CN206120770U - Medicine formulation - Google Patents

Abstract

The utility model provides a be used for peroral medicine formulation. Medicine formulation includes the base member, and it forms the compartment in inside, and held medicine matrix in the compartment. Medicine formulation's design can realize the controlled release of drug activity composition in the medicine matrix.

Description

Pharmaceutical formulation

Cross-Reference to Related Applications

This application claims the U.S. Provisional Application 62/170 that on June 3rd, 2015 submits to, 645, and on March 24th, 2016 The priority of the U.S. Provisional Application 62/313,092 of submission.The reference of entire contents here is incorporated to.

Technical field

The invention mainly relates to a kind of pharmaceutical formulation and bioactivator, diagnostic agent, reagent, enamel and agricultural/kill The controllable release of worm agent.

Background technology

Medicine must be prepared into pharmaceutical formulation could list marketing use.Conventional medication dosage form is generally by active constituents of medicine It is mixed with non-active ingredient (excipient) and other not re-usable material such as capsule shells.Pharmaceutical formulation is classified Including liquid drug dosage form (for example, solution, syrup, elixir, suspensoid and Emulsion), solid medicine dosage form (for example, tablet, glue Capsule, caplet and gel cap), and semi-solid pharmaceutical formulation (for example, ointment and suppository), wherein, for the system of oral drugs For, solid medicine dosage form most advantage.

Tablet is the most frequently used solid medicine dosage form, and which is in manufacture, packaging and transports more advantage, and is easier to know Not with swallow.After organism is applied to, tablet interacts to play drug effect with body.Active constituents of medicine must be in piece Agent is discharged before being rapidly absorbed into blood circulation.Ingredient subsequently passes through body fluid and tissue dispersion or dissolves in vivo. During this drug absorption, deposition, metabolism and elimination, pharmaceutical formulation is determining drug release patterns and biological utilisation Decisive role is played in terms of degree.Therefore, research and develop a kind of demand of the pharmaceutical formulation that controllable dispenser system is provided to exist always, The system can provide the levels of drugs needed for blood plasma, reduce side effect, and can improve adaptability of the patient to medicament.

Utility model content

On the one hand, present disclose provides a kind of pharmaceutical formulation, which includes the matrix containing at least one compartment and is received In the drug matrices of the compartment.In some embodiments, the medicine is operably secured on matrix.In some realities Apply in mode, the medicine and matrix separate and can move freely in compartment.

In some embodiments, described matrix be from hydrophilic polymer, hydrophobic polymer, polymers capable of swelling, The thermoplastic chosen in non-swelling polymer, porous polymer, non porous polymeric, erodable polymer and non-erodable polymer Property material.In some embodiments, the thermoformable material is selected from Vinylcaprolactam homopolymer polyvinyl acetate-poly- Ethylene glycol graft copolymer 57/30/13, Kollidon VA64 (PVP-VA), polyvinyl pyrrole Alkanone-VA (PVP-VA) 60/40, polyvinylpyrrolidone (PVP), polyvinyl acetate ester (PVAc) With polyvinylpyrrolidone (PVP) copolymer 80/20, polyethylene glycol vinyl alcohol graft copolymer 25/75, Kollicoat IR- polyvinyl alcohol copolymers 60/40, polyvinyl alcohol (PVA or PV-OH), polyvinyl acetate ester (PVAc), polymethylacrylic acid Butyl ester-poly- 2- dimethylaminoethyls methacrylate-polymethyl methacrylate copolymer 1：2：1, polymethylacrylic acid two Methylamino-polymethacrylate copolymer, polyethyl acrylate-polymethyl methacrylate-poly- trimethylethyl vinyl chloride Copolymer, polymethyl acrylate-polymethyl methacrylate-poly- base acrylic copolymer 7：3：1, polymethylacrylic acid-poly- first Base methyl acrylate copolymer 1：2, polymethylacrylic acid-polyethyl acrylate copolymer 1:1, polymethylacrylic acid-poly- methyl Methyl acrylate copolymer 1：1, poly(ethylene oxide) (PEO), Polyethylene Glycol (PEG), hyper-branched polyester, hydroxypropyl methyl cellulose Phthalic acid ester, Hydroxypropyl methyl cellulose phtalate, hydroxypropyl methyl cellulose or hypromellose (HMPC), hydroxyl Propyl methocel succinate or HPMC-AS-AS (HPMCAS), polylactide-poly- breast Acid copolymer (PLGA), carbomer, polyvinyl-polyvinylacetate copolymer, vinyl-vinyl acetate copolymer, polyethylene (PE) and polycaprolactone (PCL), hydroxy propyl cellulose (HPC), the Oleum Ricini of the hydrogenation of Polyethylene oxide 40, methylcellulose (MC), ethyl cellulose (EC), poloxamer, hydroxypropylmethyl cellulose phthalate (HPMCP), poloxamer, hydrogen Change Oleum Ricini, glyceryl palmitostearate, Brazil wax, polylactic acid (PLA), polyglycolic acid (PGA), acetate butyrate fiber Plain (CAB), colloidal silicon, titanium oxide, sucrose, glucose, polyvinylacetate phthalate (PVAP) and combinations thereof.

In some embodiments, compartment shape can be pie, coniform, pyramid shape, cylindric, cubic, The combination of rectangular-shape, triangle or polygon prismatic, tetrahedral or these shapes.

In some embodiments, first medicine is present with nano-particle, micropin or web form.

In some embodiments, the drug matrices include active constituents of medicine (API).In some embodiments, The API can be local anesthetic, sleep regulation medicine, antuepileptic, anticonvulsant, anti-alzheimer disease medicine, analgesic, Arthrifuge, antihypertensive, anti-arrhythmic, diuretic, treatment liver disease drug, treatment pancreatic diseases medicine, treatment in Pivot nervous system disease medicament, treatment gastrointestinal disease medicine, antihistaminic, antiallergic agent, glucocorticoid medicine, hormone drug Thing, contraceptive, blood sugar lowering, anti-osteoporotic, antibiotic, sulfa drugss, quinolones and other synthesis are anti- In bacterium medicine, antituberculotics, antiviral drugs, antitumor drug, immunomodulator, cosmetic active agent or Chinese tradition Medicine.In some embodiments, the API is for bioactive agents, diagnostic reagent, for the reagent of scientific research, cosmetic Product reagent, veterinary medicament or agricultural/pesticidal agents.

In some embodiments, the drug matrices further include excipient.In some embodiments, the tax Shape agent is made up of water-soluble material, non-water soluble material, and the material is selected from the group：Cocoa butter, Polyethylene Glycol (PEG), sucrose, glucose, galactose, Fructose, xylose, Lactose, maltose, trehalose, Sorbitol, mannitol, Fructus Hordei Germinatus Magma essence, Raffinose, stachyose, oligofructose and combinations thereof saccharide, gel-like, cellulose family, polyesters, polycyclic oxygen second The material of alkanes, polyethylene kind, polyacrylic or combinations thereof is made.

In some embodiments, the compartment has one to be blocked and/or blind bore hole by stopper (plug) (aperture).In some embodiments, the stopper is by porous polymer, erodable polymer, pH sensitive polymers Or naturally occurring material such as Lac is made.In some embodiments, the stopper be by selected from water-soluble polymer, it is non-aqueous Soluble polymer, wax class, saccharide, gel-like, cellulose family, polyesters, poly(ethylene oxide) class, polyethylene kind, polyacrylic Or combinations thereof material make.

In some embodiments, pharmaceutical formulation includes the Gas generating components positioned at the first compartment.In some realities Apply in mode, the Gas generating components are selected from the group：Water soluble carbonate, sulphite, bicarbonate, sodium carbonate, carbonic acid Hydrogen sodium, sodium metabisulfite, Calcium Carbonate or combinations thereof, can discharge carbon dioxide or sulfur dioxide gas when gastric juice is touched Body.In some embodiments, the Gas generating components are sodium bicarbonate and organic acid (for example, citric acid and tartaric acid etc.) Combination.

On the other hand, present disclose provides a kind of pharmaceutical formulation, the pharmaceutical formulation includes internal at least containing one the The matrix of one compartment and a second compartment.The pharmaceutical formulation includes the first drug matrices for being accommodated in the first compartment With the second drug matrices for being accommodated in the second compartment.

In some embodiments, the first compartment is connected with the second compartment.In some embodiments, it is described First compartment and the second compartment are not attached to.

In some embodiments, first drug matrices are identical with second drug matrices.In some embodiment party In formula, first drug matrices are different from second drug matrices.

In some embodiments, the first compartment have one by the first stopper block the first hole, described second Compartment has second hole blocked by the second stopper.In some embodiments, first stopper is than the second stopper Permeability is high.In some embodiments, first stopper is higher than the erosion rate of the second stopper.

In some embodiments, the first compartment is surrounded by the first wall, and the second compartment is surrounded by the second wall.

In some embodiments, first wall is than second wall thickness.In some embodiments, first wall It is higher than the permeability of second wall.In some embodiments, first wall is erodible higher than second wall.

On the other hand, present disclose provides a kind of pharmaceutical formulation, including：The two-layer being stacked or more layers matrix Layer, wherein at least one of described two or multiple base layers are respectively containing at least one drug matrices.

In some embodiments, described two or multiple base layers can be separated from each other.

In some embodiments, described two or multiple base layers are made up of at least one thermoplastic.

In some embodiments, described two or multiple base layers have different thickness.

In some embodiments, described two or multiple base layers have different corrosion/dissolution rates.

In some embodiments, described two or multiple base layers are arranged at least one included drug matrices Discharged based on predetermined release profiles in aqueous.

In some embodiments, described two or multiple base layers include the first base layer comprising the first ingredient And the second base layer comprising the second ingredient, wherein second base layer is set relative to first base layer It is relatively outside, so that second ingredient is discharged prior to first ingredient.

On the other hand, present disclose provides a kind of pharmaceutical formulation, including：Matrix, described matrix have on its interior Compartment；And drug matrices, which is accommodated in the compartment.

In some embodiments, the drug matrices are regularly seated in the compartment.

In some embodiments, the drug matrices are configured to the size less than the compartment such that it is able to Move in the compartment.

In some embodiments, described matrix is integrally formed.

In some embodiments, the drug matrices are encapsulated in the housing with acicular texture, and the shell Body is accommodated in the compartment.

In some embodiments, the drug matrices are made up of loose material.

In some embodiments, the loose drug matrices are made up of identical material with described matrix, and institute State the density of the density less than described matrix of loose drug matrices.

In some embodiments, the compartment is closing.

In some embodiments, the compartment be configured to pie, pyramid shape, column, taper, it is cube-shaped, three The combination of angle prismatic, polygon prismatic, tetrahedral or these shapes.

In some embodiments, described matrix is with opening corresponding with the compartment, the opening cause it is described every Drug matrices in room expose.

In some embodiments, the compartment is configured to the face from the inwardly cumulative dissolving border of the opening Product, so that the active constituents of medicine when the pharmaceutical formulation dissolves in the drug matrices is released with predetermined release profiles Put.

In some embodiments, the rate of release of the active constituents of medicine is constant.

In some embodiments, the compartment be configured to pie, pyramid shape, column, taper, it is cube-shaped, three The combination of angle prismatic, polygon prismatic, tetrahedral or these shapes.

In some embodiments, with hole corresponding with the compartment, described hole is blocked described matrix by stopper, To close the compartment.

In some embodiments, the dissolution time that the stopper is configured in aqueous is longer than described matrix most Short dissolution time so that the active constituents of medicine in the drug matrices can the stopper dissolving after Jing by described hole Discharge.

In some embodiments, multiple drug matrices are accommodated in the compartment.

In some embodiments, the plurality of drug matrices are configured to adjacent column structure.

In some embodiments, the plurality of compartment is configured to cylindrical space spaced apart from each other.

In some embodiments, the plurality of drug matrices are configured to laminated construction.

In some embodiments, the inner side of the compartment has slow release layer, and which is used to isolate the drug matrices and institute Matrix is stated, so as to the slow release layer can delay the drug matrices pharmaceutical active composition when the pharmaceutical formulation dissolves Release.

In some embodiments, Gas generating components are mounted with the compartment.

In some embodiments, the drug matrices are made up of nano-particle.

In some embodiments, the compartment is hollow.

In some embodiments, the size of the compartment is configured such that the average density of the pharmaceutical formulation is less than The density of water.

In some embodiments, the drug matrices are configured to loose structure.

In some embodiments, described matrix is made up of at least one thermoformable material.

Another aspect, present disclose provides a kind of pharmaceutical formulation, including：Matrix, described matrix have on its interior Multiple compartments；And multiple drug matrices, which is accommodated in the plurality of compartment.

In some embodiments, each compartment in the plurality of compartment is configured to column structure, and different Compartment is spaced from each other.

In some embodiments, contain different active constituents of medicine in the plurality of drug matrices.

In some embodiments, the plurality of drug matrices have different length.

In some embodiments, the plurality of drug matrices have the area on different dissolving borders.

In some embodiments, at least part of compartment in the plurality of compartment is closing.

In some embodiments, described matrix is opened with corresponding with least part of compartment in the plurality of compartment Mouthful, the opening is so that the drug matrices in corresponding compartment expose.

In some embodiments, the compartment is configured to the face from the inwardly cumulative dissolving border of the opening Product, so that the active constituents of medicine being open in corresponding drug matrices was released with predetermined when the pharmaceutical formulation dissolves Put curve release.

In some embodiments, the rate of release of the active constituents of medicine is constant.

In some embodiments, the compartment is configured to pie, pyramid shape, column, taper, cubic, just The combination of cube shape, cylindrical shape, cone, triangle prismatic, polygon prismatic, tetrahedral or these shapes.

In some embodiments, the opening is with different areas.

In some embodiments, contain different active constituents of medicine in the plurality of drug matrices.

In some embodiments, with hole corresponding with the compartment, described hole is blocked described matrix by stopper, To close the compartment.

In some embodiments, the dissolution time that the stopper is configured in aqueous is longer than described matrix most Short dissolution time so that the active constituents of medicine in the drug matrices can the stopper dissolving after Jing by described hole Discharge.

In some embodiments, different stoppers is configured to have different dissolution times in aqueous, so that The active constituents of medicine obtained in the plurality of drug matrices was discharged in the different time.

In some embodiments, different stoppers has different length.

In some embodiments, different stoppers has different rate of dissolutions.

In some embodiments, different spaces has the area on different dissolving borders.

In some embodiments, the plurality of compartment is connected with each other.

In some embodiments, the plurality of compartment is spaced from each other.

In some embodiments, the plurality of drug matrices are made up of identical host material.

In some embodiments, multiple compartments of described matrix are configured to laminated construction spaced apart from each other.

In some embodiments, the drug matrices are made up of nano-particle, and are contained in multiple spaced apart from each other In compartment.

In some embodiments, described matrix includes the multiple compartments for closing off the plurality of compartment, and institute State multiple compartments and there are different thickness.

In some embodiments, described matrix is made up of at least one thermoformable material.

Another further aspect, present disclose provides a kind of pharmaceutical formulation, including：Multiple drug matrices, wherein each drug matrices It is made up of at least one thermoformable material respectively, and the plurality of drug matrices is joined together.

In some embodiments, the plurality of drug matrices contain different active constituents of medicine.

In some embodiments, the plurality of drug matrices are made up of identical host material.

In some embodiments, the plurality of drug matrices are configured to column structure.

In some embodiments, the plurality of drug matrices have fan-shaped section.

In some embodiments, the plurality of drug matrices are stacked on together.

In some embodiments, the plurality of drug matrices are configured to laminated construction.

In some embodiments, the adjacent drug matrices in the plurality of drug matrices contain different pharmaceutically actives Composition.

In some embodiments, the plurality of drug matrices have different thickness.

In some embodiments, in the plurality of drug matrices, at least part of drug matrices are made up of nano-particle.

In some embodiments, non-outermost one or more the medicine substrate positioned at laminated construction are by nano-particle Constitute.

Description of the drawings

Figure 1A shows a kind of traditional drug dosage form containing drug matrices；

Figure 1B shows release profiles after pharmaceutical formulation medication in Figure 1A；

Blood drug level after Fig. 1 C medications.

