CN109431965A - Pharmaceutical formulation and its use - Google Patents

Abstract

Present disclose provides a kind of for oral stabilization of solid pharmaceutical formulation.The pharmaceutical formulation includes matrix, forms compartment in inside；And it is accommodated in the drug matrices in the compartment.The controlled release of drug matrices pharmaceutical active ingredient may be implemented in the design of the pharmaceutical formulation.

Description

Pharmaceutical formulation and its use

It is on June 3rd, 2016, entitled " drug agent that the application, which is application No. is the 201610395483.9, applying date, The divisional application of the Chinese invention patent application of type and its use ", original application require on June 3rd, 2015 it is submitting, application No. is 62/170,645 U.S. Provisional Patent Application and on March 24th, 2016 are submitting, application No. is 62/313,092 U.S. to face When patent application priority, this application by reference to mode be integrally incorporated herein.

Technical field

The invention mainly relates to a kind of pharmaceutical formulation and bioactivator, diagnosticum, reagent, enamel and agriculturals/kill The controlled release of worm agent.

Background technique

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

Tablet is most common solid medicine dosage form, advantage is had more in manufacture, packaging and transport, and be easier to know Not with swallow.After being applied to organism, tablet and body interact to play drug effect.Active pharmaceutical ingredient must be in piece Agent releases before being rapidly absorbed into blood circulation.Drug ingedient is then dispersed by body fluid and tissue or is dissolved in vivo. During this drug absorption, deposition, metabolism and elimination, pharmaceutical formulation is determining drug release patterns and biological utilisation Degree aspect plays decisive role.Therefore, the demand for researching and developing a kind of pharmaceutical formulation that can provide controllable application system always exists, The system can provide levels of drugs needed for blood plasma, reduce side effect, and can improve patient to the adaptability of medicament.

Summary of the invention

On the one hand, present disclose provides a kind of pharmaceutical formulations comprising the matrix containing at least one compartment and is received In the drug matrices of the compartment.In some embodiments, the drug is operably secured on matrix.In some realities It applies in mode, the drug and matrix are separated and can be moved 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 poly- selected from Vinylcaprolactam homopolymer polyvinyl acetate- Ethylene glycol graft copolymer 57/30/13, Kollidon VA64 (PVP- VA), polyethylene pyrrole Pyrrolidone-polyvinyl acetate copolymer (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 copolymer 60/40, polyvinyl alcohol (PVA or PV-OH), polyvinyl acetate ester (PVAc), The poly- 2- dimethylaminoethyl methacrylate-polymethyl methacrylate copolymer 1:2:1 of polybutyl methacrylate-gathers Dimethylaminoethyl-polymethacrylate copolymer, the poly- front three of polyethyl acrylate-polymethyl methacrylate- Base ethyl vinyl chloride copolymer, the poly- base acrylic copolymer 7:3:1 of polymethyl acrylate-polymethyl methacrylate-, poly- first Base acrylic acid-polymethyl methacrylate copolymer 1:2, polymethylacrylic acid-polyethyl acrylate copolymer 1: 1, poly- methyl Acrylic acid-polymethyl methacrylate copolymer 1:1, polyethylene oxide (PEO), polyethylene glycol (PEG), hyper-branched polyester, hydroxyl Propyl methocel phthalic acid ester, hypromellose phthalate, hydroxypropyl methyl cellulose or hydroxypropyl first Cellulose (HMPC), hydroxypropyl methyl cellulose succinate or hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polylactide-copolymer of poly lactic acid (PLGA), carbomer, polyvinyl-polyvinylacetate copolymer, ethylene-second Vinyl acetate copolymer, polyethylene (PE) and polycaprolactone (PCL), hydroxy propyl cellulose (HPC), polyoxyethylene 40 hydrogenate Castor oil, methylcellulose (MC), ethyl cellulose (EC), poloxamer, hydroxypropyl methylcellulose phthalate (HPMCP), poloxamer, rilanit special, glyceryl palmitostearate, Brazil wax, polylactic acid (PLA), polyethanol Sour (PGA), acetylbutyrylcellulose (CAB), colloidal silicon, titanium oxide, sucrose, glucose, polyvinyl acetate phthalic acid Ester (PVAP) and their combination.

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 drug is existed with nano particle, micropin either web form.

In some embodiments, the drug matrices include active pharmaceutical ingredient (API).In some embodiments, The API can be local anesthetic, sleep regulation medicine, antiepileptic, anticonvulsive drug, anti-alzheimer illness medicine, antalgesic, Arthrifuric, antihypertensive, antiarrhymic, diuretics, treatment liver disease drug, treatment pancreatic disease drug, in treatment Pivot nervous system disease medicament, treatment gastrointestinal disease drug, antihistamine, antiallergic, glucocorticoid medicine, hormone drug Object, contraceptive, hypoglycemic agent, anti-osteoporotic, antibiotic, sulfa drugs, quinolone drugs and other synthesis are anti- In bacterium medicine, antituberculotic, antiviral drugs, anti-tumor 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, makeup Product reagent, veterinary medicament or agricultural/pesticidal agents.

In some embodiments, the drug matrices further comprise excipient.In some embodiments, the tax Shape agent is made of water-soluble material, non-water soluble material, and the material is selected from the group: cocoa butter, polyethylene glycol (PEG), sucrose, glucose, galactolipin, fructose, xylose, lactose, maltose, trehalose, D-sorbite, mannitol, malt Magma essence, gossypose, stachyose, oligofructose and their combination carbohydrate, 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 have one by plug (plug) obstruction and/or closed hole (aperture).In some embodiments, the plug is by porous polymer, erodable polymer, pH sensitive polymer Or naturally occurring substance such as shellac is made.In some embodiments, the plug be by selected from water-soluble polymer, it is non-aqueous Soluble polymer, wax class, carbohydrate, gel-like, cellulose family, polyesters, polyethylene oxide class, polyethylene kind, polyacrylic Or combinations thereof material be made.

In some embodiments, pharmaceutical formulation includes the Gas generating components positioned at the first compartment.In some realities It applies 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 their combination can discharge carbon dioxide or sulfur dioxide gas when touching gastric juice 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, which 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, described First compartment and the second compartment are not attached to.

In some embodiments, first drug matrices are identical as 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 plug block the first hole, described second Compartment has second hole blocked by the second plug.In some embodiments, first plug is than the second plug Permeability is high.In some embodiments, first plug is higher than the erosion rate of the second plug.

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 Permeability than second wall is high.In some embodiments, first wall is erodible higher than second wall.

On the other hand, present disclose provides a kind of pharmaceutical formulations, comprising: the two or more layers matrix being stacked 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 of at least one thermoplastic material.

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 drug matrices for being included It is discharged in aqueous solution based on scheduled release profiles.

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

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

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

In some embodiments, the drug matrices are configured to the size for having less than the compartment, so as to It is moved in the compartment.

In some embodiments, described matrix is integrally formed.

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

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

In some embodiments, the loose drug matrices and described matrix are made of identical material, and institute The density for stating loose drug matrices is less than the density of described matrix.

In some embodiments, the compartment is closed.

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

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

In some embodiments, the compartment is configured to the face from the inside cumulative dissolution boundary of the opening Product, so that the active pharmaceutical ingredient when pharmaceutical formulation dissolution in the drug matrices is released with scheduled release profiles It puts.

In some embodiments, the rate of release of the active pharmaceutical ingredient is constant.

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

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

In some embodiments, the plug is configured to dissolution time in aqueous solution and is longer than described matrix most Short dissolution time, so that the active pharmaceutical ingredient in the drug matrices can be after plug dissolution through by described hole It releases.

In some embodiments, multiple drug matrices are accommodated in the compartment, wherein in the multiple drug matrices Contain different active pharmaceutical ingredients respectively.

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

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

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

In some embodiments, the inside of the compartment has slow release layer, is used to be isolated the drug matrices and institute Matrix is stated, so that the slow release layer can delay the drug matrices pharmaceutical active ingredient when pharmaceutical formulation dissolution Release.

In some embodiments, contain Gas generating components in the compartment.

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

In some embodiments, the compartment is hollow.

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

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

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

Another aspect, present disclose provides a kind of pharmaceutical formulations, comprising: matrix, described matrix have on its interior Multiple compartments；And multiple drug matrices, it is accommodated in the multiple compartment.

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

In some embodiments, different active pharmaceutical ingredients is contained in the multiple drug matrices.

In some embodiments, the multiple drug matrices have different length.

In some embodiments, the multiple drug matrices have the area on different dissolution boundaries.

In some embodiments, at least partly compartment in the multiple compartment is closed.

In some embodiments, described matrix has open corresponding at least partly compartment in the multiple 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 inside cumulative dissolution boundary of the opening Product, so that the active pharmaceutical ingredient being open in corresponding drug matrices is released when pharmaceutical formulation dissolution with scheduled Put curve release.

In some embodiments, the rate of release of the active pharmaceutical ingredient is constant.

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

In some embodiments, the opening has different areas.

In some embodiments, different active pharmaceutical ingredients is contained in the multiple drug matrices.

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

In some embodiments, the plug is configured to dissolution time in aqueous solution and is longer than described matrix most Short dissolution time, so that the active pharmaceutical ingredient in the drug matrices can be after plug dissolution through by described hole It releases.

In some embodiments, different plugs is configured to have different dissolution times in aqueous solution, so that The active pharmaceutical ingredient obtained in the multiple drug matrices discharges in different times.

In some embodiments, different plugs has different length.

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

In some embodiments, different gaps has the area on different dissolution boundaries.

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

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

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

In some embodiments, described matrix includes closing off multiple compartments of the multiple compartment, and institute Multiple compartments are stated with different thickness.

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

In another aspect, present disclose provides a kind of pharmaceutical formulations, comprising: multiple drug matrices, wherein each drug matrices It is made respectively of at least one thermoformable material, and the multiple drug matrices are joined together.

In some embodiments, the multiple drug matrices contain different active pharmaceutical ingredients.

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

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

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

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

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

In some embodiments, the adjacent drug matrices in the multiple drug matrices contain different pharmaceutical activity Ingredient.

In some embodiments, the multiple drug matrices have different thickness.

In some embodiments, at least partly drug matrices are made of nano particle in the multiple drug matrices.

In some embodiments, positioned at non-outermost one or more drug matrix of laminated construction by nano particle It constitutes.

Brief Description Of 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 concentration after Fig. 1 C medication.

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

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

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

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

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

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

Fig. 4 C shows a kind of exemplary pharmaceutical formulation, with matrix and positioned at intrinsic silicon different angle every Room；

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

Fig. 4 E shows a kind of exemplary pharmaceutical formulation, with matrix and positioned at multiple compartments of 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 exemplary pharmaceutical formulation containing pie compartment；

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

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

Fig. 8 A shows a kind of exemplary pharmaceutical formulation, with matrix, positioned at intrinsic silicon compartment and be received Drug matrices in the compartment.The drug matrices are configured to network structure.Described matrix in 1-5 minutes by that can dissolve Material be made, and the drug matrices can dissolve in a few seconds；

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

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

Figure 10 A shows a kind of exemplary pharmaceutical formulation, with 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 shows a kind of exemplary pharmaceutical formulation, has several drug matrices encapsulated with refracting films；It is each A matrix is all the mixture of same API and the different base with different solubilities；

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

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

Figure 11 shows the workflow schematic diagram with 3D printer preparation for the API medicament of patient；

Figure 12 A shows a kind of containing there are two types of the exemplary pharmaceutical formulations of drug matrices；

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

Figure 13 A shows a kind of exemplary pharmaceutical formulation, with matrix and positioned at three compartments of intrinsic silicon, often A compartment is mounted with a kind of drug matrices.The release process of every kind of drug is controlled by the solubility of plug；

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

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

Figure 14 B shows a kind of exemplary pharmaceutical formulation, with matrix and positioned at three compartments of 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 have API The mixture constituted with substrate.

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

Figure 15 A shows a kind of containing there are two types of the pharmaceutical formulations of API；

Figure 15 B shows the pharmaceutical formulation of one kind as shown in fig. 15 to the controlled release of two kinds of API；

Figure 16 A shows a kind of exemplary pharmaceutical formulation, with 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 solubility；

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

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

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

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

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

Figure 18 B is a kind of photo of the drug release process of drug；

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

Figure 19 A is shown containing there are two the perspective views of the pharmaceutical formulation of compartment；

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

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

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

Specific embodiment

In the above summary of the invention and detailed description and following following claims and attached drawing, with reference to both in invention Specific features (including method and step).It is to be appreciated that the disclosure of the invention in this specification includes these specific features All possible combinations.For example, when a specific aspect or embodiment of the invention or a concrete right require to disclose one A specific features, within the bounds of possibility, this feature can also be with remaining feature of the invention and embodiments, or entire hair Bright combined use.

