%, 3 days, release rate is 80%.

Example 5: the medication coat that after being absorbed water by single microgranule, physical crosslinking is formed

The composition of solid particle: drug molecule (10wt% cetirizine hydrochloride); Degradable water-soluble polymer (90wt% sodium alginate)

Preparation method: by 50g cetirizine hydrochloride, 450g sodium alginate powder (particle diameter 120 order) stirring, mix homogeneously, be dissolved in enough distilled water, be heated to 50-60 DEG C while stirring after stirring, solvent is volatilized.After the cetirizine hydrochloride and sodium alginate mixture that become solid-state version are pulverized, at 50-60 DEG C of further dry removal moisture.Add grinder grinding, to sieve granulate with 35 order screens, bulky grain continues grinding, until obtain 35 orders (that is, 500 μm) particle diameter single microgranule once.Particulate homogenous is sprayed on the surface filming of water-wet.Painting be placed on after bone dry (37 DEG C of purified water, sodium azide, PH=7.4 ± 0.2) in the molten cup of digestion instrument, do release test, 24 Hours drug release rates are that after 42%, 3 days, release rate is 65%.

Example 6: the medication coat that after being absorbed water by single microgranule, physical crosslinking is formed

The composition of solid particle: medicine (10wt% betamethasone); Degradable polymer [50wt% polycaprolactone (PCL)]; Water-soluble polymer [40wt% polyvinyl alcohol (PVA)]

Preparation method: 50g polycaprolactone (PCL) is dissolved in q. s. methylene chloride, then adds gradually by 10g betamethasone medicated powder, forms homogeneous solution.Be dissolved in by 40g polyvinyl alcohol in 4 liters of purified water, after dissolving completely, slowly added by the poly-vinyl alcohol solution of 1% in polycaprolactone and betamethasone solution, 20 DEG C of atmospheric agitation 40min, then 20min is stirred in decompression.Then filter with ultra-pure water, vacuum drying 24 hours at 30 DEG C.After oven dry, grind pelletize further, obtain the microgranule of particle diameter 20-100 μm.Microgranule is sprayed to the surface filming of water-wet.Painting be placed on after bone dry (37 DEG C of purified water, sodium azide, PH=7.2 ± 0.2) in the molten cup of digestion instrument, do release test, 24 Hours drug release rates are that after 8%, 7 days, release rate is 14%, 30 days release rates be 25%, 150 days release rates is 60%.

Example 7: the medication coat that after being absorbed water by single microgranule, physical crosslinking is formed

The composition of solid particle: drug molecule (30wt% momestasone furoate); Degradable polymer [40wt% Poly(D,L-lactide-co-glycolide PLGA(molar percentage LA:GA=85:15)]; Water-soluble polymer [30wt% chitosan (Chitosan)]

Preparation method: by 30g momestasone furoate, 40g Poly(D,L-lactide-co-glycolide PLGA(molar percentage LA:GA=85:15, M _w=120000) add while stirring in proper amount of acetone by equal increments method, at room temperature stir and make two kinds of components fully miscible.Solution nebulizer is dispersed into droplet, and with nitrogen (or air) by acetone volatilization in droplet, obtains particle diameter at 50-100 μm of mist projection granulating microgranule.Dry particles 10min is continued with vacuum drying oven 40-50 DEG C.

By soluble in water for 40g chitosan (deacetylation >=90%80 order), make chitosan solution.Chitosan solution is atomized into micro-mist by Vltrasonic device, is placed in above ebullated bed; Dried particle diameter to be placed in below ultrasonic nozzle on ebullated bed at 50-100 μm of momestasone furoate and PLGA atomized particles.Have aperture bottom ebullated bed, small aperture is less than 20 μm, interior logical 50 DEG C of warm nitrogen (or air), quick evaporate to dryness after making spraying arrive particle surface, the adhesion of the humble intergranular of a step-down of going forward side by side.Continuous sprinkling completes, and obtains core-skin type microgranule.After sprinkling completes, continue to keep ebullated bed to run 1 hour, by core-skin type microgranule bone dry.Particulate homogenous is sprayed on the surface filming of water-wet.After bone dry, painting to be placed in the molten cup of digestion instrument (37 DEG C of purified water, sodium azide, PH=7.2 ± 0.2), do release test, 24 Hours drug release rates are that after 15%, 3 days, release rate is 20%, 30 days release rates be 60%, 3 month release rates is 93%.

Example 8: the medication coat that after being absorbed water by single microgranule, physical crosslinking is formed

The composition of solid particle: medicine (30wt% epirubicin); Degradable polymer [40wt% Poly(D,L-lactide-co-glycolide PLGA(molar percentage LA:GA=70:30)]; Water-soluble polymer [30wt% polyvinyl alcohol (PVA)]

Preparation method: by 30g epirubicin, 40g Poly(D,L-lactide-co-glycolide PLGA(molar percentage LA:GA=70:30, M _w=100000) add while stirring in proper amount of acetone by equal increments method, at room temperature stir and make two kinds of components fully miscible.Solution nebulizer is dispersed into droplet, and with nitrogen (or air) by acetone volatilization in droplet, obtains particle diameter at 150-200 μm of mist projection granulating microgranule.Dry particles 10min is continued with vacuum drying oven 40-50 DEG C.