Fig. 1 D show a kind of zero order delivery profile of the pharmaceutical formulation of controllable release；

Fig. 2A shows a kind of exemplary pharmaceutical formulation, and which has matrix and the compartment positioned at intrinsic silicon and is held The drug matrices being contained in compartment；

Fig. 2 B show the release process of the API of the pharmaceutical formulation shown in Fig. 2A；

Fig. 3 shows a kind of exemplary pharmaceutical formulation, and which has matrix and the compartment positioned at intrinsic silicon, and is held Another kind of pharmaceutical formulation being contained in the compartment；

Fig. 4 A show a kind of exemplary pharmaceutical formulation, and which has matrix and the pie compartment positioned at intrinsic silicon；

Fig. 4 B show a kind of exemplary pharmaceutical formulation, and which has matrix and positioned at intrinsic silicon with different size Multiple compartments of opening；

Fig. 4 C show a kind of exemplary pharmaceutical formulation, its have matrix and positioned at intrinsic silicon difference angle every Room；

Fig. 4 D show a kind of exemplary pharmaceutical formulation, and which has matrix and has different radii positioned at intrinsic silicon Compartment；

Fig. 4 E show a kind of exemplary pharmaceutical formulation, and which has matrix and the multiple compartments positioned at intrinsic silicon, and And compartment has different geometries to adjust the rate of release of API；

Fig. 5 shows a kind of sectional view of the exemplary pharmaceutical formulation containing pie compartment；

Fig. 6 shows a kind of exemplary pharmaceutical formulation, and which has matrix and the laminated construction positioned at intrinsic silicon, and medicine Thing substrate is dispersed between lamination in the form of nano-particle；

Fig. 7 shows a kind of exemplary pharmaceutical formulation, and which has matrix, the compartment positioned at intrinsic silicon and is accommodated in The drug matrices of the micropin shape in the compartment；

Fig. 8 A show a kind of exemplary pharmaceutical formulation, and which has matrix, the compartment positioned at intrinsic silicon and is received Drug matrices in the compartment.The drug matrices are configured to network structure.Described matrix is by can dissolve within the 1-5 minutes Material make, and the drug matrices can be dissolved within the several seconds；

Fig. 8 B show the pharmaceutical formulation shown in Fig. 8 A for the quick release process of API；

Fig. 9 shows a kind of exemplary pharmaceutical formulation, and which has matrix and the multiple column compartments positioned at intrinsic silicon； Each compartment accommodates a kind of drug matrices.The release of medicine in compartment is determined by the quantity and compartment size of compartment；

Figure 10 A show a kind of exemplary pharmaceutical formulation, its have matrix and positioned at intrinsic silicon 3 columns every Room.Each compartment accommodates a kind of drug matrices.Each drug matrices has cylindrical substrate to block each compartment Opening.Each substrate suffers from different length；

Figure 10 B show a kind of exemplary pharmaceutical formulation, and which has some drug matrices encapsulated with refracting films；It is each Individual substrate is all the mixture of same API and the different base with different solubilities；

Figure 10 C show the controllable release process of three kinds of API of the pharmaceutical formulation shown in Figure 10 A and 10B；

Figure 10 D show the zero order delivery profile of the API of the pharmaceutical formulation shown in Figure 10 A or 10B；

Figure 11 shows the workflow schematic diagram that the API medicaments for patient are prepared with 3D printer；

Figure 12 A show a kind of exemplary pharmaceutical formulation containing two kinds of drug matrices；

Figure 12 B show release process of the pharmaceutical formulation shown in Figure 12 A to two kinds of API；

Figure 13 A show a kind of exemplary pharmaceutical formulation, and which has matrix and three compartments positioned at intrinsic silicon, often Individual compartment is mounted with a kind of drug matrices.The release process of every kind of medicine is controlled by the dissolubility of stopper；

Figure 13 B show the release process of three kinds of API of the pharmaceutical formulation shown in Figure 13 A；

Figure 14 A show a kind of exemplary pharmaceutical formulation, and which has matrix and three compartments positioned at intrinsic silicon, often Individual compartment is mounted with a kind of drug matrices；

Figure 14 B show a kind of exemplary pharmaceutical formulation, and which has matrix and three compartments positioned at intrinsic silicon, and Three compartments are contained in a big body, and each compartment is mounted with a kind of drug matrices.Every kind of drug matrices all carry API The mixture constituted with substrate.

Figure 14 C discharge process while showing pharmaceutical formulation as shown in figs. 14 a and 14b to 3 kinds of difference API.

Figure 15 A show a kind of pharmaceutical formulation containing two kinds of API；

Figure 15 B show a kind of controllable release of pharmaceutical formulation as shown in fig. 15 to two kinds of API；

Figure 16 A show a kind of exemplary pharmaceutical formulation, its have matrix and positioned at intrinsic silicon three columns every Room；Each compartment is mounted with a kind of drug matrices；Each drug matrices has cylindrical substrate to block each compartment Opening.Each substrate has different dissolubility；

Figure 16 B show the controllable release of pharmaceutical formulation as shown in Figure 16 A to three kinds of API；

Figure 17 A show a kind of exemplary pharmaceutical formulation, its have matrix and positioned at intrinsic silicon four columns every Room.Each compartment is mounted with a kind of drug matrices；

Figure 17 B show pharmaceutical formulation shown in Figure 17 A to release profiles while four kinds of API；

Figure 17 C show continuous release profiles of the pharmaceutical formulation shown in Figure 17 A to four kinds of API；

Figure 18 A show the schematic diagram of pie medicament forms；

Figure 18 B show the release percentage curve of pharmaceutical formulation para Toluic Acid and PEG8000 in Figure 18 A.

Figure 19 A show the perspective view of the pharmaceutical formulation containing two compartments；

Figure 19 B show the sectional view of the pharmaceutical formulation in Figure 19 A；

Figure 19 C show the exemplary release profiles of the pharmaceutical formulation in Figure 19 A；

Figure 19 D show another exemplary release profiles of the pharmaceutical formulation in Figure 19 A.

Specific embodiment

In above summary of the invention with detailed description and following claims and accompanying drawing, reference is both in invention Specific features (include method and step).It is to be appreciated that the disclosure of the invention in this specification includes these specific features Be possible to combination.For example, when a specific aspect or embodiment or a concrete right of the present invention require to disclose one Individual specific features, within the bounds of possibility, this feature with remaining feature of the present invention and embodiment, or can also entirely be sent out It is bright to be used in combination.

" including " and its synon use in text means that other components, composition, step etc. are also optionally present 's.For example, the object of " including " component A, B and C can be made up of (i.e. only by) A, B and C, or except A, B and C are also wrapped Containing more other components.

When reference is aimed at the method that includes two or more particular steps, particular step can be with any Order is performed or while perform (unless context clearly eliminates the probability), and the method includes one or more its His step, these steps can before any particular step, among or perform afterwards (unless context clearly eliminate this can Energy property).

When a numerical range is related to, it is to be appreciated that each intermediate value, to lower limit unit ten/ One unless context be clearly otherwise noted, between the scope bound, and in the scope it is any remaining refer to Definite value or intermediate value, among being contained in the disclosure, exclude the limit value in the scope of clear stipulaties.When the scope bag Containing one or two limit value, eliminate any one or two limit values scope be still comprised in the disclosure among.

" at least " it is followed by numeral to show a scope with the numeral as lower limit (according to the variable of definition, the scope may There are a upper limit or no upper limit).For example, " at least 1 " shows 1 or more than 1." at most " it is followed by numeral to show one to change Numeral for the upper limit scope (according to definition variable, the scope may with 1 or 0 as lower limit, or no lower limit).For example " extremely Many 4 " show 4 or less than 4, and " at most 40% " shows 40% or less than 40%.In the disclosure, when a scope quilt When being defined as " (first is digital) to (second is digital) " or " (first is digital)-(second is digital) ", show under this scope Limit is first digital, and the upper limit is second digital.For example, 2 to 10 millimeters of lower limits for showing a scope are 2 millimeters, and the upper limit is 10 Millimeter.

Succinct in order to what is stated, when suitable, reference number is reused to show correspondence in different drawings Or similar element.In addition, present description provides substantial amounts of detail is in order to having to embodiment described here It is thorough to understand.However, embodiment described here can also be carried out in the case where these details are lacked.In remaining situation Under, method, program and component are not disclosed in detail, to avoid the description of fuzzy correlation function.Additionally, description herein Shall not be construed as limiting the scope of embodiment as herein described.It should be understood that unless otherwise stated, the disclosure The description of the embodiment of middle elaboration and sign are not mutually exclusive.

The pharmaceutical formulation of control release

As shown in Figure 1A, conventional solid pharmaceutical formulation, such as flat tablet are to dissolve into active constituents of medicine or embedding Make in entering matrix.Existing conventional solid pharmaceutical formulation is presented single order drug release patterns (Figure 1B), the wherein medicine in blood plasma Thing level is increased sharply upon administration, is then also referred to number and is declined (Fig. 1 C).The shortcoming of the release characteristic be levels of drugs reduce and The decrease of the therapeutic efficiency for causing, or the toxicity produced by high concentration medicine.This drug release is unfavorable for blood plasma Chinese medicine The balance of thing level.The present invention relates to the oral administration system of a kind of adjustable or controllable release, the system and legacy system Compare, have the advantages that to strengthen patient compliance, selectivity pharmacological action, reduce side effect and reduce medicine frequency.Realizing controlled-release Put and extend administration process, and can be with the blood drug level in the maintaining treatment phase.For example, the dispenser system of zero order delivery profile is presented System (Fig. 1 D) cause constant dosage medicine within a prolongation cycle by sustained release, realize the dispenser of homogeneous constant Journey.Therefore, antibiotic delivery, hypertension therapeutic, pain management, antidepressant delivering and many other require Constant plasma medicine The situation of level may be also required to Zero order release feature.

Therefore present disclose provides a kind of stable oral solid medicine dosage form.In some embodiments, pharmaceutical formulation Including matrix, at least one compartment formed in intrinsic silicon and the drug matrices being loaded in compartment.Pharmaceutical formulation is designed For the active constituents of medicine in drug matrices can be caused to discharge in a controlled fashion.

A. matrix

" matrix " referred herein refers to the structure for including or having drug matrices embedded.The matrix of pharmaceutical formulation can Being arbitrarily to be suitable to oral dimensions or shapes.In some embodiments, matrix be a diameter of 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm or 12mm flattened round tablet.In some embodiments, matrix is that size is about Between 5 to 15, the value of b is between 2 to 10 for the oval tablet of a mm × b mm, the wherein value of a.In some embodiment party In formula, matrix is capsule shape.

In some embodiments, matrix is by hydrophilic polymer (for example, hydroxypropyl methyl cellulose (HPMC) and poly- (oxirane) (PEO)), hydrophobic polymer (for example, ethyl cellulose (EC)), expandable polymer, non-swelling polymer, Porous polymer, non porous polymeric, erodable polymer or non-erodable polymer are made.

In some embodiments, medicine and reagent has monomer matrix.In some embodiments, matrix has multiple parts Constitute, each part is made up of identical or different material.

In some embodiments, matrix is made up of thermoplastic." thermoplastic " herein refers to can be by adding The material of heat or pressure plasticity.In some embodiments, for example, thermoplastic can be hydrophilic gel rubber material, The material passes through dispersal events drug matrices；Or hydrophobic material, drug matrices are by the outside dispersal events in hole on matrix. Polymer, particularly cellulose ether, cellulose esters and/or acrylic resin are used as the material of hydrophilic thermoplastic.Second Base cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, poly- (methyl) acrylic acid and/or they Derivant, such as salt, amide or ester, it is also possible to as thermoplastic material.Physiologically it is recognized and for people in the art Hydrophobic material known to member, such as C12-C30 fatty acids and/or C12-C30 fatty alcohol and/or wax or their mixture List-or two glyceride can serve as thermoplastic material.Matrix be also likely to be by hydrophobic material, such as hydrophobic polymer, wax, Fat, long-chain fatty acid, fatty alcohol or corresponding ester or ether or their mixture are made.

In some embodiments, the thermoformable material selected from Vinylcaprolactam homopolymer polyvinyl acetate- Polyethyleneglycol-graft copolymer 57/30/13, Kollidon VA64 (PVP-VA), polyethylene pyrrole Pyrrolidone-VA (PVP-VA) 60/40, polyvinylpyrrolidone (PVP), polyvinyl acetate ester (PVAc) and polyvinylpyrrolidone (PVP) copolymer 80/20, polyethylene glycol vinyl alcohol graft copolymer 25/75, Kollicoat IR- polyvinyl alcohol copolymers 60/40, polyvinyl alcohol (PVA or PV-OH), polyvinyl acetate ester (PVAc) gather Butyl methacrylate-poly- 2- dimethylaminoethyls methacrylate-polymethyl methacrylate copolymer 1：2：1, poly- first Base acrylate-polymethacrylate copolymer, polyethyl acrylate-polymethyl methacrylate-poly- trimethyl Ethyl vinyl chloride copolymer, polymethyl acrylate-polymethyl methacrylate-poly- base acrylic copolymer 7：3：1, poly- methyl-prop Olefin(e) acid-polymethyl methacrylate copolymer 1：2, polymethylacrylic acid-polyethyl acrylate copolymer 1:1, polymethyl Acid-polymethyl methacrylate copolymer 1：1, poly(ethylene oxide) (PEO), Polyethylene Glycol (PEG), hyper-branched polyester, hydroxypropyl Methyl cellulose phthalate ester, Hydroxypropyl methyl cellulose phtalate, hydroxypropyl methyl cellulose or hypromellose Plain (HMPC), hydroxypropyl methyl cellulose succinate or HPMC-AS-AS (HPMCAS), gather Lactide-copolymer of poly lactic acid (PLGA), carbomer, polyvinyl-polyvinylacetate copolymer, ethane-acetic acid ethyenyl ester are common Polymers, polyethylene (PE) and polycaprolactone (PCL), hydroxy propyl cellulose (HPC), the Oleum Ricini of the hydrogenation of Polyethylene oxide 40, first Base cellulose (MC), ethyl cellulose (EC), poloxamer, hydroxypropylmethyl cellulose phthalate (HPMCP) moor Lip river Sha Mu, castor oil hydrogenated, glyceryl palmitostearate, Brazil wax, polylactic acid (PLA), polyglycolic acid (PGA), acetic acid Cellulose butyrate (CAB), colloidal silicon, titanium oxide, sucrose, glucose, polyvinylacetate phthalate (PVAP) and it Combination.

The property of various thermoplastics and source are specifically listed in table 1 below.

In certain embodiments, thermoformable material allows pharmaceutical formulation to make by additive method, for example, melt Melt deposition modeling (FDM).In certain embodiments, thermoforming material can be extruded by 3D printer and manufactures pharmaceutical formulation.It is logical Chang Di, thermoformable material melt in 3D printer, then are extruded to form matrix.In certain embodiments, it is suitable to squeeze Press is included but is not limited to, single or twin (double) screw extruder, and extruder temperature is set between 50 DEG C to 180 DEG C and 80 DEG C To between 140 DEG C.In general, extrusion process can be 10 on glass transition (Tg) temperature of thermoformable material DEG C to carrying out between 40 DEG C.Once 3D printer reaches suitable temperature, thermoformable material can be deposited to three-dimensional printing table Face.It is programmed by the printing technology to 3D printer and can be realized to the matrix by made by thermoformable material and compartment The control of shape and size.

In some embodiments, the release profiles of drug matrices can be controlled by selecting matrix material.For example, by Specific dissolubility, permeability or matrix made by erodible material, can open in a predefined manner after administration compartment and with The speed release drug matrices of needs.In some embodiments, matrix is made up of corrosion or solvable material, and medicine Active component (API) is embedded in or is dissolved in matrix.Active pharmaceutical ingredient is discharged with the corrosion or dissolving of matrix.