The use of " comprising " and its synonym in text means that other components, ingredient, step etc. are also optionally present 's.For example, the object of " comprising " component A, B and a C can be made of (i.e. only by) A, B and C, or also in addition to A, B and C It include more other components.

When with reference to being to be directed to one to include the method for two or more particular steps, particular step can be with any Sequence is executed or is performed simultaneously (unless context clearly eliminates the possibility), and this method include it is one or more its His step, these steps can before any particular step, among or execute later (unless context clearly eliminate this can Energy property).

When being related to a numberical range, it is to be appreciated that each median, to lower limit unit ten/ One unless the context clearly indicates otherwise, between the range bound and in the range it is any remaining refer to Definite value or median, are contained among the disclosure, exclude the limit value in the range of clear stipulaties.When the range packet Containing one or two limit value, the range for eliminating any one or two limit values is still comprised among the disclosure.

" at least " being followed by number shows a range using the number as lower limit (according to the variable of definition, range possibility There are a upper limit or no upper limit).For example, " at least 1 " shows 1 or greater than 1." at most " be followed by number show one to change Number is the range of the upper limit (according to the variable of definition, which may be lower limit with 1 or 0, or not have lower limit).Such as " extremely More 4 " show 4 perhaps less than 4 and " at most 40% " shows 40% or less than 40%.In the disclosure, when a range quilt When being defined as " (the first number) to (the second number) " or " (the first number)-(the second number) ", show under this range Limit is the first number, and the upper limit is the second number.For example, 2 to 10 millimeters of lower limits for showing a range are 2 millimeters, the upper limit is 10 Millimeter.

Succinct for statement, when suitable, reference label is reused in different drawings to show to correspond to Or similar element.In addition, present description provides a large amount of details in order to have to embodiment described herein It understands thoroughly.However, embodiment described herein can also be carried out in the case where lacking these details.In remaining situation Under, method, program and component there is no being disclosed in detail, to avoid the description of fuzzy correlation function.In addition, description herein It shall not be construed as limiting the range of embodiment as described herein.It should be understood that unless otherwise indicated, the disclosure Described in embodiment description and characterization be not mutually exclusive.

Control the pharmaceutical formulation of release

As shown in Figure 1A, conventional solid pharmaceutical formulation, such as flat tablet are to dissolve into active pharmaceutical ingredient or embedding Enter in matrix and is made.Single order drug release patterns (Figure 1B) is presented in existing conventional solid pharmaceutical formulation, wherein the medicine in blood plasma Object level increases sharply upon administration, is then also referred to number decline (Fig. 1 C).The shortcomings that release characteristic be levels of drugs reduce and Caused by therapeutic efficiency decrease or high concentration medicine caused by toxicity.This drug release is unfavorable for blood plasma Chinese medicine The balance of object level.The present invention relates to the oral administration system of a kind of adjustable or controllable release, the system and legacy system It compares, has many advantages, such as to enhance patient compliance, selective pharmacological action, reduces side effect and reduce medicine frequency.Realizing controlled-release It puts and extends administration process, and can be with the blood concentration in the maintenance therapy phase.For example, the application system of zero order delivery profile is presented System (Fig. 1 D) makes the drug of constant dosage, by sustained release, realize the application of homogeneous constant within an extension period Journey.Therefore, antibiotic delivery, hypertension therapeutic, pain management, antidepression delivering and many other Constant plasma drug is required Horizontal situation may be also required to Zero order release feature.

Therefore present disclose provides a kind of stable oral solid medicine dosage forms.In some embodiments, pharmaceutical formulation At least one compartment formed including matrix, in intrinsic silicon and the drug matrices that are loaded in compartment.Pharmaceutical formulation is designed For the active pharmaceutical ingredient in drug matrices can be made to discharge in a controlled fashion.

A. matrix

" matrix " referred herein refers to the structure for including or having drug matrices to be embedded in.The matrix of pharmaceutical formulation can To be any dimensions or shapes for being suitable for taking orally.In some embodiments, matrix be diameter be 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm or 12mm flattened round tablet.In some embodiments, matrix is that size is about The oval tablet of a mm × b mm, wherein the value of a is between 5 to 15, and the value of b is between 2 to 10.In some implementations In mode, matrix is capsule shape.

In some embodiments, matrix is by hydrophilic polymer (for example, hydroxypropyl methyl cellulose (HPMC) and poly- (ethylene oxide) (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 components It constitutes, each component is made of identical or different material.

In some embodiments, matrix is made of thermoplastic material." thermoplastic material " herein refers to can be by adding The material of heat or pressure plasticity.In some embodiments, for example, thermoplastic material can be hydrophilic gel rubber material, The material passes through dispersal events drug matrices；Either hydrophobic material, drug matrices pass through the outside dispersal events in hole on matrix. Polymer, especially 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 Derivative, such as salt, amide or ester are also used as thermoplastic material.It is physiologically recognized and is those skilled in the art Hydrophobic material known to member, such as C12-C30 fatty acid and/or C12-C30 fatty alcohol and/or wax or their mixture Mono- or two glyceride may be used as thermoplastic material.Matrix be also likely to be by hydrophobic material, as hydrophobic polymer, wax, Fat, long chain fatty acids, fatty alcohol or corresponding ester or ether or their mixture are made.

In some embodiments, the thermoformable material is selected from Vinylcaprolactam homopolymer polyvinyl acetate- Polyethyleneglycol-graft copolymer 57/30/13, Kollidon VA64 (PVP-VA), polyethylene pyrrole Pyrrolidone-polyvinyl acetate copolymer (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 copolymer 60/40, polyvinyl alcohol (PVA or PV-OH), polyvinyl acetate ester (PVAc) gather The poly- 2- dimethylaminoethyl methacrylate of butyl methacrylate-- polymethyl methacrylate copolymer 1:2:1, poly- first Base acrylate-polymethacrylate copolymer, the poly- trimethyl of polyethyl acrylate-polymethyl methacrylate- Ethyl vinyl chloride copolymer, the poly- base acrylic copolymer 7:3:1 of polymethyl acrylate-polymethyl methacrylate-, 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, polyethylene oxide (PEO), polyethylene glycol (PEG), hyper-branched polyester, hydroxypropyl Methyl cellulose phthalate ester, hypromellose phthalate, hydroxypropyl methyl cellulose or hypromellose Plain (HMPC), hydroxypropyl methyl cellulose succinate or hydroxypropyl methyl cellulose acetate succinate (HPMCAS) are gathered Lactide-copolymer of poly lactic acid (PLGA), carbomer, polyvinyl-polyvinylacetate copolymer, ethane-acetic acid ethyenyl ester are total Polymers, polyethylene (PE) and polycaprolactone (PCL), hydroxy propyl cellulose (HPC), the castor oil of the hydrogenation of polyoxyethylene 40, first Base cellulose (MC), ethyl cellulose (EC), poloxamer, hydroxypropyl methylcellulose phthalate (HPMCP) moor Lip river Sha Mu, rilanit special, 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.

In some embodiments, pharmaceutical formulation is made by additive method in thermoformable material, such as molten Melt deposition modeling (FDM).In some embodiments, thermoforming material can be squeezed 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 some embodiments, suitable to squeeze Press includes but is not limited to that single or twin (double) screw extruder, extruder temperature is set between 50 DEG C to 180 DEG C and 80 DEG C To between 140 DEG C.Under normal circumstances, 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.Being programmed the printing technology to 3D printer may be implemented to the matrix made of thermoformable material and compartment The control of shape and size.

In some embodiments, the release profiles of drug matrices can be controlled by selection basis material.For example, by Matrix made of specific solubility, permeability or erodible material, can open in a predefined manner after administration compartment and with The rate release drug matrices needed.In some embodiments, matrix is made of corrosion or soluble substance, and drug Active constituent (API) is embedded in or is dissolved in matrix.Active pharmaceutical ingredient is discharged with the corrosion or dissolution of matrix.

The release of drug matrices or active pharmaceutical ingredient can also control by adjusting the thickness of matrix.For example, being formed The matrix of compartment is made of soluble substance.Wall by adjusting the matrix of encirclement compartment can control the opening of compartment to control The release of drug.For example, the wall of compartment is thicker, the opening of compartment is slower, and the release of drug 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 separated, part or room.One compartment is either closed be also possible to Open (i.e. band hole).One compartment can be to load 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 shape of special designing, which makes it possible to, discharges drug matrices with special speed. In some embodiments, compartment shape can be wedge-shaped, 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 Illustrative pharmaceutical formulation is gone out, there is the matrix for forming compartment, accommodate drug matrices 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 inner wall of compartment 102 In compartment 102.Compartment 102 can provide buoyancy for pharmaceutical dosage form 100 to extend it in stomach or liquid environment or acid Residence time in property environment.The solubility of basis material determine pharmaceutical formulation there are the times, and can realize accordingly Sustained release to API as shown in Figure 2 B.

Fig. 3 shows the illustrative pharmaceutical formulation for increasing gut retention time.With reference to Fig. 3, the compartment of pharmaceutical formulation 200 202 include can free-moving second pharmaceutical formulation 203 (for example, tablet) wherein.Stop of the pharmaceutical formulation in stomach and intestine Time is limited.Floating system stops the system under one's belt and on the gastrointestinal tract, and portion discharges drug constantly to most The absorption of bigization small intestine.

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 dissolution boundary of the pie compartment is by close It is inward-facing on the outside of pharmaceutical formulation to be gradually increased, so that the pie compartment is big when the direction according to Fig. 4 A is seen from above Body is fan-shaped.Fig. 4 B shows a kind of exemplary pharmaceutical formulation, and the intrinsic silicon of the pharmaceutical formulation contains with different openings ruler Very little multiple compartments, these compartments are substantially in prism-frustum-shaped.Fig. 4 C shows a kind of exemplary pharmaceutical formulation, the base of the pharmaceutical formulation Contain the compartment of different angle in internal portion.Fig. 4 D shows a kind of exemplary pharmaceutical formulation, contains in the matrix of the pharmaceutical formulation Pie compartment with different radii.

The shape of compartment can be used to the release profiles of control pharmaceutical formulation.For example, R.A.Lipper and W.I.Higuichi just describes a kind of application system that zero order delivery profile may be implemented as shown in Figure 5.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 small opening.The compartment is mounted with Drug matrices, and drug matrices can discharge API by small outward opening circle upon dissolution.The dissolution rate and medicine of drug matrices The area on the dissolution boundary (interface between the drug matrices and compartment space) of object matrix is positively correlated.On the other hand, API exists Dissolution rate and diffusion path length λ in environment is negatively correlated.Thus, with the dissolution of drug matrices, the area for dissolving boundary increases Add, the dissolution rate of drug matrices also will increase.And on the other hand, diffusion path length dissolves also with drug matrices and is increased. So the API being released in compartment needs to be transferred longer distance to be diffused into other than pharmaceutical formulation.It is assumed that the drug agent Type can be designed as meeting zero-order release kinetics that (R.A.Lipper and W.I.Higuchi (1977) apply quasi- zero-order drug The analysis of the theoretical behavior of adding system, drug Scientific Magazine 66 (2): 163-4；D.Brooke and R.J.Washkuhn (1977) Zero-order drug application system: theoretical to be tested with primary, drug Scientific Magazine 66 (2) 159-162).

C. drug matrices

Drug matrices used herein refer to the composition containing one or more active ingredients, wherein active ingredient packet Include active pharmaceutical ingredient (API), cosmetic agent, biological reagent, diagnostic reagent and scientific experiment reagent.

Noun " medicament active composition (API) " as used herein refers to the biologically active composition in drug.One In a little embodiments, API can be selected from the following group: local anesthetic, antiepileptic and anticonvulsive drug, Kang Aercihaimoshi disease Medicine, antalgesic, arthrifuric, antihypertensive, antiarrhymic, diuretics, treatment liver diseases drug, treatment pancreas disease Medicine, antihistamine, antiallergic, glucocorticoid medicine, sex hormone drug and contraceptive, hypoglycemic agent, anti-sclerotin Loose medicine, antibiotic, sulfamido, quinolones and other synthetic antibacterial drugs, anti-tubercular drug, antiviral agent, anti-tumor drug, Immunomodulator, cosmetic active agent, Chinese traditional medicine (TCM) and Traditional Chinese doctors ' medicament extract.