By 40g polyvinyl alcohol (PVA) (M ^w=150000) soluble in water, make polyvinyl alcohol (PVA) solution.Poly-vinyl alcohol solution is atomized into micro-mist by Vltrasonic device, is placed in above ebullated bed; Dried particle diameter to be placed in below ultrasonic nozzle on ebullated bed at 150-200 μm of epirubicin and PLGA atomized particles.Have aperture bottom ebullated bed, small aperture is less than 100 μm, interior logical 40 DEG C of warm nitrogen (or air), quick evaporate to dryness after making spraying arrive particle surface, the adhesion of the humble intergranular of a step-down of going forward side by side.Continuous sprinkling completes, and obtains core-skin type microgranule.After sprinkling completes, continue to keep ebullated bed to run 1 hour, by core-skin type microgranule bone dry.Particulate homogenous is sprayed on the surface filming of water-wet.After bone dry, painting to be placed in the molten cup of digestion instrument (37 DEG C of purified water, sodium azide, PH=7.2 ± 0.2), do release test, 24 Hours drug release rates are that after 25%, 7 days, release rate is 54%, 30 days release rates is 84%.

Example 9: inhaled the medication coat managed and be cross-linked to form by non-single microgranule

The composition of solid particle: medicine (15wt% loratadine); Degradable polymer [40wt% Poly(D,L-lactide-co-glycolide PLGA(molar percentage LA:GA=50:50)]; Water-soluble polymer [45wt% polyvinylpyrrolidone (PVP)]

Preparation method: by 30g loratadine, 80g Poly(D,L-lactide-co-glycolide PLGA(molar percentage LA:GA=85:15, M _w=80000) add while stirring in proper amount of acetone by equal increments method, at room temperature stir and make two kinds of components fully miscible.Solution nebulizer is dispersed into droplet, and with nitrogen (or air) by acetone volatilization in droplet, obtains particle diameter at 400-800nm mist projection granulating microgranule.Continue dry particles 10min with vacuum drying oven 40-50 DEG C, obtain the degradable polymer microgranule of band medicine.

By 90g polyvinylpyrrolidone (PVP, M _w=1000000) be dissolved in 450g isopropyl alcohol, make PVP solution.This solution nebulizer is dispersed into droplet, and with nitrogen (or air) by isopropyl alcohol volatilization in droplet, obtains particle diameter at 400-800nm mist projection granulating microgranule.Continue dry particles 10min with vacuum drying oven 40-50 DEG C, obtain water insoluble polymer particle.

Above-mentioned two kinds of microgranules are placed on same container, after mix homogeneously, are sprayed to the surface filming of water-wet.After bone dry, painting to be placed in the molten cup of digestion instrument (37 DEG C of purified water, sodium azide, PH=7.2 ± 0.2), do release test, 24 Hours drug release rates are that after 30%, 7 days, release rate is 60%, 30 days release rates is 85%.

Above-described, be only preferred embodiment of the present invention, and be not used to limit scope of the present invention, the above embodiment of the present invention can also make a variety of changes.Namely every claims according to the present patent application and description are done simple, equivalence change and modify, and all fall into the claims of patent of the present invention.The not detailed description of the present invention be routine techniques content.

Claims (1)

1. a formation method for medication coat, is characterized in that, described method comprises:

There is provided the solid particle of at least one drying, described solid particle comprises polymer and drug molecule; Described polymer is at least two kinds of polymer, this polymer at least comprises degradable polymer and hydrophilic/water-soluble polymer, the spray solution formed by hydrophilic/water-soluble polymer is to the degradable polymer surface forming microgranule, thus form the described solid particle of skin-core structure, in described solid particle, outside, degradable polymer and drug molecule Homogeneous phase mixing are core to hydrophilic/water-soluble polymer;

Be sprayed onto on a wetted surface by the solid particle mixture that the solid particle of described drying is formed, described polymer makes, between solid particle, physical crosslinking occurs in wetting surface generation swelling and forms medication coat;

Described medication coat is that the solid particle mixture swelling formed by the solid particle of drying is cross-linked the rear thin film formed, and described medication coat itself does not rely on or be attached to any entity apparatus, directly generates at nasal cavity diseased region;

Described degradable polymer is Poly(D,L-lactide-co-glycolide;

The proportion of composing of described Poly(D,L-lactide-co-glycolide is the molar ratio 50:50-85:15 of lactide and Acetic acid, hydroxy-, bimol. cyclic ester;

The weight average molecular weight range of described Poly(D,L-lactide-co-glycolide is 6000 to 300000;

Described hydrophilic/water-soluble polymer is polyvinyl alcohol;

The mass percent of described hydrophilic/water-soluble polymer is 10% to 70%;

Described thin film can be adhered to maintaining time that time of film forming brute force and thin film be etched completely and be controlled by the ratio adjusting lactide in described Poly(D,L-lactide-co-glycolide and Acetic acid, hydroxy-, bimol. cyclic ester;

Described solid particle is micron order microgranule;

The slow-release time of described medication coat is 3 to 30 days.