The release of drug matrices or active constituents of medicine can also be controlled by the thickness of adjustment matrix.For example, formed The matrix of compartment is made up of soluble substance.The opening of compartment can be controlled so as to control by adjusting the wall of the matrix for surrounding compartment The release of medicine.For example, the wall of compartment is thicker, and the opening of compartment is slower, and the release of medicine is more late.

B. compartment

In some embodiments, pharmaceutical formulation disclosed herein includes at least one compartment in the base.Herein " compartment " is referred to by matrix mark or the space for separating, part or room.One compartment can both be that closing can also be Open (i.e. band hole).One compartment can be easy for loading the random geometry of drug matrices.In some embodiment party In formula, compartment shape can be pie, pyramid shape, column or coniform.

In some embodiments, the compartment of particular design is shaped such which can discharge drug matrices with special speed. In some embodiments, compartment shape can be wedge-like, triangle prismatic, pie, pyramid shape, column, cubic, ellipse Shape is coniform.

In some embodiments, stop in the gastrointestinal tract can be increased comprising compartment in pharmaceutical formulation.Fig. 2A shows Exemplary pharmaceutical formulation has been gone out, which has the matrix to form compartment, drug matrices is accommodated in the compartment.With reference to Fig. 2A, Pharmaceutical formulation 100 has the matrix 101 for forming compartment 102.Drug matrices 103 are accommodated in by connecting the inwall of compartment 102 In compartment 102.Compartment 102 can provide buoyancy so as to extend it in stomach or liquid environment or acid for pharmaceutical dosage form 100 The time of staying in property environment.The dissolubility of matrix material determines the existence time of pharmaceutical formulation, and can realize accordingly The sustained release to API as shown in Figure 2 B.

Fig. 3 shows the pharmaceutical formulation of exemplary increase gut retention time.With reference to Fig. 3, the compartment of pharmaceutical formulation 200 202 include the second pharmaceutical formulation 203 (for example, tablet) that can move freely wherein.Stop of the pharmaceutical formulation in gastrointestinal Time is limited.Floating system allows the system to stop under one's belt and on the gastrointestinal tract, and portion constantly discharges medicine so as to most The absorption of bigization small intestinal.

In one embodiment, the compartment of pharmaceutical formulation has different geometries.Fig. 4 A show one it is exemplary Pharmaceutical formulation, the intrinsic silicon of the pharmaceutical formulation contains pie compartment, and the area on the dissolving border of the pie compartment is by close It is inward-facing on the outside of pharmaceutical formulation gradually to increase, so that when the direction according to Fig. 4 A is seen from above, the pie compartment is big Body is in sector.Fig. 4 B show a kind of exemplary pharmaceutical formulation, and the intrinsic silicon of the pharmaceutical formulation contains with different openings chi Very little multiple compartments, these compartments are substantially in prism-frustum-shaped.Fig. 4 C show a kind of exemplary pharmaceutical formulation, the base of the pharmaceutical formulation The compartment of different angles is contained in portion in vivo.Fig. 4 D show a kind of exemplary pharmaceutical formulation, and the matrix of the pharmaceutical formulation is contained within Pie compartment with different radii.

The shape of compartment can be used to the release profiles for controlling pharmaceutical formulation.For example, R.A.Lipper and W.I.Higuichi just describes a kind of as shown in Figure 5 application system that can realize zero order delivery profile.Fig. 5 shows tool There is the sectional view of the application system of pie compartment.The compartment can be in communication with the outside by little opening.The compartment is mounted with Drug matrices, and drug matrices can pass through little outward opening circle release API upon dissolution.The dissolution rate and medicine of drug matrices The area positive correlation on the dissolving border (interface between the drug matrices and compartment space) of thing substrate.On the other hand, API exists Dissolution rate in environment is negatively correlated with diffusion path length λ.Thus, with the dissolving of drug matrices, the area for dissolving border increases Plus, the dissolution rate of drug matrices can also increase.And on the other hand, diffusion path length dissolves also with drug matrices and increases. So beyond the API being released in compartment needs to be transferred longer distance to be diffused into pharmaceutical formulation.It is assumed that the medicine agent Type can be designed as meeting zero-order release kinetics, and (R.A.Lipper and W.I.Higuchi (1977) is applied to intending zero-order drug The analysis of the theoretical behavior of adding system, medicine Scientific Magazine 66 (2)：163-4；D.Brooke and R.J.Washkuhn (1977) zero Level medicine application system：It is theoretical to test with primary, 66 (2) 159-162 of medicine Scientific Magazine).

C. drug matrices

Drug matrices used herein refer to the compositionss containing one or more active ingredient, wherein active ingredient bag Include active constituents of medicine (API), cosmetic agent, biological reagent, diagnostic reagent and scientific experimentss reagent.

Noun " medicament active composition (API) " as used herein refers to the composition with biological activity in medicine.One In a little embodiments, API can be selected from the following group：Local anesthetic, antuepileptic and anticonvulsant, Kang Aercihaimoshi are sick Medicine, analgesic, arthrifuge, antihypertensive, anti-arrhythmic, diuretic, treatment hepatic disease medicine, treatment pancreas disease Medicine, antihistaminic, antiallergic agent, glucocorticoid medicine, gonadal hormone medicine and contraceptive, blood sugar lowering, anti-sclerotin Loose medicine, antibiotic, sulfonamides, quinolones and other synthetic antibacterial drugs, antitubercular agent, antiviral agents, anti-tumor drug, Immunomodulator, cosmetic active agent, Chinese traditional medicine (TCM) and Traditional Chinese doctors ' medicament extract.