In some embodiments, API can be selected from the group: the sub- oil of (R)-folitixorin, lidocaine, bis--deuterium of 11- Acetoacetic ester, 16- dehydrogenation pregnenolone, 17-β-estradiol, 2- iminobiotin, 3,5- diiodo- thyroid gland acid, the fluoro- 2- of 5- are de- Oxygen cytidine, Ismipur, according to more bent peptides, Abacavir, Bao hemocyanin, abiraterone, Acamprosate, acamprosate calcium, A Ka Wave sugar, aceclidine, Aceclofenac, Guan-fubase A hydrochloric acid, Meng Nan, Aceneuramic Acid, paracetamol, acetylcysteine, Acetyl leucomycin, acetyl-L-carnitine hydrochloride, acetylsalicylic acid, acyclovir, Acipimox, Acitazanolast, AVM hereinafter A, A Di, aclidinium bromide, acolbifene, Acotiamide, Acrivastine, Actarit, Adapalene, Aldoforwe 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 ester, decellularized vascular matrix, not Pregnenolone, Allopurinol, almotriptan, Egelieting, alogliptin benzoate, Alosetron, Alpha's ketoglutaric acid, sulphur are pungent Acid, alpha-cyclodextrin stablize sulforaphen, alprazolam, alprazolam transdermal patch, Alprostadil, Alprostadil frost, pregnancy honey Amine, aluminum sulfate, Aiweimopan, amantadine, amantadine hydrochloride, ambrisentan, ambroxol hydrochloride, amphetamine, amphetamine sulphur Change divinylbenzene, Ah 's pyridine, Ah 's pyridinium phosphate, Amifostine, amikacin, amiloride, glycyl, glycyl Propionic acid, levulic acid hydrochloride, aminopterin, amiodarone, Amisulpride, amitriptyline, Amlexanox, Amlodipine, benzene sulphur Sour Amlodipine, amlodipine camsylate, amlodipine maleate, amlodipine niacin, orotic acid Amlodipine, cream Sour ammonium, amodiaquine, Amorolfine, Lowagan, Amoxicillin, Amoxicillin hydrate, amphetamine, asparatate phenylpropyl alcohol Amine, amphetamine sulfate, amphotericin B, amphotericin B cholesterol sulfate, ampicillin sodium, Ampiroxicam, Amrinone, ammonia are soft Than in star, Amtolmetin Guacil, my Ge Lieting, anagrelide, anamorelin, Anastrozole, An Keluo, androgen, Herba Andrographitis Ester, anecortave, anidulafungin, aniracetam, Anistreplase, peace sieve are safe and reliable for Buddhist nun, Antazoline, antiandrogen, antineoplaston Husky star hydrochloric acid, Android tonquinol, methanesulfonic acid Ah pa replace Buddhist nun, Eliquis, apomorphine, apomorphine hydrochloride, Apremilast, Ah Auspicious pyrrole is smooth, the shore A Lita, Aranidipine, Arbekacin, arbekacin sulfate, Ardeparin Sodium, Afromoterol, argatroban, Aripiprazole, Aripiprazole lauryl, l-modafinil, arsenic trioxide, arsenious acid, Artemether, artemisinol, Artesunate, Asenapine, asimadoline, Astragaloside IV, Ah that Wei, atazanavir, sulfuric acid atazanavir, atenolol, support Moses Spit of fland, Atorvastatin, Atorvastatin calcium, atorvastatin strontium, Atovaquone, atrasentan, atropine, Anranofin, Ah cutting down That non-, AVM hereinafter Batan, AVM hereinafter Batan sodium, aviptadil, Axitinib, azacitidine, cytidine, Azasetron, azelaic acid, nitrogen are tall and erect The husky smooth ester potassium of sting, azelastine hydrochloride, Azelnidipine, Azilsartan, Azilsartan, Azilsartan front three ethylethanolamine, Ah Qi Lite, azithromycin, lactobionic acid azithromycin, aztreonam, aztreonine lysine, A Zifuding, Baclofen, bar fluorine for Buddhist nun, Baicalein, scutelloside, BAK without Latanoprost, Balofloxacin, Balsalazide, Balsalazide sodium, bambuterol, Ba Ruike for Buddhist nun, bar Buddhist nun's Horizon, Bazedoxifene, beclomeasone propionate, beclomethasone dipropionate, bedoradrine, Belotecan, benazepil, phenyl ring quinoline Bromine ammonium, bendamustine, bendamustine hydrochloride, Benidipine, benserazide, benzalkonium chloride, benznidazole, benzocainum, peroxide Change benzoyl, benzydamine hydrochloride, bepotastine, bepotastine calcium dihydrate, salicylic acid bepotastine, beractant, Bei Qian Arrange plain sodium, besifloxacin, Bei Xifuwei, Besipirdine, β-olive alkene, Betahistine, anhydrous betaine, betamethasone, times his rice Loose propionic acid fourth, betamethasone cream, dipropium dipropionate, betamethasone mousse, betamethasone valerate, Betamipron, times his Lip river That, betaxolol hydrochloride, bethanechol, urecholine, betrixaban, bevacizumab, Bexarotene, Bezafibrate, ratio A Peinan, Bicalutamide, bicyclic alcohols, Birid Triple Viable, bilastine, bimatoprost, dermatol, Ecabet, peso Lip river That, bisoprolol fumarate, Bitespiramycin, bleomycin, blonanserin, hydrochloric acid win peace, boceprevir, bortezomib, The auspicious piperazine azoles of Bosentan, Bosentan hydrate, posupini, Bovactant, cloth, Brimonidine, Pai Liming, Brivaracetam, bromine husband Fixed, Bromazepam, Bromfenac, bromfenac sodium, bromocriptine, brotizolam, Bryostatin-1, bucindolol, bucladesine, cloth how Moral, Budipine, buflomedil, Bunazosin, Bupivacaine, bupivacaine HCl, buprenorphine, buprenorphin hydrochloride, Bupropion, BUPROPIONE HCl, Bu Lishafu, buserelin acetate, buspirone, buspirone hydrochloride, busulfan, cloth replace Naphthalene sweet smell, butorphanol tartrate, butylphenyl phthaleine, Cabazitaxel, Cabergoline, malic acid card it is rich for Buddhist nun, cadrofloxacin, caffeine, Caffeine citrate, Calcipotriol, calcitriol, calcium acetate, Calciumlevofolinate, Calcium Levofolinate, calcium polycarbophil, karr method It is smooth, calcium mangafodipir, camostat mesilate, camptothecine, canagliflozin, Candesartan, candesartan Cilexetil, cangrelor, big Fiber crops, capecitabine, capsaicine, captopril, carbamazepine, Carbetocin, carbetocin, carbidopa, carbinoxamine, carboxylic First department is smooth, carboplatin, carbidopa, blocks luxuriant and rich with fragrance such rice cloth, card glutamic acid, Cali's drawing, Carmustine, carteolol, hydrochloric acid card for Lip river That, carumonan, Carvedilol, phosphoric acid Carvedilol, Caspofungin, catechin, Si Dinibu, 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, ceftaroline, 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, chlorohexidene, serine progesterone acetate, chlorogenic acid, chloroquine joint, 7-chloro-4-oxo-quinoline, chlorpheniramine, chlorphenamine maleate, Chlorphenamine, chlorthalidone, Vitamin D3, cholic acid, Choline Glycerophosphate, 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 Hydrochloride, Cisatracurium besilate, suitable Platinum, Citalopram, citalopram hydrobromate, citicoline, citrulling, Cladribine, clarithromycin, potassium clavulanate, gram Clavulanic acid, carat raw smooth, clevidipine, Clevudine, clindamycin, Clindamycin Hydrochloride, clindamycin phosphate, chlorine iodine hydroxyl Quinoline, Clobazam, clobetasol propionate, Clodronate, clofibrate, Clofazimine, clomipramine, clomipramine hydrochloride, Clonazepam, Clonidine, clonidine hydrochloride, clopidogrel, clopidogrel benzene sulfonic acid, bisulfate clopidogrel, clopidogrel camphor, chlorine pyrrole lattice Thunder hydrogen sulfate, clopidogrel napadisilate, resin acid clopidogrel, clotrimazole, Clozapine, cobamamide, Kao Bitaite, can To because, colchicin, cholecalciferol, colesevelam, Colestilan, colforsin dapropate, Colfosceril Palmitate, Acarasiales Plain sodium, conivaptan, in conjunction with estrogen, Copper histidine, 17 α of cortexolone-ethylene propionic acid, cridanimod sodium, gram in the azoles base of a fruit Buddhist nun, Cromoglycic acid, nasmil, cyanocobalamin, match gram lactic acid, cyclobenzaprine hydrochloride, cyclophosphamide, hydration a cyclophosphamide, ring spore Element, cyproterone, cyproterone acetate, cytarabine, cytarabine octadecyl phosphate, dabigatran etcxilate, darafinib, His Wei of Dacca, up to gram for Buddhist nun, Dalbavancin, inhibitor is to reach plug bent, aminopyridine, dalfopristin, Dalteparin Sodium, Danaparoid sodium, reaches That azoles, dantrolene sodium, Da Lushe replace, AstraZeneca, AstraZeneca propylene glycol, Dapiprazole, Dapivirine, Dapoxetine hydrochloride, phenalgin Sulfone, darifenacin, Prezista, Da Sabuwei, Dasatinib, daunorubicin, Decitabine, La Luosi, Deferiprone, methanesulfonic acid Deferoxamine, deflazacort, De Lasha star, Yi Maidi, La Puli, delapril hydrochloride, Delavirdine, Denibulin, deoxidation Andrographolide, dermatan sulfate, desflurane, desipramine hydrochloride, Loratadine, minirin, desmopressin acetate, Desogestrel, desonide, desmethylvenlafaxine, dextromethorphan hydrobromide, Verteporfin, deuterate levodopa, deuterate text daraf(reciprocal of farad) Pungent, dexamethasone, dexamethasone acetate, dexamethasone training ester, dexamethasone palmitate, dexamethasone sodium phosphate, Dexamfetamine, The right piperazine first of dexanabinol, iron-dextrin, dexketoprofen trometamol, Dexlansoprazole, dexmedetomidine, hydrochloric acid Ester, dexrazoxane, Sotalol, dextrorotation sucrose, dextro-amphetamine sulfate, dextromethorphan, dextromethorphan hydrobromide, right third oxygen Sweet smell, diacerein, dianhydrogalactitol, diazepam, diazoxiide choline, Diclofenac, Diclofenac Potassium, C14H10Cl2NNaO2, double chlorine are non- That amine, bicycloplatin, reach promise, the pregnant element of promise, difluprednate, digoxin, linolenic acid, dihydroergocristine, dihydroergotamine, methylsulphur Acid dihydride ergotamine, diltiazem, diltiazem hydrochloride, dimesna, dimethyl fumarate, Dimiracetam, dinoprostone, Diphenyl cyclopropenone, Dipyridamole, sodium pyrophosphate, tobramycin, Shu Fentong sodium, disulfiram, leucoalizarin, methadone, more Kappa amine, Docetaxel, sweet glycol, Dofetilide, Dolasetron, Du Lutewei, domperidone, benzene sulfonic acid Sorafenib, It is donepezil, Doneppezil Hydrochloride, dopamine, doripenem, Dorzolamide, dorzolamide hydrochloride, Dosmalfate, Doxacurium Chloride, more Husky azoles piperazine, Carclura, doxepin hydrochloride, doxercalciferol, doxifluridine, doxofylline, adriamycin, hydrochloric acid Ah mould Element, Doxycycline, Doxycycline Hyclate, doxylamine succinate, Dronabinol, dronedarone, Drospirenone, Droxidopa, D- Tagatose, Duloxetine, duloxetine hydrochloride, dutasteride, Ebastine, Eberconazole, ebselen, Ecabet, nitre Sour Isoconazole determines ecopipam, Edaravone, edoxaban, efavirenz, Chinese mugwort Fluconazole, Eflornithine, hydrochloric acid according to Promised Land Flat, Egualen sodium, eicosapentaenoic acid glyceride dislike La Geli, Chinese mugwort ground ostelin, Elesclomol sodium, eletriptan, Ai Qubo Pa, angstrom for lattice Wei, Enamel Matrix Protein, Emedastine, Yi Palie be net, the life of Enbrel card, emtricitabine, enalapril, maleic acid according to That Puli, enclomifene citric acid, tamoxifen, Enoxacin Gluconate, Enoxaparin Sodium, enprostil, Entacapone, Entecavir, maleic acid Entecavir, grace for Nuo Te, the miscellaneous Shandong amine of grace, Epalrestat, Eperisone, ephedrine sulfate, hydrochloric acid according to Sting, adrenaline, epirubicin, epirubicin hydrochloride, according to pyrrole for Buddhist nun, eplerenone, Epoprostenol, epristeride, she It fills in sieve, eprosartan, eptalatin, Erdosteine, methanesulfonic acid eribulin, Tarceva, ertapenem, erythromycin, stearic acid Erythromycin, erythromycin stinoprate, escitalopram, Chinese mugwort ketamine, ketalar, eslicarbazepine acetate, hydrochloric acid Esmolol, esomeprazole, esomeprazole