In certain embodiments, API can be selected from the group：(R) the sub- oil of-folitixorin, lignocaine, bis--deuteriums of 11- Acetoacetic ester, 16- dehydrogenation pregnenolones, 17-β-estradiol, 2- iminobiotins, the acid of 3,5- diiodo-s thyroid, the fluoro- 2- of 5- take off Oxygen cytidine, Ismipur, according to how bent peptide, Abacavir, Bao hemocyanin, abiraterone, acamprosate, acamprosate calcium, A Ka Ripple sugar, aceclidine, aceclofenac, Guan-fubase A hydrochloric acid, Meng Nan, aceneuramic acid, acetaminophen, acetylcysteine, Acetyl leucomycin, acetyl-L-carnitine hydrochlorate, aspirin, acyclovir, acipimox, 3'-(1H-Tetrazol-5-yl)oxanilic acid, AVM hereinafter A, A Di, aclidinium bromide, acolbifene, Acotiamide, acrivastine, actarit, adapalene, adefovir ester, adenosine Methionine, Afatinib, agomelatine, edenaphy citric acid, nafarelin acetate, my trovafloxacin methanesulfonic acid, acetysalicylic acid phenobarbital reach Azoles, salbutamol sulfate, Alcaftadine, Alendronate sodium, alendronate sodium hydrate, alendronic Acid, alfacalcidol, A Fa Salon, alfentanil, alfuzosin, aliskiren, alitretinoin, allantoin, A Lishatan esters, decellularized vascular matrix, not Pregnenolone, allopurinol, Almogran, Egelieting, SYR-322, alosetron, Alpha's ketoglutaric acid, sulfur are pungent Acid, the stable sulforaphen of alpha-cyclodextrin, alprazolam, alprazolam transdermal patch, Alprostadil, Alprostadil frost, pregnancy honey Amine, aluminum sulfate, Aiweimopan, amantadine, amantadine hydrochloride, BSF208075, ambroxol hydrochloride, amfetamine, amfetamine sulphur Change divinylbenzene, Ah rice's pyridine, Ah rice's pyridinium phosphate, amifostine, amikacin, amiloride, glycyl, glycyl Propanoic acid, levulic acid hydrochlorate, aminopterin, amiodarone, amisulpride, amitriptyline, amlexanox, amlodipine, benzene sulphur Sour amlodipine, amlodipine camsylate, amlodipine maleate, amlodipine niacin, orotic acid amlodipine, breast Sour ammonium, amodiaquine, amorolfine, Lowagan, amoxicillin, amoxicillin hydrate, amphetamine, aspartic acid phenylpropyl alcohol Amine, amfetamine sulfate, Amphotericin B, Amphotericin B cholesterol sulfate, ampicillin, ampiroxicam, amrinone, ammonia are soft Than in star, amtolmetin guacil, my Ge Lieting, anagrelide, anamorelin, Anastrozole, peace clo, androgen, Herba Andrographis Ester, anecortave, anidulafungin, aniracetam, anistreplase, peace sieve are safe and reliable for Buddhist nun, antazoline, androgen antagonist, antineoplaston Husky star hydrochloric acid, ARIXTRA tonquinol, methanesulfonic acid Ah handkerchief replace Buddhist nun, Eliquis, apomorphine, apomorphine hydrochloride, Apremilast, Ah Auspicious pyrrole is smooth, A Lita shores, aranidipine, arbekacin, arbekacin sulfate, Ardeparin Sodium, Afromoterol, argatroban, Aripiprazole, Aripiprazole lauryl, l-modafinil, arsenic trioxide, arsenious acid, Artemether, artemisinol, artesunate, Asenapine, asimadoline, astragaloside, Ah that Wei, atazanavir, sulphuric acid atazanavir, Atenolol, support Moses Spit of fland, atorvastatin, Atorvastatin calcium, atorvastatin strontium, atovaquone, atrasentan, atropine, Auranofin, Ah cutting down That is non-, AVM hereinafter Batan, AVM hereinafter Batan sodium, aviptadil, Axitinib, azacitidine, cytidine, azasetron, Azelaic Acid, nitrogen tall and erect The husky smooth ester potassium of STING, A-5610, azelnidipine, Azilsartan, Azilsartan, Azilsartan front three ethylethanolamine, Ah Qi Lite, Azithromycin, lactobionic acid azithromycin, aztreonam, AZLI, A Zifuding, baclofen, bar fluorine for Buddhist nun, Baicalin, baicalin, BAK replace Buddhist nun, bar without latanoprost, Q-35, balsalazide, balsalazide sodium, bambuterol, Ba Ruike Buddhist nun's Horizon, Bazedoxifene, beclometasone, beclomethasone, MN-221, Belotecan, benazepril, phenyl ring quinoline Bromine ammonium, bendamustine, bendamustine hydrochloride, benidipine, benserazide, benzalkonium chloride, benznidazole, benzocaine, peroxide Change benzoyl, benzydamine hydrochloride, bepotastine, bepotastine calcium dihydrate, salicylic acid bepotastine, A-60386X, Bei Qian The plain sodium of row, besifloxacin, Bei Xifuwei, besipirdine, β-olive alkene, betahistine, anhydrous betaine, betamethasone, times his rice Loose propanoic acid fourth, betamethasone cream, betamethasone dipropionate, betamethasone mousse, betamethasone valerate, betamipron, times his Lip river That, betaxolol hydrochloride, bethanechol, urecholine, betrixaban, bevacizumab, Bexarotene, bezafibrate, ratio A Peinan, bicalutamide, bicyclol, Birid Triple Viable, bilastine, bimatoprost, bismuth gallate, ecabet, peso Lip river That, Bisoprolol Fumarate, Bitespiramycin, bleomycin, blonanserin, hydrochloric acid win peace, EBP520, bortezomib, The auspicious piperazine azoles of bosentan, bosentan hydrate, SKI-606, Bovactant, cloth, brimonidine, Azopt, Brivaracetam, bromine husband Fixed, bromazepam, bromfenac, bromfenac sodium, bromocriptine, brotizolam, Bryostatin-1, bucindolol, bucladesine, cloth ground how Moral, Budipine, buflomedil, bunazosin, bupivacaine, bupivacaine hydrochloride, buprenorphine, buprenorphin hydrochloride, Amfebutamone, BUPROPIONE HCl, Bu Lishafu, buserelin acetate, buspirone, buspirone hydrochloride, busulfan, cloth are replaced Naphthalene sweet smell, butorphanol tartrate, butyphthalide, Cabazitaxel, cabergoline, malic acid card it is rich for Buddhist nun, cadrofloxacin, caffeine, Caffeine citrate, calcipotriol, Calcitriol, calcium acetate, calcium folinate, calcium levofolinate, WL-140, karr method It is smooth, calcium mangafodipir, camostat mesilate, camptothecine, canagliflozin, Candesartan, candesartan Cilexetil, cangrelor, big Fiber crops, Capecitabine, capsaicin, captopril, Carbamazepine, Carbetocin, carbetocin, carbidopa, carbinoxamine, carboxylic First department is smooth, carboplatin, carbidopa, the luxuriant and rich with fragrance such rice cloth of card, card glutamic acid, Cali's drawings, carmustine, carteolol, hydrochloric acid card is for Lip river That, carumonam, carvedilol, phosphoric acid carvedilol, Caspofungin, catechin, AZD2171, cefaclor, cefadroxil Benzyl, cefathiamidine, cefazolin sodium pentahydrate, cefcapene, Cefdinir, cefditoren, cefepime, hydrochloric acid head Spore pyrrole oxime, cefetamet pivoxil hydrochloride, cefminox, cefoperazone, cefoperazone sodium, Cefoselis, cefotaxime, cephalo thiophene Oxime sodium, cefotiam, cefozopran, cefpirome, cefpodoxime, Cefprozil, Ceftaroline Fosamil, CPT, cephalo he Pyridine, ceftibuten, Ceftobiprole Medocaril, ceftriaxone, Ceftriaxone Sodium, cefuroxime, Cefuroxime Sodium, Celecoxib, western dagger-axe Si Wei, celiprolol, cephalosporin, Ceritinib, cerous nitrate, west for Li Sita, cetirizine, cetraxate, cevimeline, Chenodeoxycholic acid, hibitane, chlormadinone acetate, chlorogenic acid, chloroquine joint, 7-chloro-4-oxo-quinoline, chlorphenamine, Chlorphenamine Maleate, Chlorphenamine, chlortalidone, cholecalciferol, cholic acid, choline alfoscerate, choline fenofibrate, ciclesonide, ciclopirox olamine, ring spore Element, cidofovir, cidoxepine, cilastatin, cilazapril, cilnidipine, cilostazol, cimetidine, cinacalcet, horse Carry out cinepazide maleate, cinitapride tartaric acid, ciprofibrate, Ciprofloxacin, ciprofloxacin, Cisatracurium besilate, suitable Platinum, citalopram, citalopram hydrobromate, citicoline, citrulline, cladribine, clarithromycin, clavulanate potassium, gram Clavulanic acid, carat give birth to smooth, clevidipine, Clevudine, clindamycin, Clindamycin Hydrochloride, clindamycin phosphate, chlorine iodine hydroxyl Quinoline, clobazam, clobetasol propionate, clodronic acid, clofibrate, clofazimine, clomipramine, Clomipramine Hydrochloride, clonazepam, Clonidine, clonidine hydrochloride, clopidogrel, clopidogrel benzenesulfonic acid, Clopidogrel Bisulfate, clopidogrel Camphora, chlorine pyrrole lattice Thunder hydrogen sulfate, clopidogrel napadisilate, resinic acid clopidogrel, clotrimazole, clozapine, cobamamide, examine than TAD, can Treat because, Colchicine, cholecalciferol, colesevelam, Colestilan, colforsin dapropate, Colfosceril Palmitate, Acarasiales Plain sodium, conivaptan, with reference to estrogen, Copper histidine, 17 α of cortexolone-ethylene propanoic acid, cridanimod sodium, gram in the azoles base of a fruit Buddhist nun, cromoglicic acid, sodium cromoglicate, cobalamin, match gram lactic acid, cyclobenzaprine hydrochloride, cyclophosphamide, a hydration cyclophosphamide, ring spore Element, cyproterone, cyproterone acetate, cytosine arabinoside, cytosine arabinoside octadecyl phosphate, dabigatran etcxilate, Da Lafeini, His Wei of Dacca, up to gram for Buddhist nun, dalbavancin, inhibitor is to reach plug bent, aminopyridine, dalfopristin, dalteparin sodium, Danaparoid sodium, reach That azoles, dantamacrin, Da Lushe are replaced, AstraZeneca, AstraZeneca Propylene Glycol, dapiprazole, Dapivirine, dapoxetine, phenalgin Sulfone, darifenacin, Prezista, Da Sabuwei, Dasatinib, daunorubicin, decitabine, La Luosi, deferiprone, methanesulfonic acid Deferoxamine, deflazacort, De Lasha stars, Yi Maidi, La Puli, delapril hydrochloride, Delavirdine, Denibulin, deoxidation Andrographolide, dermatan sulfate, desflurane, desipramine hydrochloride, Loratadine, Desmopressin, desmopressin acetate, Desogestrel, desonide, desmethylvenlafaxine, DEXTROMETHORPHAN HYDROBROMIDE, Verteporfin, deuterate levodopa, deuterate text traction therapy Pungent, dexamethasone, dexamethasone acetate, dexamethasone training ester, dexamethasone palmitate, dexamethasone sodium phosphate, dexamfetamine, The right piperazine first of dexanabinol, iron dextran, dexketoprofen trometamol, Dexlansoprazole, dexmedetomidine, hydrochloric acid Ester, dexrazoxane, sotalol, dextrorotation sucrose, dextro-amphetamine sulfate, dextromethorphan, DEXTROMETHORPHAN HYDROBROMIDE, right third oxygen It is sweet smell, diacerein, diamorphine hydrochloride, dianhydrogalactitol, diazepam, diazoxide choline, diclofenac, diclofenac potassium, double The fragrant acid sodium of chlorine, diclofenamide (dichlorphenamide), bicycloplatin, up to promise, the pregnant element of promise, difluprednate, Digoxin, linolenic acid, dihydroergocristine, Dihydroergotamine, dihydroetgotamine, diltiazem, Diltiazem Hydrochloride, dimesna, dimethyl fumarate, it is next Western smooth, dinoprostone, diphenyl cyclopropenone, dipyridamole, sodium pyrophosphate, tobramycin, Shu Fentong sodium, disulfiram, Leucoalizarin, methadone, docarpamine, Docetaxel, sweet glycol, dofetilide, dolasetron, Du Lutewei, domperidone, Benzenesulfonic acid Sorafenib, donepezil, donepezil hydrochloride, dopamine, doripenem, dorzolamide, dorzolamide hydrochloride, many Simas Ester, doxacurium chloride, doxazosin, Carclura, doxepin hydrochloride, doxercalciferol, Doxifluridine, doxofylline, Amycin, doxorubicin hydrochloride, doxycycline, doxycycline hydrochloride, doxylamine succinate, dronabinol, dronedarone, spiral shell in the wrong Ketone, droxidopa, D-Tag, duloxetine, duloxetine hydrochloride, dutasteride, ebastine, eberconazole, ebselen Quinoline, ecabet, Fazol (Schering), determine ecopipam, Edaravone, edoxaban, efavirenz, Chinese mugwort fluconazole, Yi Luoni Plug, efonidipine, Egualen sodium, eicosapentaenoic acid glyceride, dislike La Geli, Chinese mugwort ground ostelin, Elesclomol sodium, according to Vertical Qu Tan, eltrombopag olamine, angstrom for lattice Wei, ENAMELIN EMD, emedastine, Yi Palie net, the life of Enbrel card, emtricitabine, according to that Puli, enalapril maleate, enclomifene citric acid, tamoxifen, Enoxacin Gluconate, Enoxaparin Sodium, before grace Row element, entacapone, Entecavir, maleic acid Entecavir, grace replace Nuo Te, the miscellaneous Shandong amine of grace, epalrestat, eperisone, sulfur Sour ephedrine, epinastine hydrochloride, epinephrine, epirubicin, Epirubicin Hydrochloride, according to pyrrole for Buddhist nun, eplerenone, according to prostatitis Alcohol, epristeride, her sieve ground plug, eprosartan, eptalatin, erdosteine, methanesulfonic acid eribulin, Erlotinib, ertapenem, Erythromycin, erythromycin octadecanoate, erythromycin stinoprate, escitalopram, Chinese mugwort ketamine, ketalar, acetic acid Chinese mugwort department Licarbazepine, ESMOLOL HYDROCHLORIDE, esomeprazole, esomeprazole magnesium, esomeprazole strontium, esomeprazole, E4, Estradiol, estradiol acetate, estradiol cypionate, estradiol valerate, Estratest, estradiol, estrogen, (+)-Zopiclone, Ebutol, Ethaselen, ethinylestradiol, ethyl fumaric acid calcium hydrogen phosphate, ethyl fumaric acid magnesium hydroxide, ethyl fumaric acid Hydrogen zinc, ethinylestradiol, etidronic acid, Etimicin sulfate., etizolam, etodolac, etonogestrel, etoposide, phosphorus Sour etoposide, Etoricoxib, etravirine, eupatilin, everolimuses, exemestane, Exenatide, Ezetimibe, Arensm, falecalcitriol, famciclovir, Famotidine, Fampridine, faropenem, fasoracetam, fasudil, hydrochloric acid method are relaxed Ground that, methanesulfonic acid fasudil, Favipiravir, febarbamate, Febuxostat, non-urethane, medicine felbinac, biphenyl ammonia acetate fourth Triol, Felodipine, fenfluramine hydrochloride, fenofibrate, fenofibrate, fenoldopam, fenoterol, fenretinide, sweet smell are too Buddhist nun, fentanyl citrate, fenticonazole, ferric citrate, maltol ferrum, fumaric acid Fei Suoluo, fexinidazole, fexofenadine, Fibrin Glue, Fibrinogen, fibrinogen substrate patch, feldamycin, Fimasartan, finafloxacin, hydrochloric acid are non- That husky star, finasteride, FTY720, flecainide, fleroxacin, flibanserin, flomoxef, floxuridine, fluconazole, fluorine reach Draw shore, flumazenil, flunisolide, fluocinolone acetonide, fluocinonide, fluorouracil, fluoxetine, fluoxetine Hydrochloride, Flupirtine, fluorine Than ibuprofen, Flurbiprofen axetil, flurbiprofen sodium, flurithromycin, fluticasone, fluticasone furoate, fluticasone furoate, propanoic acid Fluticasone, flutrimazole, fluvastatin, fluvoxamine, Folic Acid, folinic acid, fomepizole, Fondaparinux sodium, formestane, good fortune are not Special sieve, Formoterol Fumarate, Forodesine, Fosamprenavir, fosaprepitant, fosfluconazole, fosfomycin, fosfomycin disodium, phosphorus Mycin trometamol, fosinopril, fosinopril sodium, fosmidomycin, fosphenytoin, phosphorus propofol, fotemustine, Fu Luoqu Smooth, furan quinoline replaces Buddhist nun, Fudosteine, fulvestrant, Furosemide, Fusidic Acid, gabapentin, gabapentin En Naka ratios, first sulphur Sour gabexate, gadobutrol, Gadoversetamide, galantamine, Ganite (Fujisawa)., gamlogic acid, ganaxolone, ganciclovir, acetic acid Jia Nirui Gram, T-3811, Gatifloxacin, gatifloxacin in human, gefitinib, gemcitabine, Gemcitabine Hydrochloride, gemfibrozil, Gemifloxacin, genistein, gentamycin, gentiopicrin, gepirone, gestodene, gestrinone, maleic acid thiophene Lip river That, Gimeracil, ginsenoside, acetic acid copaxone, Glibenclamide, Gliclazide, glimepiride, Glipizide, Portugal's phosphinylidyne Amine, glutamine, glycerol benzene, Ge Long, glycopyrronium bromide, methanesulfonic acid GLYCOPYRRONIUM, glycyrrhizic acid, Ge Luomode, Ge Gelieting, lattice plast Fine jade, Granisetron Hydrochloride, guaifenesin, Guaimesal, guanfacine, hydrochloric acid gusperimuss, hemophilus influenza, propanoic acid halogen times he Rope, halofantrine, halometasone, hyaluronate sodium, hemoporphyrin, Heme Arginate, heparin, He Birong, hetastarch, hydrochloric acid go First coclaurine, Maxamine, huperzine A, hyaluronate sodium, hydralazine, hydrochloric acid, hydrochlorothiazide, hydrocodone, tartaric acid Hydrocodone, hydrocortisone, hydromorphone, dihydromorphinone hydrochloride, hydromorphone medicine, hydroxocobalamine, hydroxyurea element, oxychloroquine, Hydroxyprogesterone caproate, S-A Hydroxysafflor yellow A, hypericin, ibandronate, ibandronic acid, Ibodutant, according to Shandong for Buddhist nun, different Ding Site, ibuprofen, ibutilide, Ibolite fumarate, Herba Epimedii, Ai Lapulin, eicosapentaenoic acid, 20 carbon of ethyl Five olefin(e) acid, EPA-E, hydrochloric acid Conmana, idebenone, idoxuridine, ifetroban, ifetroban sodium, Chinese mugwort Rameau Moral, ilaprazole, iloperidone, iloprost, imatinib, imatinib mesylate, imidafenacin, imidapril, water Poplar imidazole acid, imipenum, imiquimod, imrecoxib, ineadronic acid, QAB-149, maleic acid QAB-149, Yin reach handkerchief Amine, indeloxazine, indinavir, indisetron, indomethacin, indoramine, inecalcitol, ingenol methylcrotonic acid Ester, inosine, andiconazole, ipragliflozin, ipratropium, ipratropium bromide, iptakalim hydrochloride, irbesartan, irinotecan, Irinotecan hydrochloride, irinotecan sucrosofate, Yi Luofufen, ferric succinate albumen, maleic acid Yi Suolading, isoflurane, different cigarette Hydrazine, UF-021, isosorbidi dinitrass, different Flos Chrysanthemi, isotretinoin, isradipine, istradefylline, hydrochloric acid she hold in the palm Must profit, Itraconazole, ivabradine sulfate Hemisulphate, hydrochloric acid Ivabradine, ivermectin, VEGF Trap IVT, Yi Sha Grand, kallikrein, ketamine, ketanserin, Ketoconazole, ketoprofen, ketorolac, ketorolac tromethamine, ketotifen, first sulphur Sour Kukoamine B, lacidipine, clarke amide, lactose, laflunimus, lafutidine, lamivudine, lamotrigine, orchid Ground Luo Er, hydrochloride landiolol, that Ni Na meter Wei caprylate, lanoconazole, lansoprazole, lanthanum carbonate, Lapatinib, drawing quinoline are not Moral, lasofoxifene, latanoprost, Lei Dipawei, leflunomide, lenalidomide, lentinan, sulphuric acid lentinan, happy card It is Horizon, leteprinim potassium, letrozole, leucine, leuprorelin