magnesium, esomeprazole strontium, esomeprazole, estetrol, estradiol, acetic acid are female Glycol, cycloprovera, Estradiol Valerate, Estratest, estradiol, estrogen, eszopiclone, ebutol, Ethaselen, ethinyloestradiol, ethyl fumaric acid calcium monohydrogen phosphate, ethyl fumaric acid magnesium hydroxide, ethyl fumaric acid hydrogen zinc, acetylene female two Alcohol, Etidronic Acid, Etimicin Sulfate, Etizolam, Etodolac, Etonogestrel, Etoposide, etoposide phosphate, according to Support examines former times, etravirine, eupatilin, everolimus, Exemestane, Exenatide, Ezetimibe, Arensm, fluorine bone three Alcohol, famciclovir, famotidine, Fampridine, faropenem, fasoracetam, Fasudil, Fasudic hydrochloride, methylsulphur acid system Relax ground that, Favipiravir, febarbamate, Febuxostat, non-urethane, medicine felbinac, biphenyl ammonia acetate butantriol, non-Lip river Flat, fenfluramine hydrochloride, fenofibrate, fenofibrate, fenoldopam, fenoterol, Suwei A amine, fentanyl, citric acid sweet smell Too Buddhist nun, Fenticonazole, ironic citrate, maltol iron, fumaric acid Fei Suoluo, Fexinidazole, fexofenadine, Fibrin Glue, Fibrinogen, fibrinogen matrix patch, feldamycin, Fimasartan, finafloxacin, hydrochloric acid finafloxacin, it is non-that Male amine, fingomode, Flecainide, fleraxacin, flibanserin, Flomoxef, floxuridine, Fluconazole, fludarabine, fluorine Ma Xi Buddhist nun, flunisolide, fluocinolone acetonide, Fluocinonide, fluorouracil, Prozac, Fluoxetine hydrochloride, Flupirtine, Flurbiprofen, fluorine ratio Ibuprofen ester, flurbiprofen sodium, Flurithromycin, fluticasone, fluticasone furoate, fluticasone furoate, fluticasone propionate, fluorine Bent horse azoles, Fluvastatin, Fluvoxamine, folic acid, folinic acid, Fomepizole, Fondaparinux sodium, formestane, Formoterol, fumaric acid Formoterol, Forodesine, Fosamprenavir, fosaprepitant, fosfluconazole, phosphonomycin, phosphonomycin disodium, fosfomycin amine fourth three Alcohol, fosinopril, fosinopril sodium, fosmidomycin, Fosphenytoin, phosphorus propofol, Fotemustine, SB 209509, furan quinoline for Buddhist nun, Fudosteine, fulvestrant, frusemide, Fusidic Acid, Gabapentin, Gabapentin En Naka ratio, gabexate mesilate, gadolinium cloth Alcohol, galanthamine, gallium nitrate, gambogicacid, ganaxolone, Ganciclovir, ganirelix acetate, T-3811, adds Gadoversetamide For husky star, gatifloxacin in human, Gefitinib, gemcitabine, gemcitabine hydrochloride, Gemfibrozil, gemifloxacin, dyewood Flavones, gentamicin, gentiamarin, Gepirone, gestodene, gestrinone, timolol maleate, Gimeracil, ginseng Saponin(e, acetic acid copaxone, glibenclamide, gliclazide, Glimepiride, Glipizide, glufosfamide, glutamine, glycerol Benzene, Ge Long, glycopyrronium bromide, methanesulfonic acid glycopyrronium, glycyrrhizic acid, Ge Luomode, Ge Gelieting, Granisetron, Granisetron Hydrochloride, Gualfenesin, Guaimesal, guanfacine, hydrochloric acid Gusperimus, haemophilus influenzae, halobetasol propionate, halofantrine, halogen rice Pine, Sodium Hyaluronate, haematoporphyrin, Heme Arginate, heparin, He Birong, hydroxyethyl starch, Higenamine hydrochloride, disalt Sour histamine, huperzine, Sodium Hyaluronate, hydralazine, hydrochloric acid, Hydrochioro, hydrocodone, hydrocodone tartrate, hydrogenation can Pine, Hydromorphone, dihydromorphinone hydrochloride, Hydromorphone medicine, hydroxocobalamine, hydroxycarbamide element, hydroxychloroquine, hydroxyprogesterone caproate, hydroxyl Base carthamus tinctorius yellow colour A, hypericin, ibandronate, ibandronic acid, Ibodutant, according to Shandong for Buddhist nun, Ibudilast, brufen, Ibutilide, Ibolite fumarate, Herba Epimedii, Ai Lapulin, eicosapentaenoic acid, ethyl eicosapentaenoic acid, 20 carbon Pentaene acetoacetic ester, hydrochloric acid Conmana, Idebenone, iodoxuridine, ifetroban, ifetroban sodium, Ailamode, Iprazole, Iloperidone, iloprost, Imatinib, imatinib mesylate, imidafenacin, Imidapril, imidazole salicylate, imines Train south, imiquimod, imrecoxib, Incadronic Acid, datro, maleic acid datro, indapamide, Indeloxazine, indenes That Wei, indisetron, Indomethacin, indoramin, inecalcitol, ingenol methyl butene acid esters, inosine, Ai Dikang Azoles, ipragliflozin, ipratropium, Ipratropium Bromide, iptakalim hydrochloride, Irbesartan, Irinotecan, irinotecan hydrochloride, Irinotecan Sucrosofate, Yi Luofufen, ferric succinate albumen, maleic acid Yi Suolading, Isoflurane, isoniazid, Unoprostone Isopropyl ester, isosorbidi dinitras, different stevia rebaudianum, isotretinoin, isradipine, istradefylline, Itopride Hydrochloride, Itraconazole, Ivabradine sulfate Hemisulphate, hydrochloric acid Ivabradine, ivermectin, VEGF Trap IVT, Ipsapirone, kassinin kinin release Enzyme, ketamine, ketanserin, ketoconazole, Ketoprofen, ketorolac, ketorolac tromethamine, Ketotifen, methanesulfonic acid Kukoamine B, lacidipine, clarke amide, lactitol, Laflunimus, Lafutidine, Lamivudine, Lamotrigine, Landiolol, hydrochloric acid Landiolol, that Ni Na meter Wei caprylate, lanoconazole, Lansoprazole, lanthanum carbonate, Lapatinib, laquinimod, drag-line former times Sweet smell, Latanoprost, Lei Dipawei, leflunomide, lenalidomide, lentinan, sulfuric acid lentinan, Lercanidipine, come it is general Found peaceful potassium, Letrozole, leucine, leuprorelin acetate, Levalbuterol, albuterol hydrochloride, levamisol, left-handed Amlodipine, Levamlodipine besylate, maleic acid levo amido chloro diping, Levetiracetam, levobupivacaine, Zuo Kaba Sting, levocabastine hydrochloride, levocarnitine, levocetirizine, levodopa, lavo-ofloxacin, left-handed 18- methyl alkynes promise Ketone, Levonorgestrel, levonorgestrel oxime butyric acid, left-handed benzene ring nonyl ester, l-ornidazole, Levosimendan, L- paddy ammonia Amide, lidocaine, Ligustrazine Hydrochloride, limaprost, BI 1356, Linezolid, liothyronine, Cyronine, rouge Teichoic acid, Liranaftate, lisinopril, theophylline, maleic acid hydrogen lisuride, lithium citrate, lithium succinic acid, lobaplatin, Luo Dina Non- carbonic ester, lofexidine, Lomefloxacin, Lomerizine, double lomerizine hydrochlorides, Lonidamine, Lopinavir, Loratadine Piece, Lorazepam, L-Orn ASPARTIC ACID, Lornoxicam, Losartan, Losartan Potassium, Loteprednol, Lovastatin, Loxapine succinate, loxoprofen, levo-praziquantel, lumiracoxib, the aspirin of lysine, mafenide, magnesium carbonate, Magnesium isoglycyrrhetate, mangafodipir, Manidipine, Manidipine dihydrochloride, mannitol, Maraviroc, maribavir, Marseille are replaced Buddhist nun, mebendazole, mustargen, Mecobalamin, megestrol acetate, megestrol acetate, Meloxicam, Memantine hydrochloride, Memantine hydrochloride hydrochloric acid Salt, Memantine sodium sulfite, Menatetrenone, mepacrine, atabrine, mequinol, mercaptamine, mercaptamine hydrogen tartrate Salt, mercaptamine hydrochloride, mercaptopurine, Meropenem, mesalazine, Mei Takawei, metadoxine, analgin, metaxalone, wheat Angle benzyl ester, melbine, Metformin hydrochloride, methadone, methadone hydrochloride, methazolamide, methotrexate, methoxyflurane, first Base valerate hydrochlorate, methyl naltrexone bromine, methyl naltrexone, methylphenidate, methylphenidylacetate hydrochloride, 6- first prednisolone, Methylprednisolone aceponate, methylenum careuleum, methyltyrosine, Metoclopramide, metroprolol succinate, metoprolol, metronidazole, first pyrrole Ketone, mexiletine, mibefradil, Miconazole, miconazole nitrate, midazolam, midazolam hydrochloride, midodrine, midostaurin, Rice lumbering peptide, mifepristone, Miglitol, Milnacipran, milrinone, Miltefosine, Minaprine, minocycline, minot ring Plain hydrochloride, minodronic acid, minoxidil, Mirabegron, Miboplatin hydrate, meter Luo Nafei, meter Luo Nafei hydrochloride, rice nitrogen Flat, Misoprostol, Mitiglinide, mitomycin, mitoxantrone, mitoxantrone hydrochloride, mivotilate, Mizolastine, miaow Azoles founds guest, Moclobemide, modafinil, Doxycycline, Modipafant, Moexipril, not fragrant azoles acid, morpholine hydrochloride ketone, furancarboxylic acid Mometasone, furancarboxylic acid not rice, ammonium glycyrrhizinate, monobenzone, luminol, monoterpene perilla alcohol, montelukast, Montelukast Sodium, illiteracy De- stone, Moracizine, tigecycline, morpholine nitre azoles, morphine, morphine gluconate aldehydic acid, the morphine of Pitavastatin, morphine sulfate, Mosapride, Moxidectin, Moxifloxacin, moxifloxacin hydrochloride, moxonidine, moxonidine hydrochloride, mozavaptan, not Luo Xing, mycophenolate, myristyl alcohol nicotinate, nabilone, Nabumetone, N-acetylcystein, Nadifloxacin, Na Duoluo That, Nadroparin Calcium, naftifine hydrochloride, naftifine hydrochloride gel, naftopidil, Nalbuphine, Nalbuphine decanedioic acid, furan of receiving are drawn Coffee, nalmefene hydrochloride, naloxol ether, naloxone, naloxone hydrochloride, naltrexone, Naltrexone Hydrochloride, abolon, naphazoline, Naphthols quinoline, naproxen, naproxen sodium, naratriptan, Nasaruplase, Nateglinide, Nebivolol, Nedaplatin, nedocromil, how Draw shore, Nai Feinawei, Nemonapride, nemonoxacin, neoandrographolide, Neosaxitonin, methyl-sulfuric acid neostigmine, Nai Patan Spy, nepafenac, nepicastat, Ni La, linatinib, Neridronic Acid, Netilmicin, Netupitant, nevirapine, niacin, Nicardipine, Nicergoline, nicorandil, nicotiflorin, nicotine, niacin, 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin, nifedipine, Nifekalant, Buddhist nun are non- Wei Luo, nifurtimox, Nifurzide, Nikemycin, nilotinib, Ni Lute meter, Nilvadipine, aulin, Nimodipine, Quinoline nitre azoles, Nisoldipine, Nitazoxanide, nitisinone, nitrendipine, nitric oxide, nitroglycerin, nitroglycerine, Buddhist nun prick and replace Fourth, nolatrexed, nomegestrol acetate, norelgestromine, norepinephrine, norethindrone, norethindrone acetate, norethindrone enanthic acid Salt, norethindrone, norethindrone acetate, Norfloxacin, norgestimate, shellfish cholic acid difficult to understand, Octenidine, amber octahydro acridine, Octreotide, Austria Bent peptide hydrochloride, Ofloxacin, Olanzapine, olaparib, agile west, Olmesartan, olmesartan medoxomil, datro, salt difficult to understand Sour Ao Dateluo, olopatadine, Olopatadine hydrochloride, Olprinone, Olsalazine, Oltipraz, homoharringtonine, Ao Ge Arrange spit of fland, Omeprazole, Omoconazole, Onapristone, Ondansetron, difficult to understand piperazine, methylphenidate, Ao Shengle Saite, oritavancin, Orlistat, ornithine phenylacetic acid, ornoprostil, Oseltamivir, ospemifene, Oteracil Potassium, oxaliplatin, oxalyl second Acid, oxandrolone, Oxazepam, Oxcarbazepine, oxfendazole, oxidized form of glutathione sodium, Oxiracetam, oxybutynin, hydrochloric acid Oxybutynin, Oxycodone, oxycodone hydrochloride, oxymetazoline, oxymetazoline hydrochloride, Oxymorphone, oxytocins, sodium ozagrel, Ozagrel hydrochloride, sodium ozagrel, Ao Zesha star, taxol, taxol polyglutamic acid, 9-hydroxy-risperidone, palmitinic acid Pa Lipei Ketone, palmidrol, palonosetron, Paro cut down spit of fland, Pamidronate Disodium, pancreatic lipase, Panipenem, pabishta, Pan Tuola Azoles, paracetamol, SC 69124, paricalcitol, Pa Liruiwei, Parnaparin Sodium, Paro lattice column, paromomycin, Paro Xi Ting, paroxetine hydrochloride hemihydrate close object, methanesulfonic acid Paxil, pa native dragon, pazopanib, Pazufloxacin, methanesulfonic acid Pazufloxacin, Pegylation rouge is white, pelubiprofen, pemetrexed disodium, Pemirolast, Pemirolast Potassiu, Pemirolast sodium, Penciclovir, long support be peaceful, pentamidine, calcium trisodium pentetate, Pentetic Acid zinc sodium, pentylenetetrazol, pentosan sodium sulphate, Pentostatin, oneself Ketone theobromine, Peramivir, pyrrole Lun Panai, thioacetazone, perflenapent, perfluoro capryl bromination ammonium, pergolide, perhexiline horse Come, perifosine, Perindopril, perindopril arginine, Perospirone, phenchlobenpyrrone, phenyl-ethyl isothiocyanate, hydrochloric acid phenol benzyl Bright, Phentermine, Topiramate, wilpo, phentolamine mesilate, phenylbutyrate sodium, neo-synephrine, hydrochloric acid deoxygenate kidney Upper parathyrine, neo-synephrine bolt, phenytoinum naticum, phosphatidyl choline and acetylsalicylic acid, Sapylin, picroliv, podophyllotoxin Element, Pidotimod, pilocarpinum, pilocarpinum hydrochloride, Pilsicainide, piperazine Ma Selin, Elidel, Pimobendan, pine Belong to element, Pioglitazone, PIOGITAZONE HYDROCHLORIDE, pipamperone, Pipecuronium Bromide, Piperacillin, avocin, piperaquine, phosphoric acid Piperaquine, piperidine hydrochloride ketone, piperine, Piracetam, pirarubicin, pirfenidone, Pirmenol, piperazine sieve for Buddhist nun, piroxicam, Cut down statin, Pitavastatin Calcium, pixantrone, Pulekang Buddhist nun, Pu Kenali, Plerixafor, podofilox, L-Car-Zn, polyphenyl third Raw 20 Carmustine, polydatin, pomalidomide, pa are received for Buddhist nun, Porfimer Sodium, posaconazole, saleratus, citric acid Potassium, potassium clavulanate, para De Fuwei, Pu Defuwei, aminopterin, Pramipexole, pramiracetam, pranlukast, Pu Lusi Special hydrate, prasugrel, Pravastatin, prazosin, prednimustine, prednisolone, Econopred, sprinkles Prasterone Ni Songlong sodium phosphate, prednisone, Pregabalin, Premelle, prilocaine, Procaterol Hydrochloride, prochlorperazine, the third chlorine of maleic acid Draw piperazine, progesterone, progestational hormone, progestational hormone Dienogest, chloroguanide, fenazil, Propafenone, Propagermanium, propofol, Propranolol, Propranolol Hydrochloride, Prostat, proxodolol, Pu Luka, prulifloxacin, Prussian blue, pseudoephedrine, hydrochloric acid False path The general quinoline of alkali, Puerarin, methanesulfonic acid for Buddhist nun, pyrazinamide, hydrochloric acid pyridoxamine, puridoxine hydrochloride, pyrimethamine, Pyronaridine, Malaridine, Quazepam, quetiapine fumarate, kui gentle ziprasidone, hydrochloric acid quinoline Gao Lai, quinapril hydrochloride, quinidine sulfate, quinine sulfate, Kui slave are general Fourth, Kui are miscellaneous to replace Buddhist nun, Raloxifene, Lei Luoxifen, Na Luoxi for Buddhist nun, Rabeprazole, RABEPRAZOLE SODIUM, racecadotril, drawing more Fragrant, drawing is for drawing Wei, Raltitrexed, Leimaquban, Ramelteon, Ramipril, Ramosetron, ranitidine, bismuth citrate thunder Buddhist nun replaces fourth, ranolazine, Rasagiline, Rebamipide, Reboxetine, reboxetine mesylate, brufen, naproxen, the grand bromine of lattice It is ammonium, Diclofenac, mebendazole, progesterone, ulcerlmin, zoledronic acid, Rui Gefeini, Remifentanil, remifentanil hydrochloride, auspicious Ge Lienai, Repirinast, amlexanox, chlorcyclizine hydrochloride, Bucillamine, guanabenz, mazindol, 5-(4-chlorophenyl)-2,5-dihydro-3H-imadazo[2,1-a, naltrexone, Nitisinone, Ondansetron, retigabine, Rosiglitazone, phenylbutyrate sodium, resin toxin, Resiquimod, resveratrol, Rui Ge Spit of fland, Retapamulin, Retapamulin, retigabine, vitamin A acid, Revaprazan, Reviparin Sodium, Rhein, rhenium -186 are arranged according to for phosphine Sour sodium, Ribavirin, Mycobutin, rifampin, rifamycin, Rifapentine, rifaximin, Rui Lapa, rilpivirine, salt Sour rilpivirine, Riluzole, rimantadine, Rimexolone, auspicious department's melon spy, the western croak hydrochloride of Leo, risedronate sodium, Li Pei Ketone, Ritonavir, razaxaban, Rivastigmine, rizatriptan, Lizakuputan benzoate, roflumilast, rokitamycin, Roller pyrrole is smooth, Romurtide, Ropinirole, ropinirole hydrochloride, Ropivacaine, Rose Bengal Sodium, Rosiglitazone, maleic acid Roger column Ketone, Rosiglitazone sodium, rosuvastatin, rosuvastatin calcium, rotigotine, roxithromycin, rubitecan, rufinamide, reed Flucloxacillin, Rupatadine, Luso benefit are for Buddhist nun, l-ornidazole disodium hydrogen phosphate, Sha Kubi song, sorbamide, salbutamol, husky butylamine Alcohol like Sha's breathing, salbutamol sulfate, salicylic acid, salmeterol, SALMETEROL XINAFOATE, Salvicine, samariumlexidronam, 3- formamide -4- hydroxyl Naltrexone, S- amlodipine niacin, Sapropterin, Sapropterin dihydrochloride, sand Kui Nawei, saracatinib, sarpogrelate hydrochloride, saxagliptin, hyoscine, scorpion venom, seal oil omega-3 polyunsaturated fatty acids, Secnidazole, selegiline, SelegilineHydrochloride, department's beauty replace Buddhist nun, Seratrodast, seratrodast, Celiprolol Hydrochorid, She Takang Azoles gives up his nitrate, Sertindole, Sertraline, sertraline hydrochloride, sesquiterpene, 2-Propen-1-amine polymer with(chloromethyl)oxirane carbonate, sevelamer hydrochloride, seven Fluorine ether, maleic acid sibutramine, methanesulfonic acid sibutramine, silaenafil, sildenafil citrate, (R)-5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzensulfonamide, sulphadiazine The general Wei of silver salt, sago, hydrochloric acid west do not replace Buddhist nun, Simvastatin, hinotec, Xin Bomode, sirolimus, sitafloxacin, west he Arrange spit of fland, sitagliptin phosphate, sivelestat, sizofiran, Sizofiran, Sizofiran, smilonin, S- modafinil, Suo Bu Help life, Sodium Aescinate, sodium ascorbate, sodium benzoate, sodium bicarbonate, nasmil, glycididazole sodium, Sodium Gualenate, saturating Bright matter acid sodium, ibandronate, sodium nitrate, sodium nitrite, sodium hydroxybutyrate, sodium phenylacetate, phenylbutyrate sodium, sodium sulfuric acid pula testis Ketone, Sodium Pyruvate, natrium taurocholicum, sodium thiosulfate, hypo, Sodium Thiosulfate, sodium zirconium cyclosilicate, Suo Feibuwei, Suo Li That new, soluble ferric pyrophosphate citric acid, soluble guanylate cyclase stimulation, sophocarpine, hydrochloric acid Sophoridine, Sorafenib, D-sorbite, Sparfloxacin, Spirapril, antisterone, squalamine, stannsoporfin, stavudine, S-tenatoprazole, Stepronin, Stiripentol, streptozotocin, malonic acid strontium, strontium ranelate, succinic acid, ulcerlmin, sucrose gel, sufentanil, Shu Talan Zinc, the more glucose that relaxes, Sulbactam, sulbactam, Schuqindin sulfate, sulfamethoxazole, salicylazosulfapyridine, Suo Fan replace Buddhist nun, sulphur Ureas, sulforaphen, sodium tanshinon Ⅱa silate, sulindac, Sulodexide, sulfamethoxazole, sulthiam, sumatriptan, Sumatriptan succinate, Sutent, sunstone, Suplatast Tosilate, naganol, verapamil hydrochloride, rilpivirine, his cassie Alcohol, Tachocomb, Tacrine, tacrolimus, Tadalafei, Lonazolac, tafenoquine, tafluprost, talaporfin, he benefit Ke Suo, Taltirelin, Tamibarotene, tamoxifen, Tamsulosin, tamsulosin hydrochloride, Tandospirone, tanespimycin, he Spray his more, Ta Linaxin, Ta Simeiqiong, his quinoline not moral, tazarotene, Tazobactam Sodium, sodium-tazobactam, L-084, spy Kao Weirui, tectorigenin sodium sulfonate, Tedisamil, phosphoric acid safe ground azoles amine, tegafur, tegaserod, teicoplanin, special drawing Wei, Telatinib, Sebivo, thyrite, Telmisartan, Temocapril, m-THPC, Temoporfin, Temozolomide, Xi Luomo Department, teneligliptin, tenofovir, tenofovir Chinese mugwort draw phenol amine, tenofovir aspartic acid, tenofovir disoproxil fumarate, replace promise Former times health, Teprenone, Terazosin, Terbinafine, terbinafine HCl, Terguride, teriflunomide, Te Suofenxin, testosterone, Testosterone undecanoate, butylbenzene, Ding Ka, tetracaine hydrochloride, quadracycline, tetrathiomolybdate, Tetryzoline, nyson (tetryzoline), sand Sharp degree amine, Thenorphine Hydrochloride, thio-tepa, fibrin ferment, fibrin ferment micro-capsule, thyroxine, Tiagabine, Nai Puting, replaces suddenly theophylline Dragon, Ticagrelor, ticlopidine, tigecycline, Tiludronic Acid disodium, timolol, timolol maleate, Tinidazole, sulphur Metronidazole, tinzaparin sodium, tioconazole, Tiopronin, Tiotropium Bromide, tiotropium bromide monohydrate, tipepidine, extra large benzoic acid replace Training pyridine, mention training it is fixed, for pyrrole method Buddhist nun, tipranavir, Tirapazamine, Tiritazad, tirofiban, tirofiban hydrochloride, oka Xiping, tirofiban hydrochloride, Tizanidine, tobramycin, tocofersolan, vitamin A acid dimension E ester, dimension A fertility alcohol ester, support method are replaced Buddhist nun, tofogliflozin, Tolcapone, tolimidone, Tolperisone, Tolterodine, Tolterodine tartrate, tolvaptan, Tuo Nabosha, Topiramate, Topiroxostat, topotecan, topotecan hydrochloride, Torasemide, Toremifene, Tuo Sheduote, tosufloxacin, support Spy mother Bo Page choline, tributidine, C16H25NO2, tramadol hydrochloride, Trimetinib, Trandolapril, tranexamic acid, Qu Nisi Spy, chlorhydric acid tranditerol, travoprost, Trazodone, trehalose, song Ge Lieting succinate, treosulfan, treprostinil, Treprostinil ethanol amine, vitamin A acid, Triamcinolone acetonide, triazolam, trichloromethiazide, triciribine, Triclabendazole, triclocarban, Syprine Hydrochloride, trifluorothymidine, triflusal, three enanthic acid glycerolipid, Trilostane, Trimebutine 3- thiocarbamoyl- Benzene, toluenesulfonic acid Trimebutine, Trimegestone, trimethoprim, Trimetrexate, trisnitrate, Colloidal Bismuth Subcitrate, tropoyl Amine, Tropisetron, trospium chloride, trovafloxacin, troxipide, Tulobuterol, safe happy Horizon, ubenimex, ubidecarenone, crow Ground that non-, excellent that non-, ulinastatin of ground, Ulipristal, Ulobetasol, uracil, Urapidil, three acetic acid uridines, urine polyacid Peptide, ursodesoxycholic acid, ursolic acid, Valaciclovir, valaciclovir hydrochlordide, valdecoxib, valganciclovir, valproic acid, penta soft ratio Star, Valsartan, half pentahydrate tertiary sodium phosphate of Valsartan, vancomycin, vancomycin hydrochloride, Vande Thani, Vanoxerine, salt Sour Vardenafil, varenicline, dimension department bent lattice, Wei Luofeini, Venlafaxine, VENLAFAXINE HCL, Verapamil, hydrochloric acid Wella Pa rice, phenol auspicious net, Vernakalant, vernakalant hydrochloride, Verteporfin, Vesnarinone, Wei Sinali ketone, Vesnarinone, dimension card Gray, sabril, Vilantro, vilazodone, vildagliptin, vincristine sulphate, vinflunine, vinorelbine, Changchun Xi Ting, vismodegib, vitamine E nicotinate, vitamin E, voglibose, Vonoprazan fumarate, Wella pa Sha, Fu Likang Azoles, Vorinostat, Vortioxetine, hydrobromic acid Vortioxetine, warfarin, xemilofiban, meter Luo Feiban, Yi meter Ta Wei, excellent gram That non-, zafirlukast, zalcitabine, Zaleplon, Zaltoprofen, zanamivir, Zidovudine, retrovir, zidovudine, Zileuton, zinc acetate, Zinostatin stimalamer, Ziprasidone, zofenopril calcium, left Fen Puli, zoledronate disodium, azoles carry out phosphine Acid, Zomitriptan, zolpidem, Zolpidemtar Trate, Zonisamide, zopiclone, Zotepine, zucapsaicin, Zuclopenthixol.