acetate, Levalbuterol, albuterol hydrochloride, left-handed Imidazoles, Levamlodipine, Levamlodipine besylate, maleic acid levo amido chloro diping, levetiracetam, left-handed Bu Bika It is cause, levocabastine, levocabastine hydrochlorate, levocarnitine, levocetirizine, levodopa, Levofloxacin, left-handed LNG, levonorgestrel, levonorgestrel oxime butanoic acid, left-handed benzene ring nonyl ester, l-ornidazole, Zuo Xi Meng Dan, L-glutaminate, lignocaine, ligustrazine hydrochloride, limaprost, BI 1356, Linezolid, liothyronine, iodine Sai Luoning sodium, lipoteichoic acid, liranaftate, lisinopril, theophylline, maleic acid hydrogen lisuride, lithium citrate, lithium succinic acid, Lobaplatin, sieve ground that non-carbonic ester, lofexidine, lomefloxacin, lomerizine, double lomerizine hydrochlorides, lonidamine, Lip river that Wei, loratadine tablet, lorazepam, L-Orn ASPARTIC ACID, lornoxicam, losartan, Losartan Potassium, chlorine are for bold and vigorous Promise, lovastatin, Loxapine succinate, loxoprofen, levo-praziquantel, lumiracoxib, the aspirin of lysine, sulfanilamide rice Grand, magnesium carbonate, magnesium isoglycyrrhetate, mangafodipir, Manidipine, Manidipine dihydrochloride, Mannitol, Maraviroc, horse Li Bawei, Masitinib, mebendazole, chlormethine, mecobalamin, megestrol, megestrol acetate, Meloxicam, Memantine hydrochloride, Memantine hydrochloride, memantine sodium sulfite, menatetrenone, mepacrine, atabrine, mequinol, mercaptamine, mercapto second Amine biatrate, mercaptamine hydrochlorate, mercaptopurine, meropenem, mesalazine, Mei Takawei, metadoxine, dipyrone, Metaxalone, liserdol, metformin, metformin hydrochloride, methadone, methadone hydrochloride, methazolamide, methotrexate, Methoxiflurane, methylpentanoic acid hydrochloride, methyl naltrexone bromine, methyl naltrexone, methylphenidate, methylphenidylacetate hydrochloride, 6- first Andrographolide, methylprednisolone aceponate, methylene blue, metirosine, metoclopramide, metroprolol succinate, metoprolol, Metronidazole, Metopirone, mexiletine, mibefradil, miconazole, Miconazole Nitrate, midazolam, midazolam hydrochloride, meter Duo Monarch, midostaurin, rice lumbering peptide, mifepristone, miglitol, midalcipran, milrinone, miltefosine, Minaprine, minot Ring element, minocycline hydrochloride, minodronic acid, minoxidil, Mirabegron, Miboplatin hydrate, meter Luo Nafei, meter Luo Na non-salt Hydrochlorate, mirtazapine, misoprostol, Mitiglinide, mitomycin, mitoxantrone, mitoxantrone hydrochlorate, mivotilate, miaow Azoles STING, mizoribine, moclobemide, modafinil, doxycycline, modipafant, moexipril, not fragrant azoles acid, hydrochloric acid Quinoline ketone, momestasone furoate, furancarboxylic acid not rice, monoammonium glycyrrhizinate, monobenzone, luminol, monoterpene perilla alcohol, montelukast, Meng Lu The special sodium of department, montmorillonite, moracizine, tigecycline, morpholine nitre azoles, morphine, morphine gluconate aldehydic acid, the morphine of Pitavastatin, Morphine sulfate, mosapride, Moxidectin, Moxifloxacin, moxifloxacin hydrochloride, moxonidine, moxonidine hydrochloride, not prick cut down Pu Tan, Mupirocin, mycophenolate, myristyl alcohol nicotinate, nabilone, nabumetone, N-acetylcystein, that fluorine are husky Star, nadolol, nadroparin calcium, naftifine hydrochloride, naftifine hydrochloride gel, naftopidil, nalbuphine, the nalbuphine last of the ten Heavenly stems two Acid, furan of receiving draw coffee, nalmefene hydrochloride, naloxol ether, naloxone, Naloxone Hydrochloride, naltrexone, Naltrexone Hydrochloride, abolon, Naphazoline, naphthols quinoline, naproxen, naproxen sodium, naratriptan, nasaruplase, Nateglinide, nebivolol, nedaplatin, how Many sieve rice, nelarabine 506u, viracept see nelfinaivr, nemonapride, nemonoxacin, neoandrographolide, Neosaxitonin, methyl-sulfuric acid it is new this Bright, nepadutant, nepafenac, nepicastat, Ni La, HKI-272, neridronic acid, netilmicin, Netupitant, Nai Weila Flat, nicotinic acid, nicardipine, Nicergoline, nicorandil, nicotiflorin, nicotine, nicotinic acid, 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin, nifedipine, Buddhist nun are non- Card orchid, nifeviroc, nifurtimox, nifurzide, Nikemycin, AMN107, Ni Lute meter, nilvadipine, nimesulide, Buddhist nun Horizon, morpholine nitre azoles, nisoldipine, nitazoxanide, nitisinone, nitrendipine, nitric oxide, nitroglycerin, nitrification be not sweet Oil, nizatidine, nolatrexed, nomegestrol acetate, norelgestromine, norepinephrine, norethindrone, norethindrone acetate, alkynes Promise ketone enanthate, norethindrone, norethindrone acetate, norfloxacin, norgestimate, shellfish cholic acid difficult to understand, octenidine, succinum octahydro acridine, Octreotide, octreotide hydrochlorate, Ofloxacin, olanzapine, olaparib, agile west, Olmesartan, olmesartan medoxomil, indenes difficult to understand Da Teluo, hydrochloric acid Ao Dateluo, olopatadine, Olopatadine hydrochloride, olprinone, Olsalazine, oltipraz, high Folium et Ramulus Cephalotaxi Ester alkali, Ao Gelieting, omeprazole, omoconazole, onapristone, ondansetron, a difficult to understand piperazine, methylphenidate, Ao Shengle Saites, Oritavancin, orlistat, ornithine phenylacetic acid, ornoprostil, Oseltamivir, ospemifene, Oteracil Potassium, Ao Shali Platinum, oxaloacetic acid, oxandrolone, oxazepam, oxcarbazepine, oxfendazole, oxidized form of glutathione sodium, oxiracetam, former times difficult to understand Cloth is peaceful, ditropan XL, oxycodone, oxycodone hydrochloride, oxymetazoline, Oxymetazoline hydrochloride, oxymorphone, oxytocin, Austria Ozagrel sodium, ozagrel hydrochloride, sodium ozagrel, Ao Zesha stars, paclitaxel, paclitaxel polyglutamic acid, 9-hydroxy-risperidone, Petiolus Trachycarpi Sour handkerchief Risperidone, palmidrol, palonosetron, Paro cut down spit of fland, Pamidronate Disodium, pancreatic lipase, panipenem, Pa Bisi He, pantoprazole, acetaminophen, Parecoxib, paricalcitol 19-Nor-1,25-dihydroxyvitamin D2, Pa Liruiwei, Parnaparin Sodium, Paro lattice row, Ba Long Mycin, paroxetine, paroxetine hydrochloride hemihydrate compound, methanesulfonic acid paroxetine, a handkerchief soil dragon, pazopanib, handkerchief pearl are husky Star, Pazufloxacin Mesilate, Pegylation fat are white, pelubiprofen, pemetrexed disodium, pemirolast, Pemirolast Potassiu, pyrrole Phonetic department spy sodium, penciclovir, peaceful long support, pentamidine, calcium trisodium pentetate, pentetic acid zinc sodium, pentetrazole, pentosan sodium sulfate, spray Si Tading, pentoxifylline, Peramivir, pyrrole Lun Panai, thioacetazone, perflenapent, perfluoro capryl bromination ammonium, training usury Spy, GUANXINNING Malaysia, perifosine, perindopril, perindopril arginine, cis-N-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl, KMBZ-009 Phenchlobenpyrrone., isothiocyanic acid benzene second Ester, phenoxybenzamine hydrochloride, phentermine, Topiramate, wilpo, phentolamine mesylate, phenylbutyrate sodium, deoxidation adrenal gland Element, phenylephrine hydrochloride, phenylephrine bolt, phenytoin, phosphatidylcholine and aspirin, recklessly Sapylin, Huang Connect cytokines, podophyllotoxin, pidotimod, pilocarpine, pilocarpine hydrochlorate, pilsicainide, piperazine Ma Selin, pyrrole U.S.A not Department, pimobendan, pinocembrin, pioglitazone, pioglitazone hydrochloride, pipamperone, pipecuronium bromide, piperacillin, piperacillin Sodium, piperaquine, piperaquine phosphate, piperidine hydrochloride ketone, piperine, piracetam, Pirarubicin, pirfenidone, pirmenol, piperazine sieve are replaced Buddhist nun, Piroxicam, Pitavastatin, Pitavastatin Calcium, pixantrone, Pulekang Buddhist nun, Pu Kenali, Plerixafor, podofilox, L- Carnosine zinc, 20 carmustine of polifeprosan, polydatin, pomalidomide, handkerchief are received for Buddhist nun, porfimer sodium, posaconazole, carbonic acid Hydrogen potassium, potassium citrate, clavulanate potassium, para De Fuwei, Pu Defuwei, aminopterin, pramipexole, pramiracetam, Pu Lu Department spy, pranlukast hydrate, prasterone, prasugrel, pravastatin, prazosin, prednimustine, meticortelone, acetic acid Prednisolone, Inflamase, prednisone, Pregabalin, Premelle, prilocaine, Procaterol Hydrochloride, the third chlorine draw Piperazine, prochlorperazine maleate, progesterone, progestogen, progestogen dienogest, proguanil, promethazine, Propafenone, propagermanium, isopropyl Phenol, Propranolol, propranolol hydrochloride, Prostat, proxodolol, Pu Luka, prulifloxacin, Prussian blue, pseudoephedrine, The general quinoline of pseudoephedrine hydrochloride, puerarin, methanesulfonic acid replaces Buddhist nun, pyrazinamide, hydrochloric acid pyridoxamine, pyridoxine hydrochloride, pyrimethamine, double quinolines Piperazine, malaridine, quazepam, quetiapine fumarate, kui gentle ziprasidone, hydrochloric acid quinoline Gao Lai, quinapril hydrochloride, quinidine sulfate, sulphuric acid Quinine, quinupristin, Kui are miscellaneous more for Buddhist nun, raloxifene, Lei Luo for Buddhist nun, rabeprazole, RABEPRAZOLE SODIUM, racecadotril, drawing Western sweet smell, raloxifene, draw replace Laevolac, Raltitrexed, Leimaquban, Ramelteon, ramipril, ramosetron, ranitidine, Bismuth citrate ranitidine, ranolazine, rasagiline, rebamipide, reboxetine, reboxetine mesylate, ibuprofen, Nabumetone Life, glycopyrronium bromide, diclofenac, mebendazole, Progesterone, sucralfate, zoledronic acid, Rui Gefeini, remifentanil, hydrochloric acid are auspicious Fentanyl, Repaglinide, repirinast, amlexanox, chlorcyclizine hydrochloride, bucillamine, guanabenz, mazindol, horse Yin Diindyl, naltrexone, nitisinone, ondansetron, retigabine, rosiglitazone, phenylbutyrate sodium, RTX, Resiquimod, white Herba chenopodii Reed alcohol, Rui Gelieting, Retapamulin, Retapamulin, retigabine, retinoic acid, Revaprazan, Reviparin Sodium, chrysophanic acid, rhenium- 186 etidronates, ribavirin, Mycobutin, rifampicin, rifamycin, rifapentine, rifaximin, Rui Lapa ground, profit Wei Lin, hydrochloric acid rilpivirine, riluzole, rimantadine, rimexolone, auspicious department's melon spy, the western croak hydrochlorate of Leo, profit plug phosphine Sour sodium, Risperidone, ritonavir, razaxaban, Rivastigmine, rizatriptan, Lizakuputan benzoate, roflumilast, Rokitamycin, smooth Lora pyrrole, romurtide, ropinirole, ropinirole hydrochloride, ropivacaine, Rose Bengal Sodium, rosiglitazone, horse Come sour rosiglitazone, Rosiglitazone sodium, rosuvastatin, rosuvastatin calcium, rotigotine, Roxithromycin, rubitecan, Lu Non- amide, rufloxacin, Rupatadine, Luso profit are for Buddhist nun, l-ornidazole disodium hydrogen phosphate, Sha Kubi songs, FCE-26743A, husky butylamine Alcohol, albuterol like Sha's breathing, salbutamol sulfate, salicylic acid, salmaterol, SALMETEROL XINAFOATE, Squamocin A, next former times Certainly southern samarium, 3- Methanamide -4- hydroxyl Naltrexones, S- amlodipine niacins, Sapropterin, Sapropterin disalt Hydrochlorate, Saquinavir, saracatinib, sarpogrelate hydrochloride, BMS-477118, scopolamine, scorpion venom, seal oil ω -3 how unsaturateds Fatty acid, secnidazole, selegiline, SelegilineHydrochloride, department are beautiful for Buddhist nun, seratrodast, seratrodast, hydrochloric acid Sai Liluo That, Sertaconazole, give up his nitrate, Sertindole, Sertraline, sertraline hydrochloride, sesquiterpene, 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate, hydrochloric acid department Wella nurse, sevoflurane, maleic acid sibutramine, methanesulfonic acid sibutramine, sldenafil, Sildenafil Citrate, (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide, Buddhist nun, simvastatin, YC-8, Xin Bomode, sirolimuss, Xi Tasha are not replaced in the general Wei of silver sulfadiazin, sago, hydrochloric acid west Star, sitagliptin, sitagliptin phosphate, sivelestat, sizofiran, Sizofiran, Sizofiran, smilonin, S- Mo Dafei Buddhist nun, sobuzoxane, aescine, sodium ascorbate, sodium benzoate, sodium bicarbonate, sodium cromoglicate, CMNa, croak logical sequence Sour sodium, hyaluronate sodium, ibandronate, sodium nitrate, sodium nitrite, sodium oxybate, sodium phenylacetate, phenylbutyrate sodium, sodium sulphuric acid Prasterone, Sodium Pyruvate, sodium taurocholate, sodium thiosulfate, hypo, Sodium Thiosulfate, sodium zirconium cyclosilicate, Suo Feibu Wei, Solifenacin, soluble ferric pyrophosphate citric acid, sGC stimulation, sophocarpine, hydrochloric acid sophoridine, rope La Feini, Sorbitol, Sparfloxacin, spirapril, spironolactone, Squalamine, stannsoporfin, stavudine, S-tenatoprazole, department For Luo Ning, stiripentol, streptozotocin, malonic acid strontium, strontium ranelate, succinic acid, sucralfate, sucrose gel, sufentanil, Shu Talan zinc, relax more glucose, sulbactam, Sulbactam Sodium, Schuqindin sulfate, sulfalene, sulfasalazine, Suo Fan are replaced Buddhist nun, sulphanylureas, sulforaphen, sodium tanshinon IIA silate injection, sulindac, Sulodexide, sulfamethoxazole, sulthiam, horse of relaxing Qu Tan, Sumatriptan Succinate, Sutent, sunstone, suplatast tosilate, naganol, Verapamil Hydrochloride, rilpivirine, Tacalcitol, Tachocomb, tacrine, tacrolimuss, tadanafil, Lonazolac, tafenoquine, tafluprost, he draw pool Sweet smell, talipexole, Taltirelin, Tamibarotene, tamoxifen, Tamsulosin, tamsulosin hydrochloride, tandospirone, smooth spiral Mycin, tapentadol hydrochloride, Ta Linaxin, Ta Simeiqiong, his quinoline not moral, tazarotene, Tazobactam Sodium, sodium-tazobactam, for than training The safe ground azoles amine of southern ester, Te Kaoweirui, tectorigenin sodium sulfonate, tedisamil, phosphoric acid, tegafur, tegaserod, teicoplanin, VX-960, Telatinib, Sebivo, thyrite, telmisartan, temocapril, m-THPC, temoporfin, temozolomide, Sirolimuss, teneligliptin, tenofovir, tenofovir Chinese mugwort draw phenol amine, tenofovir aspartic acid, fumaric acid tenofovir Ester, tenoxicam, teprenone, terazosin, terbinafine, terbinafine HCl, terguride, teriflunomide, Te Suofen Pungent, testosterone, testosterone undecanoate, butylbenzene, Ding Ka, tetracaine hydrochloride, quadracycline, tetrathiomolybdate, tetrahydrozoline (tetryzoline), naphthane Oxazoline, Thalidomide, theophylline, Thenorphine Hydrochloride, thio-tepa, thrombin, thrombin microcapsule, thyroxine, tiagabine, Nai Pu Spit of fland, tibolone, Ticagrelor, ticlopidine, tigecycline, tiludronic acid disodium, timolol, timolol maleate, replace Nitre azoles, fasigyne, tinzaparin sodium, tioconazole, tiopronin, tiotropium bromide, tiotropium bromide monohydrate, tipepidine, Extra large benzoic acid tipepidine, carry that training is fixed, Rofe is replaced for pyrrole method Buddhist nun, tipranavir, tirapazamine, tirilazad, tirofiban, hydrochloric acid Class, oxcarbazepine, tirofiban hydrochloride, tizanidine, tobramycin, tocofersolan, retinoic acid dimension E esters, dimension A fertility alcohol ester, Tropsch imatinib, tofogliflozin, tolcapone, tolimidone, tolperisone, tolterodine, Tolterodine tartrate, tolvaptan, support Na Bosha, Topiramate, Topiroxostat, topotecan, topotecan hydrochloride, torasemide, toremifene, Tuo Sheduote, it is appropriate relax The special mother Bo Page choline of Sha Xing, support, ET-743, tramadol, Tramadol Hydrochloride, Sibutramine Hydrochloride replace Buddhist nun, trandolapril, tranexamic acid, Tranilast, chlorhydric acid tranditerol, travoprost, trazodone, trehalose, song Ge Lieting succinates, treosulfan, Qu Qianlie Ring element, Treprostinil ethanolamine, retinoic acid, triamcinolone acetonide, triazolam, trichlormethiazide, triciribine, triclabendazole, trichlorine Card class, Syprine Hydrochloride, trifluorothymidine, triflusal, three enanthic acid glyceride, trilostane, trimebutine 3- sulfo-aminos Formyl-benzene, toluenesulfonic acid trimebutine, trimegestone, trimethoprim, trimetrexate, trisnitrate, bismuth potassium citrate, N-ethyl-N-(.gamma.-picolyl)tropamide, tropisetron, trospium chloride, trovafloxacin, troxipide, Tulobuterol, safe happy Horizon, ubenimex, the general last of the ten Heavenly stems Sharp ketone, udenafil, it is excellent ground that non-, ulinastatin, Ulipristal, ulobetasol, uracil, urapidil, three acetic acid uridnine, Uropoly acid-peptide, ursodesoxycholic acid, ursolic acid, valaciclovir, valaciclovir hydrochlordide, valdecoxib, valganciclovir, valproic acid, Valrubicin, Valsartan, half pentahydrate tertiary sodium phosphate of Valsartan, vancomycin, Lyphocin (Fujisawa), ZD6474, cut down promise Department woods, Vardenafil hydrochloric acid, varenicline, the bent lattice of dimension department, Wei Luofeini, venlafaxine, VENLAFAXINE HCL, verapamil, Verapamil Hydrochloride, phenol auspicious net, Vernakalant, vernakalant hydrochloride, Verteporfin, vesnarinone, Wei Sinali ketone, wiener quinoline Ketone, Vicagrel, vigabatrin, Wei Lanteluo, vilazodone, vildagliptin, vincristine sulfate, vinflunine, Changchun are auspicious Shore, vinpocetine, vismodegib, vitamin E Nicotinate, Vitamin E, voglibose, Vonoprazan fumarate, Wella handkerchief Sha, voriconazole, Vorinostat, it is fertile for Xi Ting, hydrobromic acid it is fertile for Xi Ting, warfarin, xemilofiban, meter Luo Feiban, according to rice His Wei, excellent Ke Nafei, zafirlukast, zalcitabine, Zaleplon, zaltoprofen, zanamivir, zidovudine, azidothymidine AZT, Zidovudine, zileuton, zinc acetate, Zinostatin stimalamer, Ziprasidone, zofenopril calcium, left Fen Puli, zoledronic acid two Sodium, zoledronic acid, Zomitriptan, zolpidem, Zolpidemtar Trate, zonisamide, zopiclone, zotepine, zucapsaicin, pearl Diuril alcohol.