In some embodiments, traditional Chinese medicine is selected from sunset abelmoschus flower, Canton love-pea vine, lotus pockmarks, five power mouth skins, thorn five Add, wilsonii leaching descendants, luxuriant grass, radix achyranthis bidentatae, fohum aconiti kusnezoffii, wild aconite root, radix aconiti agrestis, monkshood, aconiti preparata,radix, monkshood, Rhizoma Acori Calami, rhizoma acori graminei, south The root of straight ladybell, appearance Luo Zi, long-nosed pit viper, hairyvein agrimony, stick skin, carpet bugle, caulis akebiae, Akebia Fruit, cortex albiziae, Flos Albiziae, pool weldering, lotus is white, garlic, Semen allii tuberosi, aloe, grass beans are slightd, galangal, intelligence development, Bai Subcommittee-to, beans are slightd, fructus amomi, it is white hereby, Herba Andrographitis, andrographolide, rhizoma anemarrhenae, two Head point, the root of Dahurain angelica, Radix Angelicae Pubescentis, Radix Angelicae Sinensis, octagonal bacterium perfume, Folium Apocyni Veneti, agalloch eaglewood, blood clam, ox base of a fruit, bicolor, ardisia japonica, big abdomen Skin, the township Jiao Mo, mould willow, arisaema cum bile, Rhizoma Arisaematis (processed), rhizoma arisaematis, horse study carefully bell, herba aristolochiae, semen armeniacae amarae, Asian puccoon, green high, folium artemisiae argyi, mattress Old, asarum, asiatic moonseed extract, Ah limb, asparagus fern, aspongopus, aster, semen astragali complanati, process yellow seedling, Huang Miao, Rhizoma Atractylodis Macrocephalae, rhizoma atractylodis, radix aucklandiae, Product is real, product shell, before bamboo, tabasheer, rhizoma et Radix Baphicacanthis Cusiae, blackberry lily, grass before stream leaching descendants, top before medicinal extract, top before top, waxgourd peel, styrax, Barberry, purple bergenia herb, Bergenin, adder-wort, bletilla, the rhizoma bolbostemmae, stiff perfume, borneol (borneolum syntheticum), natural borneol (dextrorotation dragon Brain), calculus bovis factitius, In vitro cultured Calculus Bovis, cow-bezoar, lamp use up florigen, stifled real son, Java brucea, cornu bubali, butterflybush flower, gallbladder revive, money It is agkistrodon, radix bupleuri, calamine, callicarpa kwangtungensis Chun, folium callicarpae pedunculatae, bigleafbeautyberry root or leaf, calomel mercurous chloride, Chinese trumpet creeper, Chinese olive, sword bean, fructus cannabis, peppery Green pepper, Nan Hefeng, crane wind, safflower, cloves, Fructus Caryophylli, cassia seed, castor oil, catechu, cockscomb, seed of feather cockscomb, asiatic centella total be bitter, Centella, crane do not eat grass, worm it is white gambling, bee arrange, cornu cerve degelatinatum, deer mythical bird like the phoenix, deer horn, deer horn glue, pawpaw, Radix changii, FRUCTUS TERMINALIAE IMMATURUS, river son, Greater celandine, danggui extract, danggui liujin gao, green commonplace stone, wide rate, chrysanthemum, wild chrysanthemum, river be curved, rhizoma cibotii, bee are de-, chrysanthemum official, cimicifugae foetidae, cinnabar, cortex cinnamomi, It is ramulus cinnamomi, cinnamon oil, small jasmine, big jasmine charcoal, big jasmine, Common Cissampelos Herb (the raw rattan of tin), meat ash Rong, Exocarpium Citri Rubrum, fragrant rubber, Exocarpium Citri Grandis, green peel, old Skin, tangerine seed, fingered citron, caulis clematidis armandii, the root of Chinese clematis, clinopodium polycephalum, frutus cnidii, Radix Codonopsis, adlay, first bird plantar grass, conyza blinii, the coptis, winter Worm summer grass, rainbow conk, mountain Lay cornel, corydlis bungeana, decumbent corydalis tuber, rhizoma corydalis (corydalis tuber), mountain plant leaf, hawthorn, edible tulip, carbonized hair, west It is safflower, crotons, defatted croton seed powder, thizoma curculiginis, turmeric, Radix Curcumae, curcuma zedoary, mil, radix cyathulae, HuanweihuangyangxingD, radix cynanchi atrati, paniculate swallowwort, white Before, cynomorium songaricum, rhizoma cyperi, daurian rhododendron oil, dalbergia wood, datura flower, stone tiltedly, iron sheet stone tiltedly, it is lepidium seed, Desmodium styracifolium, beautiful wheat, Changshan, white Fresh hide, Dioscorea Panthcica, powder leather Soviet Union, rhizoma dioscoreae nipponicae, Chinese yam, continuous leather Soviet Union, teasel root, dragon's blood, the rhizome of davallia, thick wood-fern rhizome charcoal, thick wood-fern rhizome, Yu State Radix Rhapontici seu Radix Echinopsis, eclipta, plant vine, red gentian, Chinese ephedra, radix ephedrae, Herba Epimedii, E. wushanense T. S. Ying, scouring rush, lamp use up asarum (lamp Flower to the greatest extent), batch leaf, pipewort, heroubill, erycibe obtusifolia benth, eucalyptus oil, Cortex Eucommiae, folium cortex eucommiae, Wu Laihuang, eupatorium, eupatorium lindleynun var. trifoliolatum, radix euphorbiae lantu, winged Raise grass, Herba Euphorbiae Humifusae, Beijing spurge root, defatted MOLEPLANT SEED, semen euphorbiae, the whole worm (hut worm) of soil, prominent reality, cymose buckwheat rhizome, tussilago, asafoetide, herba fibraureae recisae, Fibrauretine, amethyst, small mattress perfume, fructus forsythiae, the bark of ash, bulbus fritillariae cirrhosae, Hupeh Fritillary Bulb, Siberian fritillary bulb, fritillaria thunbergii, fritillary bulb, red bean slight, five Gall nut, endothelium corneum gigeriae galli, ganoderma lucidum, capillary extract, coke grip son, grip son, Rhizoma Gastrodiae, clam break, aleppo avens, small-leaf bonesetting, lilac daphne, Qin Chong, dragon Gallbladder, ginger stream leaching descendants, ginkgo leaf, ginkgo biloba p.e, gingko, folium panacis japonici cum caule, red ginseng, ginseng, Glabrous Sarcandra Herb medicinal extract, Longtube Ground Ivy Herb, pig tooth It is abundant, big Fu Jiao, Fu Jiao thorn, Radix Glehniae, radix glycyrrhizae preparata, Radix Glycyrrhizae, common bombax flower, granatum, Shi Yi, forging stone descendants, ochre, the shell of seaear, big Green salt, red stone moon purport, mountain plant leaf extract, the red seedling of moxibustion, red seedling, cottonrose hibiscus leaf, hippocampus, sea-buckthorn, rhizoma homalonemae, malt, fish it is swollen It is grass, rouge and powder, henbane seed, Herba Hyperici Monogyni, Chinese holly, holly leaf, iron holly bark, anisetree bark, the seed of garden balsam, rhizoma imperatae, indigo naturalis, sheathed Flower, gold boiling grass, elecampane, Rhizoma Belamcandae, folium isatidis, Radix Isatidis, walnut kernel, big rate, rush, desert Caulis Spatholobi, mountain abandoning, the calyx and receptacle of a persimmon, The luxuriant son of the root of gansui, Knoxia valerianoide, the fruit of summer cypress, Semen Lablab Album, Wingedtooth Laggera Herb, Hong Lian, thallus laminariae, lamiophlomis rotata, Lasiosphaera fenzlii, constitution, motherwort, motherwort Stream leaching descendants, extract of licorice root, Radix Glycyrrhizae stream leaching educate, rhizoma ligustici, the fruit of glossy privet, lily, aetite, the root of three-nerved spicebush, linseed, Fructus Liquidambaris, hold face cream, Radix Liriopes, cladoptosis core, leather it is clear before, lobelia chinensis, arillus longan, Honeysuckle flower, caulis lonicerae, honeysuckle, lophatherum gracile, luffa, the root bark of Chinese wolf-berry, Chinese holly offer sacriffices to the gods or the spirits of the dead son, Herba Lycopi, lycopodium calvatum, Lygodium japonicum, herba lysimachiae, lysiontus pauciflorus ,/- L-Borneol (L-Borneol) ,/- menthol, magnetite, the flower bud of lily magnolia, Cortex Magnoliae Officinalis, Flos Magnoliae Officinalis, leatherleaf mahonia, Fructus Malvae Vertillatae, pangolin, mulberry wipe pin, pearl, mother-of-pearl, CAULIS MARSDENIAE TENACISSIMAE, honey, abundant Gong (green sail), hardship Chinaberry skin, muskmelon seed, rhizoma menispermi, peppermint, the clear leaf of clam shell, Lapis Micae Aureus, cloth, water melon frost, semen momordicae, the root bark of white mulberry, mulberry leaf, Sang Kan, mulberry Branch, Morinda officinalis, Ying Xiang, elscholtiza, cortex moutan, plum blossom, dark plum, kamuning, spot are sweet, Pork and beans is slightd, myrrh, rhizoma nardostachyos, the compound of glauber-salt and liquorice, awns Always abundant glycosides, notoginseng triol bear glycosides, younger brother for nitre, lotus leaf, Lotus Plumule, lotus pod, close section, lotus seeds, stamen nelumbini, fennelflower seed, Radix Notoginseng, Radix Notoginseng Work, basil oil, olibanum, stone-like omphalia, marmor serpentinatum, Radix Ophiopogonis, Orostachys fimbriatus, Oroxylum indicum, rice bud, Japanese Flowering Fern Rhizome, oyster, it is white it is careless, red it is careless, Panax japonicus, panax japonicus majoris, American Ginseng, grain shell, Paris polyphylla, patchouli oil, high mountain horseradish dish, peppermint oil dementholized, Caulis Perillae, perilla leaf, purple Perillaseed, cortex periplocae, peach branch, peach kernel, RADIX PEUCEDANI, the root of purple-flowered peucedanum, kaladana, CORTEX PHELLODENDRI AMURENE, Cortex Phellodendri, pheretima, reed root, emblic, bright and beautiful lamp Cage, Physochlaina macrophylla, Phytolacca acinosa, quassia, picria fel tarrae, Radix picrorrhizae, prepared RHIZOMA PINELLIZE without adju-vant, pinellia, rhizoma pinellinae praeparata, the tuber of pinellia, Pine Nodular Branch, pollen pini, Hu Green pepper, caulis piperis futokadsurae, Bi water chestnut, Asiatic plantain, semen plantaginis, cacumen biotae, the seed of Oriental arborvitae, knot stalk, Pogostemon cablin, Extractum Polygalae Liquidum, Japanese polygala, far Will, radix polygonati officinalis, rhizoma polygonati, piece storage, polygonum cuspidate, the vine of multiflower knotweed, prepared fleece flower root, the fleece-flower root, fructus polygoni orientalis, polygonum perfoliatum, few folium isatidis, pig etc., Poria cocos, obtain tea skin, dent is looked for, potentilla chinensis, potentilla discolor, PULVIS CORNUS BUBALI CONCEN TRATUS, Yi Ren, propolis, Prunella vulgaris, brush-cherry seed, tuniclike psammosilene root, Golden Larch Bark, radix pseudostellariae, Psoralen moon purport, hooker winghead root, pueraria lobata, Pachyrhizua angulatus, the Chinese bulbul, the right copper of@, pyrola, pyrrosia lingua, the fruit of Rangoon creeper, winter insult Grass breathes out spiral shell oil, radix ranunculi ternati, Lay vine, realgar, Rehmannia glutinosa, glutinous rehmannia, Radix Rhapontici seu Radix Echinopsis, rheum officinale, root of kirilow rhodiola, Rhododendron dauricum, Rhododendron molle, rheum officinale Soak descendants, Extractum Rhei Liquidum, bacterium pockmarks, China rose, Jin Louzi, rose, raspberry, Juncao, tinkling of pieces of jade goat's horn, the total intoxicated acid extraction of Radix Salviae Miltiorrhizae Object, Radix Salviae Miltiorrhizae, pleased, santal, radix saposhnikoviae, bush, middle of the month wind, seaweed, sargentodoxa cuneata, Folium Sauropi, saururus chinensis, Herba Saussureae Involueratae, five hide Extracts, Sculellaria barbata, the Huangs such as son, kadsura longepedunculata, charred schizonepeta, schizonepeta, ching-chieh charcoal, ching-chieh, Hou Song, scorpio, radix scrophulariae, Huang Son, climbing groundsel, kind muddy leaf, cuttlebone, snake ant, sesame oil, Semen sesami nigrum, rice sprout, Herba Siegesbeckiae, powder-refining with water are played Deng, stringy stonecrop, Selaginella tamariscina, day Jasmine, mustard seed, caulis sinomenii, Himalayan mayapple fruit, siphonostegia chinensis, Siraitia grosvenorii, shafts chinaroot greenbrier, soil obtains etc., semen sojae germinatum, semen sojae atricolor, tasteless preserved soybean, solidago plant Flower, kuh-seng, sophora flower, the Fructus Sophorae, subprostrate sophora, trigone, Caulis Spatholobi, spicebush oil, duckweed, stachyurus pith, stalactite, octagonal mattress sesame oil, open country Pawpaw, radix stellariae dichotomae, the tuber of stemona, the root of fangji, the sterculia seed, prepared nux vomica, vomiting nut, storax, Pulvis Fellis Suis, Sulfur, when medicine, swertia mileensis, Sea otter, Cortex Syringae, talcum powder, talcum, Chinese tamarisk tops, tanshinone extract, dandelion, herba taxilli ,-tea oil, terminaliae billericae,fructus, tortoise plastron Glue, tortoise plastron, the stem pith of the rice-paper plant, firewood be lonely, the bulb of thunberg fritillary stream leaching side of body, golden fruit pull, ginseng stem and leave general saponin, Fructus meliae toosendan, vertebra, ginseng always abundant glycosides, do Paint, palm, Cai Chenopodiaceae, Snakegourd Fruit, cortex trichosanthis, radices trichosanthis, fries wither son, melon of melon and withers son, fenugreek, whole first, tsaoko, turpentine caulis trachelospermi Oil, acute turpinia leaf, cattail pollen, rhizoma typhonii, uncaria, the seed of cowherb, thin spider perfume, Verbena officinalis, honeycomb, rde bean, viola mandshurica, tree are posted Life, oil of negundo chastetree, fructus viticis, leaf of negundo chastetree, radix jurineae, fructus forsythiae extract, rhizoma curcumae longae concisa, the achene of Siberian cocklebur, Chinese prickly ash, Radix zanthoxyli, zaocys dhumnade, cultivation Art oil, baked ginger, ginger, rhizoma zingiberis, acid evil benevolence 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 It can be dispersed in substrate.

In some embodiments, medium includes water soluble excipient.Water soluble excipient is selected from the following group: cocoa Rouge, polyethylene glycol (PEG), sucrose, glucose, galactolipin, fructose, xyloselactose, maltose, trehalose, sorbose Alcohol, mannitol, maltodextrin, gossypose, stachyose, oligofructose either their combination.In some embodiments In, substrate further includes plasticizer.

In some embodiments, medium has corrosion/dissolution rate than API high.

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

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

In some embodiments, drug matrices, which are molded, is 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 pie to fill the full compartment.

In some embodiments, as shown in fig. 6, drug matrices exist in the form of nano particle.Drug matrices with it is molten There is API or be dispersed with the solution of API and mixes.During subsequent 3D printing pharmaceutical formulation, solution is atomized/is injected in On printable layer.Solution containing drug matrices is once dried, and drug matrices are just dispersed among pharmaceutical formulation.Nanometer Particle has biggish surface area, thus has higher dissolution rate.

Nanoparticle size (preferably 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、 The size of 400nm, 500nm, 600nm, 700nm, 800nm, 900nm).The size of nano particle can be suitable by selecting Synthetic method and/or system control.Wishing the nano particle in size range in order to obtain, can suitably control or changing Become synthesis condition to provide, for example, it is desired to solution concentration or the cavity ranges of needs (comment in detail visible: Vincenzo Liveri, the controlledly synthesis of nano particle, Springer, 2006 in microcosmic heterogeneous system).

As shown in fig. 7, in some embodiments, drug matrices can exist in the form of micropin.The drug of micropin form In the usually packed shell with acicular texture of matrix.During 3D printing pharmaceutical formulation, micropin can also and drug Dosage form prints together, can also be embedded in pharmaceutical formulation.Micropin can by carbohydrate, PLGA polymer, API or they Combination is constituted.When being administered to parenteral or intestines, micropin can help API to enter the circulatory system 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.The basal structure of drug matrices is at a network, such as by loose Material is made, and the density of loose drug matrices is usually less than the density of matrix.The frame structure of tablet is by can be at 1-10 minutes The material of interior dissolution is made, substrate can the dissolution in 2-60 seconds, preferably 2,5,10,15,20,25,30,35,40,45,50, 55, the substrate dissolved in 60 seconds.As shown in Figure 8 B, after pharmaceutical formulation is applied, API can be released in several seconds.

Drug matrices content can be made by using additive method, such as 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 is uniformly mixed with the substrate melted.Alternatively, before extrusion, the API (such as powder) of solid form It can mix or be dispersed among substrate with the substrate of thawing.Usually, extrusion process is in substrate glasses transition temperature On carried out between 10 to 40 DEG C and close at a temperature of the fusing point of API.Once 3D printer has reached suitable temperature, substrate Stereosopic printing surface will be deposited to.It can control the shape of drug matrices and big by being programmed to 3D printing process It is small.In some embodiments, drug matrices can have not only been manufactured in same technique but also manufacture matrix.In some embodiments In, first manufacture drug matrices and remanufacture matrix, and among the manufacturing process of matrix or later 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 the base.In some embodiments, when drug matrices are packed into compartment It waits, drug matrices can be separated with matrix.

D. controlled release

The pharmaceutical formulation of the disclosure has different release processes after oral.In some embodiments, drug 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 drug measures in aqueous solution.Aqueous solution include gastric juice, intestinal juice, body fluid and Containing inorganic or organic compound aqueous solution.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 to reduce peak level/slot level ratio, and it is fixed to realize the specific region into gastrointestinal tract To release drug matrices and the absorption process unrelated with feed status, therefore the curve can be used to improve deviation, reduce secondary The adaptability of patient is acted on and improves, these features are very necessary for treatment ADHD disease.In another example loading dose Maintenance dose is followed by for treating chronic disease, as hypertension and diabetes there may be advantage.

Several mechanism using the pharmaceutical formulation control release profiles in the disclosure have been discussed above.For example, passing through By the exposed area of the matrix of lasting corrosion, the drug matrices being embedded in matrix can be provided for a long term the drug of constant basis for adjustment. In addition, the geometry of size and/or compartment that the release profiles rate of API can be open by compartment controls.

In some embodiments, release profiles can by design one with by plug close or block hole every Room controls.Plug is to work as pharmaceutical formulation by water-soluble, porous or solvable corrosion material or pH sensitive material or hydrophobic material etc. By gastrointestinal tract will receive dissolution, degradation, structure variation material be 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.Have by selection suitable molten The plug water-soluble material of Xie Du, permeability and solvable erosion degree can control the release profiles rate of drug matrices.Alternatively, It, can be by using suitable shape and/or the plug of size (for example, suitable for the plug of the hole for blocking on compartment The column of length) control the release profiles rate of drug matrices API.The release profiles can also pass through the compartment of different number To control.Fig. 9 shows a kind of exemplary dosage forms, and intrinsic silicon contains multiple column compartments and is distributed in the two of pharmaceutical formulation Side.Each compartment accommodates drug matrices.The hole that each compartment has a column plug to block.These plugs have Different solubility.Depending on the size, shape and solubility of plug, the release of API can be lasting, continuous, same When, successively or pulse feature.

Figure 10 A shows a kind of exemplary pharmaceutical formulation with successively release profiles.0A referring to Fig.1, the pharmaceutical formulation 700 matrix 701 is included there are three column compartment 702-704.Each compartment is mounted with the drug base containing same API Matter.Each compartment has the hole blocked by stick-like plug 705-707.Length still is made by same material in these plugs It is different, therefore it is also different to open the time needed for compartment release drug matrices to dissolve plug.As illustrated in figure 10 c, most short Plug dissolve first and release API from first compartment.After the API in first compartment is released completely, in it is isometric The plug of degree dissolves and releases API from second compartment.After the API in second compartment is released completely, third plug Dissolution is to discharge API from third compartment.Therefore, after the drug matrices in first compartment are released, Plasma Drug Level Reach first peak value.It is consumed when the API discharged since first compartment, 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 again increase.When the API discharged in second compartment reaches the second peak value and opens When beginning is consumed, the plug of third compartment is dissolved 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.

Successively release characteristic may be implemented by another exemplary pharmaceutical formulation.The pharmaceutical formulation contains such as Figure 10 B institute Several drug matrices encapsulated with refracting films shown.Dissolving each layer may be implemented the sustained release of API simultaneously, to provide as schemed Continuous lasting API release shown in 10C.In some embodiments, after pharmaceutical formulation is applied, the outer layer of the pharmaceutical formulation It can dissolve immediately and discharge the drug matrices being embedded into.But since outer layer has blocked exchanging for the layer being clipped in the middle and environment, Make that middle layer is insoluble or solution rate is very slow.In other words, the dissolution of outer layer typically precedes the dissolution of middle layer, thus The effective ingredient contained in outer layer typically precedes the effective ingredient release of middle layer.During the dissolution of outer layer makes to be sandwiched in Between layer be exposed to accelerate their dissolution, it is thus achieved that the successively release profiles as shown in Figure 10 C.One In a little embodiments, pharmaceutical formulation includes the Gas generating components being loaded in first compartment.In some embodiments, the gas Component occurs and is selected from the following group: organic acid plus carbonate, sulphite, bicarbonate, sodium carbonate, sodium bicarbonate, inclined sulfurous acid Hydrogen sodium, calcium carbonate and their combination.Gas generating components and gastric juice can discharge carbon dioxide or sulfur dioxide gas when contacting. When matrix is dissolved under one's belt, permeates or when corrosion, due to gas generator part be exposed to acidic environment or water penetration into Enter compartment and cause acid and reacted with sodium bicarbonate, which can generate gas in a manner of effervesce to discharge drug base Matter.It should be noted that can be come according to each layer of thickness, dissolution rate, permeability and the corrosion rate etc. for adjusting pharmaceutical formulation The dissolution time of different layers is set, so that different layers can be dissolved with preset time or solubility curve, so that wherein Effective ingredient can be discharged with preset release profiles.

The pharmaceutical formulation of the disclosure include at least with one or more drug matrices existing for section retards releasing pattern, Middle sustained release can be controlled by traditional material or mode well known to those skilled in the art, for example, pass through by API is embedded into matrix/substrate of sustained release or is realized by using one or more sustained release coatings.By prolonging Slowbreak is put, and API release can be controlled to twice a day or once be administered and can meet the requirements, this has for needing by continuing The active constituent of dosage has advantage come the treatment for fighting pain.

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

In some embodiments, pharmaceutical formulation further comprises conventional adminicle well-known to those skilled in the art Matter, preferably glycerin monostearate, the derivative of semi-synthetic triglyceride, semi-synthetic glyceride, rilanit special, palm fibre Palmitic acid acid glyceride, Compritol 888 ATO, polyvinylpyrrolidone, gelatin, magnesium stearate, stearic acid, odium stearate, talcum, benzene Sodium formate, boric acid and colloidal silicon dioxide, fatty acid, substituted triglycerides, glyceride, polyoxyalkylene diols and they spread out Biology.

The preparation of pharmaceutical formulation

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

3D printing used herein refers to the process for producing 3D article in layer according to Digital Design.In U.S.Pat. Nos.5,204,055；5,260,009；5,340,656；5,387,380；5,503,785；And it is described in 5,633,0213D The basic process of 3D printing.Remaining is related to the United States Patent (USP) of 3D printing and application includes: 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.About The detailed description of 3D printing may refer to above-mentioned patent and application.