In some embodiments, Chinese medicine is selected from Flos abelmoschi manihot, Herba Abri, lotus pockmarks, five power mouth skins, thorn five Plus, Radix Et Caulis Acanthopanacis Senticosi leaching descendants, luxuriant grass, Radix Achyranthis Bidentatae, Folium Aconiti Kusnezoffii, Radix Aconiti Kusnezoffii Preparata, Radix Aconiti Kusnezoffii, Radix Aconiti Lateralis Preparata, Radix Aconiti Preparata, Radix Aconiti, Rhizoma Acori Calami, Rhizoma Acori Graminei, south Radix Adenophorae (Radix Glehniae), appearance Luo Zi, Agkistrodon, Herba Agrimoniae, rod skin, Herba ajugae ciliatae (Herba Ajugae Ajuga ciliata Bge.), Caulis Akebiae, Fructus Akebiae, Cortex Albiziae, Flos Albiziae, pool weldering, Lotus white, Bulbus Allii, Semen Allii Tuberosi, Aloe, slight, Rhizoma Alpiniae Officinarum, Fructus Alpiniae Oxyphyllae, Bai Subcommittee-to, bean are slightd by bean for grass, Fructus Amomi, it is white hereby, Herba Andrographis, andrographolide, the Rhizoma Anemarrhenae, two Head point, the Radix Angelicae Dahuricae, Radix Angelicae Pubescentiss, Radix Angelicae Sinensis, anistree bacterium perfume, Folium Apocyni Veneti, Lignum Aquilariae Resinatum, Concha Arcae, cattle base of a fruit, Radix Ardisiae Crenatae, Herba Ardisiae Japonicae, big abdomen Skin, Jiao Mo Township, mould willow, Arisaema Cum Bile, Rhizoma Arisaematis (processed), Rhizoma Arisaematiss, horse study carefully bell, Herba Aristolochiae, Semen Armeniacae Amarum, Radix Arnebiae (Radix Lithospermi), QINGSONG, Folium Artemisiae Argyi, mattress Old, Herba Asari, Rhizoma Menispermi extract, Ah limb, Radix Asparagi, Aspongopuss, Radix Asteriss, Semen Astragali Complanati, process HUANGMIAO, HUANGMIAO, the Rhizoma Atractylodis Macrocephalae, Rhizoma Atractylodis, the Radix Aucklandiae, Product reality, Fructus Aurantii, before bamboo, Concretio Silicea Bambusae, Rhizoma Et Radix Baphicacanthis Cusiae, Rhizoma Belamcandae, extractum before top, stream leaching descendants before top, the front grass in top, Exocarpium Benincasae, Benzoinum, Radix Berberidis, Rhizoma Seu Herba Bergeniae, Bergeninum, Rhizoma Bistortae, Pseudobulbus Bletillae (Rhizoma Bletillae), Rhizoma Bolbostematiss, stiff perfume, Borneolum Syntheticum (borneolum syntheticum), natural Broneolum Syntheticum (dextrorotation dragon Brain), artificial Calculus Boviss, In vitro cultured Calculus Boviss, Calculus Boviss, Deng Do florigen, stifled real son, Fructus Bruceae, Cornu Bubali, Flos Buddlejae, Bile Jesus, money It is Agkistrodon, Radix Bupleuri, Calamina, Callicarpa kwangtungensis Chun, Folium Callicarpae Formosanae, Folium Callicarpae Macrophyllae, Calomelass, Flos Campsiss, Fructus Canarii, Semen Canavaliae, Fructus Cannabiss, peppery Green pepper, Nan He Wind, crane Wind, Flos Carthami, Flos Caryophylli, Fructus Caryophylli, Semen Cassiae, Oleum Ricini, catechu, Flos Celosiae Cristatae, Semen Celosiae, asiatic centella total be bitter, Herba Centellae, crane BUSHICAO, worm are gambled in vain, honeybee is arranged, Cornu Cervi Degelatinatum, deer mythical bird like the phoenix, Cornu Cervi, Colla cornus cervi, Fructus Chaenomeliss, Radix Changii, FRUCTUS TERMINALIAE IMMATURUS, river son, Herba Chelidonii, danggui extract, danggui liujin gao, blue or green commonplace stone, wide rate, Flos Chrysanthemi, Flos Chrysanthemi Indici, curved river, Rhizoma Cibotii, honeybee de-, chrysanthemum official, Rhizoma Cimicifugae, Cinnabaris, Cortex Cinnamomi, It is Ramulus Cinnamomi, Oleum Cinnamomi, little jasmine, big jasmine charcoal, big jasmine, Herba Cissampelotiss, meat ash Rong, Exocarpium Citri Rubrum, XIANGXIANG, Exocarpium Citri Grandises, Pericarpium Citri Reticulatae Viride, old Skin, Semen Citri Reticulatae, Fructus Citri Sarcodactylis, Caulis Clematidis Armandii, Radix Clematidis, Herba Clinopodii, Fructus Cnidii, Radix Codonopsis, Semen Coicis, first bird plantar grass, conyza blinii, Rhizoma Coptidis, winter Worm summer grass, Coriolous Dersicolor (Fr.) Quel, mountain Lay cornel, Herba Corydalis Bungeanae, Rhizoma Corydalis Decumbentiss, Rhizoma Corydalis, crataegus pin natifida var. Major leaf, Fructus Crataegi., Pseudobulbus Cremastrae Seu Pleioness, Crinis Carbonisatus, west It is Flos Carthami, Fructus Crotonis, Semen Crotonis Pulveratum, Rhizoma Curculiginises, Rhizoma Curcumae Longae, Radix Curcumae, Rhizoma Curcumae, English SIZI, Radix Cyathulae, HuanweihuangyangxingD, Radix Cynanchi Atrati, Radix Cynanchi Paniculati, white Before, Herba Cynomorii, Rhizoma Cyperi, Oleum Rhododendri Daurici, Lignum Dalbergiae Odoriferae, Flos Daturae, stone tiltedly, iron sheet stone tiltedly, it is Semen Lepidii (Semen Descurainiae), Herba Desmodii Styracifolii, Korea wheats, Radix Dichroae, white Cortex Dictamni, Dioscorea panthaica Prain et Burkill, Fen Ge Sue, Rhizoma Dioscoreae Nipponicae, Rhizoma Dioscoreae, Mian Ge Sue, Radix Dipsaci, Sanguis Draxonis, Rhizoma Drynariae, Rhizoma Dryopteris Crassirhizomatiss charcoal, Rhizoma Dryopteris Crassirhizomatiss, Yu State Radix Rhapontici, Herba Ecliptae, plant vine, red Radix Gentianae, Herba Ephedrae, Radix Ephedrae, Herba Epimedii, Epimedium wushanense, Herba Equiseti Hiemalises', Deng Do Herba Asari (lamps Do spends), batch leaf, Flos Eriocauli, geranium, Caulis Erycibess, Oleum Eucalypti, the Cortex Eucommiae, Folium Eucommiae, Wu Lai Yellow, Herba Eupatorii, Herba Eupatorii Lindleyani, the Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae), winged Raise grass, Herba Euphorbiae Humifusae, Radix Euphorbiae Pekinensiss, Semen Euphorbiae Pulveratum, Semen Euphorbiae, native whole worm (Eupolyphaga Seu Steleophaga), prominent reality, Rhizoma Fagopyri Dibotryiss, Flos Farfarae, Resina Ferulae, Caulis Fibraureae, Fibrauretin, Fluoritum, little mattress perfume, Fructus Forsythiae, Cortex Fraxini, Bulbus Fritillariae Cirrhosae, Hupeh Fritillary Bulb, Bulbus Fritillariae Pallidiflorae, Bulbus Fritillariae Thunbergii, Bulbus Fritillariae Ussuriensiss, Semen Phaseoli are slightd, five Gall nut, Endothelium Corneum Gigeriae Galli, Ganoderma, Herba Artemisiae Scopariae extract, burnt Fructus Gardeniae, Fructus Gardeniae, Rhizoma Gastrodiae, disconnected clam, Radix seu Herba Gei aleppici, Herba Gendarussae, Flos Genkwa, Qin Chong, dragon Gallbladder, Rhizoma Zingiberis Recens stream leaching descendants, Folium Ginkgo, Ginkgo Biloba Extract, Semen Ginkgo, Folium Ginseng, Radix Ginseng Rubra, Radix Ginseng, Herba Sarcandrae extractum, Herba Glechomae, pig tooth It is abundant, big Fu Jiao, abundant Fructus Gleditsia acupuncture, Radix Glehniae, Radix Glycyrrhizae Preparata, Radix Glycyrrhizae, Flos Bombacis Malabarici, Pericarpium Granati, Shi Yi, forging stone descendants, Haematitum, Concha Haliotidis, big Halitum, red stone moon purport, crataegus pin natifida var. Major leaf extract, the red Seedling of moxibustion, red Seedling, Folium Hibisci Mutabiliss, Hippocampus, Fructus Hippophae, Rhizoma Homalomenae, Fructus Hordei Germinatus, Yu Swollen Grass, Hydrargyri Oxydum Rubrum, Semen Hyoscyami, Herba Hyperici Monogyni, Ilex purpurea Hassk.[I.chinensis Sims, Folium Ilicis Cornutae, Cortex Ilicis Rotundae, Maple skins, Semen Impatientis, Rhizoma Imperatae, Indigo Naturaliss, sheathed Flower, Herba Inulae, Radix Inulae, Rhizoma Belamcandae, Folium Isatidiss, Radix Isatidis, Semen Juglandis, big rate, Medulla Junci, unconcerned Caulis Spatholobi, mountain Abandoned, Calyx Kaki, The luxuriant son of Radix Kansui, Radix Knoxiae, the Fructus Kochiae, Semen Lablab Album, Wingedtooth Laggera Herb, Lagotis clarkei Hook. F (Lagotis brevituba Maxim.), Thallus Laminariae (Thallus Eckloniae), Radix Lamiophlomidis Rotatae, Lasiosphaera Seu Calvatia, constitution, Herba Leonuri, Herba Leonuri Stream leaching descendants, Radix Glycyrrhizae extractum, Radix Glycyrrhizae stream leaching educate, Rhizoma Ligustici, Fructus Ligustri Lucidi, Bulbus Lilii, Limonitum, the Radix Linderae, Semen Lini, Fructus Liquidambaris, hold face cream, Radix Liriopes, cladoptosis core, remove from office it is clear before, Herba Lobeliae Chinensis, Arillus Longan, Flos Lonicerae, Caulis Lonicerae, Flos Lonicerae, Herba Lophatheri, Retinervus Luffae Fructuss, Cortex Lycii, Fructus Lycii, Herba Lycopi, Herba Lycopodii, Spora Lygodii, Herba Lysimachiae, Herba Lysionoti Pauciflori ,/- Blumeae preparatum Tabellae (L-Borneol) ,/- Mentholum, Magnetitum, Flos Magnoliae, Cortex Magnoliae Officinalis, Flos Magnoliae Officinalises, Caulis Mahoniae, Fructus Malvae, Squama Maniss, Sang Ca Pins, Margarita, Concha Margaritifera, Caulis Marsdeniae Tenacissimae, Mel, abundant Gong (green sail), hardship Chinaberry skin, Semen Melo, Rhizoma Menispermi, Herba Menthae, the clear leaf of Concha Meretricis Seu Cyclinae, Lapis Micae Aureuses, cloth, watermelon crystal, Semen Momordicae, Cortex Mori, Folium Mori, Sang Kan, Mulberry Branch, Radix Morindae Officinaliss, Should perfume, Herba Moslae, Cortex Moutan, Flos Mume, Fructus Mume, Folium Et Cacumen Murrayae, speckle honey, lima bean slight, Myrrha, Radix Et Rhizoma Nardostachyos, Matrii Sulfas Exsiccatus, awns The total mound glycosides of nitre, Folium Nelumbinis, Plumula Nelumbiniss, Receptaculum Nelumbiniss, Pro sections, Semen Nelumbinis, Stamen Nelumbiniss, Semen Nigellae, Radix Notoginseng, Radix Notoginseng, notoginseng triol bear glycosides, younger brother Work, Oleum Ocimi Gratissimi, Olibanum, Omphalia, Ophicalcitum, Radix Ophiopogonis, Herba Orostachyos, Semen Oroxyli, Fructus Oryzae Germinatus, Rhizoma Osmundae Japonicae, Concha Ostreae, BAIJU, it is red it is careless, Rhizoma Panacis Japonici, Rhizoma Panacis Majoris, Radix Panacis Quinquefolii, foxtail millet shell, Rhizoma Paridis, patchouli oil, high mountain Radix Cochleariae officinalises dish, Oleum menthae, Caulis Perillae, Folium Perillae, purple Fructus Perillae, Cortex Periplocae, Ramulus Persicae, Semen Persicae, RADIX PEUCEDANI, Radix Peucedani, Semen Pharbitidiss, Cortex Phellodendri, Cortex Phellodendri, Pheretima, Rhizoma Phragmitiss, Fructus Phyllanthi, bright and beautiful lamp Cage, Radix Physochlainae, Radix Phytolaccae, Ramulus Et Folium Picrasmae, Radix Picriae felterrae, Rhizoma Picrorhizae, Rhizoma Pinelliae, Rhizoma Pinelliae (processed with Rhizoma Zingiberis Recens), Rhizoma Pinelliae Preparatum, the Rhizoma Pinelliae, Pine Nodular Branch, Pollen Pini, Hu It is green pepper, Caulis Piperis Kadsurae, Bi Pedicellus et Pericarpium Trapaes, Herba Plantaginiss, Semen Plantaginiss, Cacumen Platycladi, Semen Platycladi, Knot stalks, Herba Pogostemonis, Radix Polygalae fluid extractum, Herba Polygalae Japonicae, remote Will, Rhizoma Polygonati Odorati, Rhizoma Polygonati, Herba Polygoni Avicularis, Rhizoma Polygoni Cuspidati, Caulis Polygoni Multiflori, Radix Polygoni Multiflori Preparata, Radix Polygoni Multiflori, Fructus Polygoni Orientaliss, Herba Polygoni cymosi, few Folium Isatidiss, pig etc., Poria, obtain tea skin, Dens Equi look for, Herba Potentillae Chinensis, Herba Potentillae Discoloris, Pulvis Cornus Bubali Concentratuss, Righteousness core, propolis, Spica Prunellae, Semen Pruni, Radix Psammosileness, Cortex Pseudolariciss, Radix Pseudostellariae, Psoralen moon purport, Herba pterocephali, Radix Puerariae, Pachyrhizua angulatus, the Radix Pulsatillae, the right copper of@, Herba Pyrolae, Folium Pyrrosiae, Fructus Quisqualis, winter insult Grass, Kazakhstan spiral shell oil, Radix Ranunculi Ternati, Lay vine, Realgar, Radix Rehmanniae Preparata, Radix Rehmanniae, Radix Rhapontici, Radix Et Rhizoma Rhei, Radix Rhodiolae, Folium Rhododendri Daurici, Flos Rhododendri Mollis, Radix Et Rhizoma Rhei Leaching descendants, Extractum Rhei Liquidum, bacterium pockmarks, Flos Rosae Chinensiss, Jin Louzi, Flos Rosae Rugosae, Fructus Rubi, bacterium glass, tinkling of pieces of jade Cornu Caprae seu Oviss, the total intoxicated acid of Radix Salviae Miltiorrhizae are extracted Thing, Radix Salviae Miltiorrhizae, pleased, Lignum Santali Albi, Radix Saposhnikoviae, Lignum Sappan, middle of the month wind, Sargassum, Caulis Sargentodoxae, Folium Sauropi, Rhizoma Saururi (Herba Saururi), Herba Saussureae Involueratae, five hide The extracts such as son, Fructus Schisandrae Sphenantherae, Herba Schizonepetae charcoal, Herba Schizonepetae, Herba Schizonepetae, Herba Schizonepetae, Hou Song, Scorpio, Radix Scrophulariae, Huang, Herba Scutellariae Barbatae, Huang Son, Herba Senecionis Scandentiss, kind muddy leaf, Endoconcha Sepiae, Serpentiss ant, Oleum Sesami, Semen Sesami Nigrum, Fructus Setariae Germinatuss, Herba Siegesbeckiae, fine grinding are played in, Herba Sedi, Herba Selaginellae, day Jasmine, Semen Sinapiss, Caulis Sinomenii, Fructus Sinopodophylli, siphonostegia chinensiss, Fructus Momordicae, shafts chinaroot greenbrier, native Poria, Semen Glycine Germinatum, Semen sojae atricolor, tasteless preserved soybean, solidago plant Flower, Radix Sophorae Flavescentiss, Flos Sophorae, the Fructus Sophorae, Radix Sophorae Tonkinensiss, Rhizoma Sparganii, Caulis Spatholobi, Oleum Linderae, Herba Spirodelae, Medulla Stachyuri (Medulla Helwingiae), Stalactitum, anistree mattress Oleum sesami, open country Fructus Chaenomeliss, Radix Stellariae, the Radix Stemonae, Radix Stephaniae Tetrandrae, Semen Sterculiae Lychnophorae, Semen Strychni Pulveratum, Semen Strychni, Styrax, Pulvis Fellis Suiss, sulfur, when medicine, Herba Swertiae Mileensises, Solenognathus, Cortex Syingae Amurensiss, Pulvis Talci, Talcum, Cacumen Tamariciss, tanshinone extract, Herba Taraxaci, Herba Taxilli ,-Oleum Camelliae, Fructus Terminaliae Billericae, Carapax Et Plastrum Testudiniss Glue, Carapax Et Plastrum Testudiniss, Medulla Tetrapanacis, firewood are lonely, Bulbus Fritillariae Thunbergii Liu Jin Threats, gold fruit pull, the total mound glycosides of stem and leaf of Radix Ginseng total saponins, Fructus Toosendan, vertebra, Radix Ginseng, do Paint, Caulis Trachelospermi, Petiolus Trachycarpi, Cai Herba chenopodii, Fructus Trichosanthis, cortex trichosanthis, Radix Trichosanthis, stir-fry Semen Fructus Trichosanthis, Semen Fructus Trichosanthis, Semen Trigonellae, whole first, Fructus Tsaoko, Lignum Pini Nodi Oil, leaf of Turpinia pomifera (Roxb) D O., Pollen Typhae, Rhizoma Typhonii, Ramulus Uncariae Cum Uncis, Semen Vaccariae, Fine spiders perfume, Herba Verbenae, Nidus Vespae, Semen Phaseoli, Herba Violae, Trees are posted Life, Oleum Viticis Negundo, Fructus Viticises, Folium Viticis Negundo, Radix Vladimiriae, Fructus Forsythiae extract, Rhizoma Wenyujin Concisum, Fructus Xanthii, Pericarpium Zanthoxyli, Radix Zanthoxyli, Zaocyss, cultivation Art oil, Rhizoma Zingiberis Preparatum, Rhizoma Zingiberis Recenss, Rhizoma Zingiberiss, acid evil core etc..

In some embodiments, drug matrices still further comprise medium.Medium can be associated with API, for example, base Bottom can have physical contact with API.In some embodiments, API can be embedded into substrate.In some embodiments, API Can be dispersed in substrate.

In some embodiments, medium includes water soluble excipient.Water soluble excipient is selected from the following group：Cocoa Fat, Polyethylene Glycol (PEG), sucrose, glucose, galactose, Fructose, xyloselactose, maltose, trehalose, sorbose Alcohol, mannitol, maltodextrin, Raffinose, stachyose, oligofructose or combinations thereof.In some embodiments In, substrate also includes plasticizer.

In some embodiments, medium is with the corrosion/dissolution rate higher than API.

Drug matrices can be loaded in compartment with any desired configuration or size.

In some embodiments, drug matrices operability DIYU compartment passes through covalent bond, non-covalent bond or connector It is connected.Therefore, it is connected by covalent bond or non-covalent bond after drug matrices can be prepared respectively with matrix.In some embodiments In, pharmaceutical formulation disposably produces drug matrices and matrix by the method for 3D printing.

In some embodiments, drug matrices are molded and are pressed into tablet, oval tablet, pill or capsule.One In a little embodiments, drug matrices shape is consistent with compartment shape.For example, when compartment shape is pie, drug matrices shape It is that pie expires the compartment to fill.

In some embodiments, as shown in fig. 6, drug matrices are in the form of nano-particle.Drug matrices with it is molten The solution for having API or being dispersed with API is mixed.During subsequent 3D printing pharmaceutical formulation, solution is atomized/is injected in On printable layer.Solution containing drug matrices is once dried, among drug matrices are just dispersed in pharmaceutical formulation.Nanometer Granule has larger surface area, thus has higher dissolution rate.

Nanoparticle size (preferred 100-800nm, 100-700nm, 100-600nm, 100- between 1nm to 900nm 500nm、100-400nm、100-300nm、100-200nm、1nm、2nm、3nm、4nm、5nm、6nm、7nm、8nm、9nm、10nm、 11nm、12nm、13nm、14nm、15nm、16nm、17nm、18nm、19nm、20nm、100nm、200nm、300nm、400nm、 The size of 500nm, 600nm, 700nm, 800nm, 900nm).The size of nano-particle can be by selecting suitable synthetic method And/or system is controlling.The nano-particle in size range is being wished in order to obtain, can suitably control or change synthesis bar Part to provide, for example, it is desired to solution concentration or the cavity scope of needs (comment in detail visible：Vincenzo Liveri, The controlledly synthesis of nano-particle in microcosmic heterogeneous system, Springer, 2006).

As shown in fig. 7, in some embodiments, drug matrices can be present with micropin form.The medicine of micropin form In the substrate generally packed housing with acicular texture.During 3D printing pharmaceutical formulation, micropin can also and medicine Dosage form is printed together, it is also possible to be embedded in pharmaceutical formulation.Micropin can by saccharide, PLGA polymer, API or they Combination is constituted.When to parenteral or intestinal dispenser, micropin can help API to enter the blood circulation of patient.

In some embodiments, drug matrices can be configured to a network.As shown in Figure 8 A, a kind of pharmaceutical formulation Drug matrices are loaded in the compartment of intrinsic silicon., into a network, which is for example by loose for the basal structure of drug matrices Material is made, and the density of loose drug matrices is typically smaller than the density of matrix.The frame structure of tablet is by can be in 1-10 minutes The material of interior dissolving is made, and substrate can be dissolved within the 2-60 seconds, preferably 2,5,10,15,20,25,30,35,40,45,50, 55th, the substrate dissolved in 60 seconds.As shown in Figure 8 B, after pharmaceutical formulation is applied in, API can be discharged in several seconds.

Drug matrices content can be made by using additive method, for example fused glass pellet (FDM) method.One In a little embodiments, the mixture of API and excipient can be crushed to by drug matrices by 3D printing.Before extrusion, API is melted and uniformly mixed with the substrate melted.Alternately, before extrusion, the API (such as powder) of solid form Can be with the substrate mixing melted or among being dispersed in substrate.As a rule, extrusion process is in substrate glasses transition temperature On between 10 to 40 DEG C and be close at a temperature of the fusing point of API and carry out.Once 3D printer has reached suitable temperature, substrate Stereosopic printing surface will be deposited to.By the shape that can control drug matrices and big is programmed to 3D printing process It is little.In some embodiments, drug matrices can have not only been manufactured in same technique but also had manufactured matrix.In some embodiments In, first manufacture drug matrices and remanufacture matrix, and among the manufacture process of matrix or afterwards by drug matrices be loaded into every Room.

In some embodiments, when drug matrices are loaded into compartment, drug matrices are connected with matrix, example Such as, drug matrices are embedded into or are fixed in matrix.In some embodiments, when drug matrices load compartment Wait, drug matrices can be separated with matrix.

D. controllable release

The pharmaceutical formulation of the disclosure has different release processes after oral.In some embodiments, medicine agent Type has constant release, pulse release, sustained release or non-linear release profiles.In some embodiments, pharmaceutical formulation With zero-order release kinetics.

In the disclosure, the release of medicine is measured in aqueous.Aqueous solution include gastric juice, intestinal juice, body fluid and Aqueous solution containing inorganic or organic compound.Aqueous solution also includes water.

For specific Drug therapy field, a suitable release profiles can bring many benefits.For example, pulse release Curve realizes controlled absorbed so as to reduce the ratio of peak level/groove level, and it is fixed to realize the specific region into gastrointestinal tract Can be used to improve deviation to release drug matrices and the absorption process unrelated with feed status, therefore the curve, reduce secondary The adaptability of patient is acted on and improves, these features are very necessary for treatment ADHD diseases.Again for example, loading dose Maintenance dose is followed by for treatment chronic disease, such as hypertension and diabetes there may be advantage.

Several mechanism using the pharmaceutical formulation control release curve in the disclosure have been discussed above.For example, pass through Adjustment can be provided for a long term the medicine of constant basis by the exposed area of the matrix of lasting corrosion, the drug matrices being embedded in matrix. In addition, the release profiles speed of API can be controlled by the geometry of the size of compartment opening and/or compartment.

In certain embodiments, release profiles can pass through design one with by stopper close or block hole every Room is controlling.Stopper is to work as pharmaceutical formulation by water solublity, porous or solvable corrosion material or pH sensitive materials or hydrophobic material etc. Can be dissolved, be degraded through gastrointestinal tract, the material of structure variation is made.When pharmaceutical formulation is applied to an object, plug Son can be melted, permeate or corrosion, thus the drug matrices in compartment will be released.By selecting with suitable molten The stopper water-soluble material of Xie Du, permeability and solvable erosion degree can control the release profiles speed of drug matrices.Alternately, For the stopper of the hole for blocking on compartment, can be by using the stopper of suitable shape and/or size (for example, properly The column of length) controlling the release profiles speed of drug matrices API.The release profiles can also be by the compartment of varying number To control.Fig. 9 shows a kind of exemplary dosage forms, and its intrinsic silicon contains multiple column compartments and is distributed in the two of pharmaceutical formulation Side.Each compartment accommodates drug matrices.Each compartment has the hole of a column stopper obstruction.These stoppers have Different dissolubility.Size, shape and dissolubility depending on stopper, the release of API can be lasting, continuous, same When, successively or pulse feature.

Figure 10 A show a kind of exemplary pharmaceutical formulation with release profiles successively.Reference picture 10A, the pharmaceutical formulation 700 matrix 701 is contained within three column compartment 702-704.Each compartment is mounted with the medicine base containing same API Matter.Each compartment has the hole blocked by stick-like stopper 705-707.These stoppers make length still by same material It is different, therefore it is also different to open the time that compartment is discharged needed for drug matrices to dissolve stopper.As illustrated in figure 10 c, it is most short Stopper dissolve first and API discharged from first compartment.After the API in first compartment is released completely, in it is isometric The stopper dissolving of degree simultaneously discharges API from second compartment.After the API in second compartment is released completely, the 3rd stopper Dissolve to discharge API from the 3rd compartment.Therefore, after the drug matrices in first compartment are released, Plasma Drug Level Reach first peak value.When the API discharged from first compartment starts to be consumed, Plasma Drug Level is begun to decline (see figure 10D).Before Plasma Drug Level drops to critical levels (parallel lines, the drug ineffective under the line), in second compartment API be released, then Plasma Drug Level increases again.When the API discharged in second compartment reaches the second peak value and opens When beginning is consumed, the stopper of the 3rd compartment dissolves to open compartment.Therefore, plasma A PI level can be maintained pass for a long time On key level, this is very helpful for the treatment of specified disease.

Release characteristic successively can be realized by another kind of exemplary pharmaceutical formulation.The pharmaceutical formulation contains such as Figure 10 B institutes The some drug matrices encapsulated with refracting films for showing.Dissolve the sustained release that each layer can realize API simultaneously, to provide as schemed Continuous lasting API releases shown in 10C.In certain embodiments, after pharmaceutical formulation is applied in, the outer layer of the pharmaceutical formulation Can dissolve and discharge the drug matrices being embedded into immediately.But as outer layer has blocked exchanging for the layer being clipped in the middle and environment, Make intermediate layer insoluble or dissolution velocity is very slow.In other words, the dissolving of outer layer typically precedes the dissolving in intermediate layer, thus The effective ingredient contained in outer layer typically precedes the effective ingredient release in intermediate layer.During the dissolving of outer layer makes to be sandwiched in Between layer come out so as to accelerate their dissolving, it is thus achieved that release profiles successively as illustrated in figure 10 c.At some In embodiment, pharmaceutical formulation includes the Gas generating components being loaded in first compartment.In certain embodiments, the gas is sent out Raw component is selected from the following group：Organic acid plus carbonate, sulphite, bicarbonate, sodium carbonate, sodium bicarbonate, inclined bisulfite Sodium, Calcium Carbonate and combinations thereof.Gas generating components and gastric juice can discharge carbon dioxide or sulfur dioxide gas when contacting.When Matrix is dissolved under one's belt, infiltration or during corrosion, as gas generator part is exposed to sour environment or water penetration is entered Compartment causes the reaction of acid and sodium bicarbonate, the gas generator part produce gas to discharge drug matrices in effervescent mode. It should be noted that can be set according to the thickness of adjust pharmaceutical formulation each layer, dissolution rate, permeability and corrosion rate etc. The dissolution time of different layers is put, so that different layers can be dissolved with Preset Time or solubility curve, so that therein Effective ingredient can be discharged with default release profiles.

The pharmaceutical formulation of the disclosure includes one or more drug matrices at least existing with section retards releasing pattern, its Middle sustained release can be controlled by traditional material or mode well known to those skilled in the art, for example, by inciting somebody to action Realize during API is embedded into the matrix/substrate of sustained release or by using one or more sustained release coating.By prolonging Slowbreak is put, and API releases can be controlled to twice a day or dispenser and can just meet requirement, and this has for needs are by continuing The active component of dosage has advantage come the treatment for resisting pain.

In some embodiments, pharmaceutical formulation can discharge active component at once in the oral cavity.For example, it is released in mouth In chamber or take sublingual area.

In some embodiments, pharmaceutical formulation further includes conventional adminicle well-known to those skilled in the art Matter, preferred glyceryl monostearate, the derivant of semisynthetic triglyceride, semisynthetic glyceride, castor oil hydrogenated, palm fibre Palmitic acid acid glyceride, Glyceryl Behenate, polyvinylpyrrolidone, gelatin, magnesium stearate, stearic acid, sodium stearate, Talcum, benzene Sodium formate, boric acid and silica sol, fatty acid, the triglyceride for replacing, glyceride, polyoxyalkylene diols and they spread out It is biological.

The preparation of pharmaceutical formulation

Controllable release pharmaceutical formulation disclosed herein can be produced by any appropriate process.In some embodiments In, the pharmaceutical formulation is produced by 3 D-printing (3D printing).

3D printing used herein refers to the process that 3D articles are in layer produced according to Digital Design. U.S.Pat.Nos.5,204,055；5,260,009；5,340,656；5,387,380；5,503,785；And 5,633,0213D In describe the basic process of 3D printing.Remaining United States Patent (USP) for being related to 3D printing is included with application：U.S.Pat.Nos.5, 490,962；5,518,690；5,869,170；6,530,958；6,280,771；6,514,518；6,471,992；8,828, 411；U.S.P G Pub.Nos:2002/0015728；002/0106412；2003/0143268；2003/0198677；2004/ 0005360.Above-mentioned patent and application be may refer to regard to the detailed description of 3D printing.

For the production of pharmaceutical formulation, the different 3D printing method of different raw materials, equipment and condition of cure has been related to it Jing is developed.These 3D printing methods include binder deposition (see L Gibson etc. (2015) Additive Production technology：3D Print, rapid shaping and direct digitization are produced, 2 editions, Springer, New York；W.E.Katstra etc. (2000) 3 D-printing system The oral drug dosage form made, control release magazine 66：1-9；W.E.Katstra etc. (2001) manufactures complicated mouth by 3 D-printing Oral dosage form, Materials Science and Engineering technical college thesis, the Massachusetts Institute of Technology；H.Lipson etc. (2013) is assembled：3D beats The New World of print, John Wiley father and son company；G.Jonathan, A.Karim (2016), the 3D printing of medicament：Design customization Delivery system new tool, international medical magazine, 499：376-394), injection of material (see G.Jonathan, A.Karim (2016), the 3D printing of medicament：The new tool of the delivery system of design customization, international medical magazine, 499： 376-394), extruding is (see L Gibson etc. (2015) Additive Production technology：3D printing, rapid shaping and Direct Digital metaplasia Produce, 2 editions, Springer, New York) and photopolymerization (see F.P.Melchels etc. (2010) to stereolithography and its in biomedicine Application in engineering, biomaterial 31：6121-30).

In some embodiments, pharmaceutical formulation disclosed herein is manufactured by pressing method.In extrusion process, material From the nozzle extrusion that robot is activated.Unlike binder deposition needs a powder bed, pressing method be printed upon any base On bottom.Multiple material can all be extruded to realize 3D printing, including thermoplastic disclosed herein, paste and colloidal suspension Liquid, silicone and other semisolids.A kind of common type of extrusion printing is fusion sediment modeling, and which uses solid polymer thin Silk is printed.In fusion sediment modeling, gear train is introduced into filament in the nozzle assembly of heating and is extruded (see L Gibson etc. (2015) Additive Production technology：3D prints, and rapid shaping and direct digitization are produced, 2 editions, Springer, knob About).

The production of printing work indicates to generate by various ways, including direct coding, pushes away from solid CAD model Lead, or other are for the computer interface and application software of 3D printer.The quantity and space cloth of the drop that these instructions include Confidence ceases, general printing parameter, such as the decline interval on each linear dimension (X, Y, Z), and in each drop The volume or quality of liquid.The material given for one group, can be with adjusting parameter improving the architecture quality of creation.The knot of creation The whole resolution of structure is the size of powder particle size, the fluid droplet sizes, print parameters and material behavior.

As 3D printing can process a series of drug materials and can be with Partial controll component and structure, 3D printing is very There is suitable for the manufacture present invention the pharmaceutical formulation of complex geometry mechanism and component.

Manufacture the pharmaceutical formulation that personalization is also allowed for using 3D printing method.Personalised drug is referred to based on biological marker Thing, produces the dosage form design of Treatment decsion and personalization to help the layering to patients.Modification Digital Design is than modification Physical equipment is easier.Additionally, automatization, the operation cost of small-scale 3D printing may be negligible.Therefore, 3D Printing can allow multiple small-sized, and personalized batch production is economically feasible, and make to be intended to improve the personalized dosage form of compliance Production becomes possibility.

Individual character dosage form allows customization to pay the medication amount of body weight and metaboilic level according to patient.The dosage form of 3D printing can be with Child and highly effective medicine in guaranteeing to grow up has accurately personalized dosage.Personalized dosage form can also be combined The medicine of all patients adheres to medication into a single daily dosage, so as to improve patient.

Figure 11 is shown with 3 D-printing come the method for manufacturing the dosage form of personalization.For each patient, can obtain each Plant the result of clinical trial, including body weight, age, metabolism index and genome biomarker etc..The knot of clinical trial Fruit is imported into computer software, and the prescription with reference to doctor and pharmacological kinetics model are designing given dose and drug regimen Dosage form.Then the instruction is sent to a three-dimensional printer manufacture dosage form.The dosage form of generation is applied to patient.

The controllable release of multi-medicament substrate

The pharmaceutical formulation and method of the disclosure can be used to the release for controlling two or more drug matrices, so as to realize The optimization of the drug regimen in specific medical field.For example, the tablet for treating hypercholesterolemia can be designed as instant-free Atorvastatin calcium but prolongation release nicotinic acid.In another example, lenitive nonsteroidal anti inflammatory drugs (NSAID) are set The mucosa injury that sustained release NSAID, but quick release H2 receptor antagonist are calculated as to prevent NSAID from inducing.

In some embodiments, matrix is contained within multiple compartments, and each compartment is mounted with a kind of drug matrices.One In a little embodiments, multiple compartments are connected with each other.In some embodiments, multiple compartments are mutually not attached to.In some embodiment party In formula, the drug matrices being loaded in different compartments are identical.In some embodiments, the medicine base being loaded in different compartments Matter is different.The pharmaceutical formulation can be designed as provide and simultaneously or sequentially discharge multi-medicament substrate to realize Synergistic treatment work With.

In some embodiments, the release to multi-medicament substrate can be and meanwhile, successively, pulse or this is several The combination of the mode of kind.Figure 12 A show a kind of exemplary pharmaceutical formulation, and the pharmaceutical formulation can discharge various API simultaneously.Reference As illustrated in fig. 12, the pharmaceutical formulation 800 includes three lamination 801-803, and per layer is all embedded into different drug matrices.As schemed Shown in 12B, after pharmaceutical formulation 800 is applied in, the drug matrices are released simultaneously but rate of release has with the dissolving of layer Institute is different.

Figure 13 A depict another to be had while the exemplary pharmaceutical formulation of release profiles.With reference to 13A, the medicine agent Type 900 includes three column compartment 901-903, and these compartments are loaded with three kinds of drug matrices.Each drug matrices Substrate suffers from different identical dissolubility, and API is embedded in substrate.As shown in Figure 13 B, in 900 quilt of pharmaceutical formulation After applying, these three API are released simultaneously, but have different rates of release with the substrate dissolving of drug matrices. The rate of release of API can be controlled by the size of the shape of compartment or compartment opening.

Figure 14 A and 14B depict can while discharge another kind of exemplary pharmaceutical formulation of three kinds of API, with reference to Figure 14 A, The pharmaceutical formulation 1000 includes three pie section 1001-1003 for being embedded with drug matrices.As shown in Figure 14 C, as section is molten Solution, multi-medicament substrate discharges simultaneously and the rate of release of drug matrices can be controlled by the dissolubility of section.With reference to 14B, the pharmaceutical formulation 1100 include the three pie section 1101-1103 wrapped up by shell 1104, and shell 1104 is molten compared to section Solution is slower.The rate of release of the drug matrices in potential section has blocked the boundary of section 1101-1103 and environment due to shell 1104 Face and slow down.

Figure 15 A show a kind of exemplary pharmaceutical formulation that can sequentially discharge two kinds of API.With reference to Figure 15 A, the medicine agent Type 1200 includes matrix 1202, and matrix contains the compartment for filling drug matrices 1202.The matrix 1201 includes an API, medicine Substrate 1202 includes the 2nd API.As shown in fig. 15b, after pharmaceutical formulation applies, with matrix dissolution, an API is released Put.Until matrix dissolution and when exposing drug matrices, the 2nd API can just be released, it is achieved thereby that the order of various API Release profiles.

Figure 16 A show another exemplary pharmaceutical formulation of order release profiles.Reference picture 16A, medicine agent The matrix 1301 of type 1300 is contained within three column compartment 1302-1304 for being mounted with three kinds of drug matrices.Compartment 1302-1304 Suffer from the hole blocked by column stopper.Each stopper suffers from different length and/or dissolubility.As shown in fig 16b, with Stopper order dissolving and open compartment, various API are sequentially discharged.

Figure 17 A show a kind of with while the exemplary pharmaceutical formulation of release or order release profiles.With reference to 17A, should The matrix of pharmaceutical formulation 1400 is contained within different solubilities four section 1401-1404.In some embodiments, such as Shown in Figure 17 B, drug matrices are embedded in section 1401-1404.After matrix is dissolved, drug matrices are released simultaneously. In some embodiments, each section includes the compartment of a loading drug matrices.As shown in Figure 17 C, work as matrix dissolution When, drug matrices are sequentially discharged.

Embodiment one

This illustration show a kind of design of the pharmaceutical formulation of controllable release.

As shown in Figure 18 A, pharmaceutical formulation includes a flat tablet matrix and matrix is contained within pie compartment.The matrix by PEG8000 is constituted.Benzoic acid is used as drug matrices model.

In pharmaceutical formulation, benzoic release profiles can be measured with following manner.The Na of pH=8 is prepared first₂HPO₄Water Used as benzoic lysate, compound concentration is the benzoic acid mother solution of 120 μ g/mL to solution, is diluted to concentration successively for 30 μ g/ ML, 15 μ g/mL, 7.5 μ g/mL, 3.75 μ g/mL, the diluent of 1.875 μ g/mL, are being absorbed with spectrophotometry instrument Wavelength is at 226nm.Data to measuring make linear regression, obtain benzoic acid standard curve y=0.0599x+0.0347.In order to Benzoic burst size is measured, pharmaceutical formulation is dissolved in the Na of pH=8₂HPO₄Aqueous solution, degassed process, temperature control exist 37 DEG C ± 0.5 DEG C, it is 100rpm to turn basket rotating speed, respectively in different point in time sampling 5mL to measure concentration of benzoic acid, while Supplement 5mL media again in solution.0.45 μm of filtering with microporous membrane of sample liquid Jing, precision pipette certain volume subsequent filtrate and with purple Outward-visible honourable photometer determines light absorption value A at wavelength 226nm, calculates concentration of benzoic acid by standard curve, and counts as the following formula Calculate benzoic release percentage ratio：

1.

2. wherein c_nRepresent measured concentration, v_tRepresent medium volume, v_sRepresent sample volume, Q_{benzoic acid}Represent medicine agent Benzoic amount in type.

The drug release determination of PEG8000：The standard curve of PEG8000 is drawn first, weighs 0.1275g PEG8000 standard specimens It is put in 25ml volumetric flasks, with water dissolution and is diluted to scale；Above-mentioned solution 1ml, 2ml, 5ml and 10ml are pipetted respectively in 10ml In volumetric flask, scale is diluted with water to, as reference substance solution.Precision measures 50 μ l injection chromatograph of liquid (Waters Ultrahydrogel^TM120/250/500 3 series connection, flow velocity are 0.5ml/min, and column temperature is 40 DEG C, and detector is to show poor folding Photodetector).Record chromatogram, using the logarithm value of reference substance concentration as abscissa, the logarithm value of the peak area of respective concentration Used as vertical coordinate, calculating regression equation is：Y=1.024x+8.918.Wherein chromatographic condition is：Chromatographic column is Waters Ultrahydrogel^TM120/250/500 3 series connection, flow velocity are 0.5ml/min, and column temperature is 40 DEG C, and detector is to show poor folding Photodetector.Capacity area is measured and is denoted as y-axis.The logarithm of contrast solution is used as x-axis.Use y=1.024x+8.918 Generate the standard curve of PEG8000.The release percentage ratio of PEG8000 can be calculated with below equation：

3. wherein c_nShow to measure concentration, v_tShow liquor capacity, v_sShow sample volume, Q_PEG8000Show pharmaceutical formulation The amount of middle PEG8000.

As a result：As shown in figure 18b, benzoic release profiles and D.Brooke and R.J.Washkuhn (zero level dispenser systems System：Theoretical and results of initial tests, medical science magazine, 1977) in model coincide, and receive effect of the interface.Therefore, base A controllable release curve can be designed in the pharmaceutical formulation of the disclosure.

Embodiment two

This example describes the design of the pharmaceutical formulation of the controllable release of the drug matrices that can realize different compartments.

Medicine is designed：Two kinds of pharmaceutical formulations are prepared with fusion sediment modeling method.The matrix of pharmaceutical formulation by Copolyvidone (VA64) 72%, PEG150018% and19% is constituted.Drug matrices are by moxifloxacin hydrochloride 30%, PEG150070% are constituted.Figure 19 A and 19B are the schematic diagrams of these pharmaceutical formulations.Reference picture 19A and 19B, pharmaceutical formulation 1600 include matrix 1601 and two compartments 1602 and 1603 in matrix.Each compartment is wrapped by wall 1604 and 1605 respectively Enclose.For the first pharmaceutical formulation, wall of described two compartments respectively by thickness for 0.75mm and 1.5mm is surrounded.For the second medicine Product dosage form, wall of described two compartments respectively by thickness for 0.75mm and 2.25mm are surrounded.

In order to detect the release of drug matrices, the pharmaceutical formulation is added into the pH6.8 phosphorus of 900mL under rotating speed 100rpm In phthalate buffer.The uv absorption of the buffer is measured to judge the release of drug matrices.

The result that release is determined is as shown in Figure 19 C and 19D.As shown in fig. 19 c, the first pharmaceutical formulation is added to the buffer In after 20 minutes, first compartment is opened, and the drug matrices in first compartment are released.The pharmaceutical formulation is added To after buffer 40 minutes, second compartment is opened.For the second pharmaceutical formulation, its result as shown in Figure 19 D, the pharmaceutical formulation It is added in buffer after 60 minutes, second compartment is opened.Therefore, the release profiles of the pharmaceutical formulation can be by surrounding The thickness of the wall of compartment is controlling.

Table 1 can use thermoplastic list

Although being illustrated to the principle of the present invention already in connection with embodiment, it should be appreciated that these descriptions are only It is not used to limit the scope of the present invention to illustrate.Content of this disclosure is intended merely to example and is used with explanation, can not Limit can not limit open scope in a particular form.For a person skilled in the art, many adjustment are aobvious with change And be clear to.Present disclosure select basis be in order to preferably explanation embodiment principle and practical application, thus Those skilled in the art can be with it is understood that a variety of embodiments and the adjustment carried out for application-specific.The disclosure Context be defined by following claims or its equivalence.

Claims (25)

1. a kind of pharmaceutical formulation, it is characterised in that include：

Matrix, described matrix have compartment on its interior；And

Drug matrices, which is accommodated in the compartment.

2. pharmaceutical formulation according to claim 1, it is characterised in that the drug matrices be regularly seated in it is described every In room.

3. pharmaceutical formulation according to claim 1, it is characterised in that the drug matrices are configured to be had less than described The size of compartment such that it is able to move in the compartment.

4. pharmaceutical formulation according to claim 1, it is characterised in that described matrix is integrally formed.

5. pharmaceutical formulation according to claim 1, it is characterised in that the drug matrices are encapsulated in acicular texture Housing in, and the housing is accommodated in the compartment.

6. pharmaceutical formulation according to claim 1, it is characterised in that the drug matrices are made up of loose material.

7. pharmaceutical formulation according to claim 6, it is characterised in that the loose drug matrices are with described matrix by phase Same material is constituted, and the density of the loose drug matrices is less than the density of described matrix.

8. pharmaceutical formulation according to claim 1, it is characterised in that the compartment is closing.

9. pharmaceutical formulation according to claim 8, it is characterised in that the compartment is configured to pie, pyramid shape, post The combination of shape, taper, cube-shaped, triangle prismatic, polygon prismatic, tetrahedral or these shapes.

10. pharmaceutical formulation according to claim 1, it is characterised in that described matrix is opened with corresponding with the compartment Mouthful, the opening is so that the drug matrices in the compartment expose.

11. pharmaceutical formulations according to claim 10, it is characterised in that the compartment is configured to from the opening The area on inwardly cumulative dissolving border so that the pharmaceutically active when the pharmaceutical formulation dissolves in the drug matrices into Divide and discharged with predetermined release profiles.

12. pharmaceutical formulations according to claim 11, it is characterised in that the rate of release of the active constituents of medicine is permanent Fixed.

13. pharmaceutical formulations according to claim 12, it is characterised in that the compartment be configured to pie, pyramid shape, The combination of column, taper, cube-shaped, triangle prismatic, polygon prismatic, tetrahedral or these shapes.

14. pharmaceutical formulations according to claim 1, it is characterised in that described matrix is with hole corresponding with the compartment Hole, described hole are blocked by stopper, to close the compartment.

15. pharmaceutical formulations according to claim 14, it is characterised in that it is molten that the stopper is configured in aqueous The solution time is longer than the most short dissolution time of described matrix, so that the active constituents of medicine in the drug matrices can be described After stopper dissolving, Jing is discharged by described hole.

16. pharmaceutical formulations according to claim 1, it is characterised in that multiple drug matrices are accommodated in the compartment.

17. pharmaceutical formulations according to claim 16, it is characterised in that the plurality of drug matrices are configured to adjacent Column structure.

18. pharmaceutical formulations according to claim 16, it is characterised in that the plurality of compartment is configured to spaced apart from each other Cylindrical space.

19. pharmaceutical formulations according to claim 16, it is characterised in that the plurality of drug matrices are configured to lamination knot Structure.

20. pharmaceutical formulations according to claim 1, it is characterised in that the inner side of the compartment has slow release layer,

Which is used to isolate the drug matrices and described matrix, so as to when the pharmaceutical formulation dissolves, the slow release layer can prolong Delay the release of the drug matrices pharmaceutical active composition.

21. pharmaceutical formulations according to claim 1, it is characterised in that be mounted with Gas generating components in the compartment.

22. pharmaceutical formulations according to claim 1, it is characterised in that the drug matrices are made up of nano-particle.

23. pharmaceutical formulations according to claim 1, it is characterised in that the compartment is hollow.

24. pharmaceutical formulations according to claim 23, it is characterised in that the size of the compartment is configured such that described Density of the average density of pharmaceutical formulation less than water.

25. pharmaceutical formulations according to claim 1, it is characterised in that the drug matrices are configured to loose structure.