For the production of pharmaceutical formulation, the different 3D printing methods of different raw material, equipment and condition of cure have been related to it Through being developed.These 3D printing methods include binder deposition (see L Gibson etc. (2015) Additive Production technology: 3D Printing, rapid shaping and direct digitization production, 2 editions, Springer, New York；W.E.Katstra etc. (2000) 3 D-printing The oral drug dosage form of manufacture, control release magazine 66:1-9；W.E.Katstra etc. (2001) is manufactured multiple by 3 D-printing Miscellaneous peroral dosage form, Materials Science and Engineering technical college thesis, the Massachusetts Institute of Technology；H.Lipson etc. (2013) assembly: The New World of 3D printing, John Wiley father and son company；G.Jonathan, A.Karim (2016), the 3D printing of medicament: design The new tool of the delivery system of customization, international medical magazine, 499:376-394), material injection (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), it squeezes (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 The nozzle activated from robot squeezes out.Unlike binder deposition one powder bed of needs, pressing method can be printed upon any base On bottom.Multiple material can be all extruded to realize 3D printing, including thermoplastic material disclosed herein, paste and colloidal suspension Liquid, silicone and other semisolids.A kind of common type for squeezing out printing is fusion sediment modeling, thin using solid polymer Silk is printed.In fusion sediment modeling, filament is introduced into the nozzle assembly of heating and is squeezed (see L by gear train Gibson etc. (2015) Additive Production technology: 3D printing, rapid shaping and direct digitization production, 2 editions, Springer, knob About).

The production instruction of printing work can be generated by diversified forms, including direct coding, be pushed away from solid CAD model It leads or other is directed to the computer interface and application software of 3D printing machine.The quantity and space cloth for the drop that these instructions include Confidence breath, general printing parameter, for example, on each linear dimension (X, Y, Z) decline interval and each drop in The volume or quality of liquid.The material given for one group, adjustable parameter is to improve 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 property.

Since 3D printing can handle a series of drug materials and can be with Partial controll component and structure, 3D printing is very Suitable for manufacturing the pharmaceutical formulation the present invention with complex geometry mechanism and component.

Manufacture is also convenient for personalized pharmaceutical formulation using 3D printing method.Personalised drug is referred to based on biological marker Object generates Treatment decsion and personalized dosage form design to help the layering to patients.Digital Design is modified than modification Physical equipment is easier.In addition, automation, the operation cost of small-scale 3D printing may can be ignored.Therefore, 3D Printing can allow multiple small-sized, personalized batch production to be economically feasible, and make the dosage form for being intended to improve compliance personalization Production becomes possible.

Individual character dosage form, which allows to customize, delivers according to the weight of patient and the medication amount of metaboilic level.The dosage form of 3D printing can be with Children and highly effective drug in ensuring to grow up have accurately personalized dosage.Personalized dosage form can also combine The drug of all patients adheres to taking medicine at a single daily dosage so as to improve patient.

Figure 11 shows using 3 D-printing the method for manufacturing personalized dosage form.It is available each for each patient Kind of clinical test as a result, including weight, age, metabolic index and genome biomarker etc..The knot of clinical test Fruit is input into computer software, and prescription in conjunction with doctor and pharmacological kinetics model design given dose and pharmaceutical composition 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 controlled release of a variety of drug matrices

The pharmaceutical formulation and method of the disclosure can be used to control the release of two or more drug matrices, to realize The optimization of the pharmaceutical composition in specific medical field.For example, the tablet for the treatment of hypercholesterolemia can be designed as instant-free Atorvastatin calcium but extended release niacin.In another example, lenitive nonsteroidal anti inflammatory drugs (NSAID) quilt It is designed as sustained release NSAID, but mucosa injury of the quick release H2 receptor antagonist to prevent NSAID from inducing.

In some embodiments, multiple compartments are contained in matrix, 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 drug base being loaded in different compartments Matter is different.The pharmaceutical formulation, which can be designed as can provide, discharges a variety of drug matrices simultaneously or sequentially to realize that synergistic treatment is made With.

In some embodiments, the release of a variety of drug matrices can be at the same, successively, pulse or this is several The combination of kind mode.Figure 12 A shows a kind of exemplary pharmaceutical formulation, which can discharge a variety of API simultaneously.Ginseng According to as illustrated in fig. 12, which includes three lamination 801-803, and every layer is all embedded into different drug matrices.Such as Shown in Figure 12 B, after pharmaceutical formulation 800 is applied, the drug matrices be released simultaneously but rate of release with the dissolution of layer and It is different.

Figure 13 A depicts another exemplary pharmaceutical formulation with release profiles simultaneously.With reference to 13A, the drug 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 solubility, and API is embedded in substrate.As shown in Figure 13 B, in 900 quilt of pharmaceutical formulation After application, these three API are released simultaneously, but have different rates of release as the substrate of drug matrices dissolves. The rate of release of API can be controlled by the size that the shape or compartment of compartment are open.

Figure 14 A and 14B depict the exemplary pharmaceutical formulation of another kind that can discharge three kinds of API simultaneously, with reference to Figure 14 A, The pharmaceutical formulation 1000 includes three pie section 1001-1003 embedded with drug matrices.As shown in Figure 14 C, as section is molten Solution, a variety of drug matrices discharge simultaneously and the rate of release of drug matrices can be controlled by the solubility 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 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 shows a kind of exemplary pharmaceutical formulation that can sequentially discharge two kinds of API.With reference to Figure 15 A, the drug agent Type 1200 includes matrix 1202, and matrix contains the compartment for filling drug matrices 1202.The matrix 1201 includes the first API, drug Matrix 1202 includes the 2nd API.As shown in fig. 15b, after pharmaceutical formulation applies, as collective dissolves, the first API is released It puts.Until matrix dissolution and when exposing drug matrices, the 2nd API can be just released, to realize the sequence of a variety of API Release profiles.

Figure 16 A shows another exemplary pharmaceutical formulation of sequence release profiles.6A referring to Fig.1, drug agent Contain three column compartment 1302-1304 for being mounted with three kinds of drug matrices in the matrix 1301 of type 1300.Compartment 1302- 1304 suffer from the hole blocked by column plug.Each plug suffers from different length and/or solubility.Such as Figure 16 B institute Show, opens compartment as plug sequence dissolves, a variety of API are sequentially discharged.

Figure 17 A show it is a kind of with and meanwhile release or sequence release profiles exemplary pharmaceutical formulation.It, should with reference to 17A Contain four section 1701-1704 with different solubilities in the matrix of pharmaceutical formulation 1400.In some embodiments, such as Shown in Figure 17 B, drug matrices are embedded into section 1701-1704.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 designs of the pharmaceutical formulation of controlled release.

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

The release profiles of benzoic acid can be measured with such as under type in pharmaceutical formulation.The Na of pH=8 is prepared first₂HPO₄Water Lysate of the solution as benzoic acid, compound concentration are the benzoic acid mother liquor of 120 μ g/mL, and being successively diluted to concentration is 30 μ g/ The dilution of mL, 15 μ g/mL, 7.5 μ g/mL, 3.75 μ g/mL, 1.875 μ g/mL, are being absorbed with spectrophotometry instrument Wavelength is at 226nm.Linear regression is made to the data of measurement, obtains benzoic acid standard curve y=0.0599x+0.0347.For The burst size of measurement benzoic acid, pharmaceutical formulation are dissolved in the Na of pH=8₂HPO₄Aqueous solution, degassed processing, temperature control At 37 DEG C ± 0.5 DEG C, turning basket revolving speed is 100rpm, and point sampling 5mL is to measure concentration of benzoic acid in different times respectively, together 5mL medium is supplemented in Shi Zaixiang solution.Sample liquid through 0.45 μm of filtering with microporous membrane, be used in combination by the subsequent filtrate that precision pipettes certain volume Ultraviolet-visible scene photometer measures light absorption value A at wavelength 226nm, calculates concentration of benzoic acid by standard curve, and press The release percentage of formula calculating benzoic acid:

1.

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

The drug release determination of PEG8000: the standard curve of PEG8000 is drawn first, weighs 0.1275g PEG8000 standard specimen It is put in 25ml volumetric flask, is dissolved with water and be diluted to scale；Pipette respectively above-mentioned solution 1ml, 2ml, 5ml and 10ml in In 10ml volumetric flask, it is diluted with water to scale, as reference substance solution.Precision measures 50 μ l and injects liquid chromatograph (Waters Ultrahydrogel^TM120/250/500 3 series connection, flow velocity 0.5ml/min, column temperature are 40 DEG C, and detector is to show poor folding Photodetector).Record chromatogram, using the logarithm of reference substance concentration as abscissa, the logarithm of the peak area of respective concentration As ordinate, regression equation is calculated are as follows: y=1.024x+8.918.Wherein chromatographic condition are as follows: chromatographic column Waters Ultrahydrogel^TM120/250/500 3 series connection, flow velocity 0.5ml/min, column temperature are 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 of PEG8000 can be calculated with following formula:

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 18 c, release profiles and D.Brooke and R.J.Washkuhn (the zero level application system of benzoic acid System: theoretical and results of initial tests, medical science magazine, 1977) in model coincide, and by effect of the interface.Therefore, base A controlled release curve can be designed in the pharmaceutical formulation of the disclosure.

Embodiment two

This example describes the designs of the pharmaceutical formulation of the controlled release for the drug matrices that different compartments may be implemented.

Drug design: two kinds of pharmaceutical formulations are prepared with fusion sediment modeling method.The matrix of pharmaceutical formulation is 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 diagrames of these pharmaceutical formulations.9A and 19B referring to Fig.1, drug agent Type 1600 includes matrix 1601 and intracorporal two compartments 1602 and 1603 of base.Each compartment is respectively by wall 1604 and 1605 It surrounds.For the first pharmaceutical formulation, described two compartments are respectively by the wall encirclement with a thickness of 0.75mm and 1.5mm.For second Pharmaceutical formulation, described two compartments are respectively by the wall encirclement with a thickness of 0.75mm and 2.25mm.

In order to detect the release of drug matrices, which is added into the pH6.8 phosphorus of 900mL at revolving speed 100rpm In phthalate buffer.The release to judge drug matrices is measured to the UV absorption of the buffer.

The result of measurement is discharged 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 twenty minutes, first compartment is opened, and the drug matrices in first compartment are released.The pharmaceutical formulation is added After forty minutes to buffer, second compartment is opened.For the second pharmaceutical formulation, result as shown in figure 19 D, the pharmaceutical formulation It is added in buffer after sixty minutes, second compartment is opened.Therefore, the release profiles of the pharmaceutical formulation can be by surrounding The thickness of the wall of compartment controls.

Although having been combined embodiment the principle of the present invention is illustrated, it should be appreciated that these descriptions are only It is not used to limit the scope of the invention to illustrate.Content of this disclosure is intended merely to example and illustrates use, can not It is exhaustive to limit the open scope in a particular form.For those skilled in the art, many adjustment are aobvious with change And it is clear to.The selection basis of present disclosure be in order to preferably explain explain embodiment principle and practical application, thus Those skilled in the art can be it is understood that a variety of different embodiments and the adjustment carried out for specific application.

Content of this disclosure range is defined by following following claims or its equivalence.

Claims (9)

1. a kind of pharmaceutical formulation, comprising:

The matrix of compartment is formed, wherein

Described matrix includes non-erodable polymer, and

The compartment has hole, and described hole has scheduled shape,

Drug matrices are accommodated in the compartment；And

Block the plug of described hole, wherein the plug is water-soluble or erodable,

The compartment is configured to the combination of pie, coniform, pyramid shape, polygon-prism or these shapes, the drug Matrix is made of loose material, and the loose drug matrices and described matrix are made of identical material, and described thin The density of the drug matrices of pine is less than the density of described matrix.

2. pharmaceutical formulation as described in claim 1, described matrix is made of at least one thermoformable material.

3. pharmaceutical formulation as claimed in claim 2, the thermoformable material is selected from the poly- acetic acid of Vinylcaprolactam homopolymer Vinyl acetate-polyethyleneglycol-graft copolymer 57/30/13, Kollidon VA64 (PVP-VA), Kollidon VA64 (PVP-VA) 60/40, polyvinylpyrrolidone (PVP), polyvinyl acetate Ester ester (PVAc) and polyvinylpyrrolidone (PVP) copolymer 80/20, polyethylene glycol vinyl alcohol graft copolymer 25/75, Kollicoat IR- polyvinyl alcohol copolymer 60/40, polyvinyl alcohol (PVA or PV-OH), polyvinyl acetate ester (PVAc) gather The poly- 2- dimethylaminoethyl methacrylate of butyl methacrylate-- polymethyl methacrylate copolymer 1:2:1, poly- first Base acrylate-polymethacrylate copolymer, the poly- trimethyl of polyethyl acrylate-polymethyl methacrylate- Ethyl vinyl chloride copolymer, the poly- base acrylic copolymer 7:3:1 of polymethyl acrylate-polymethyl methacrylate-, 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, polyethylene oxide (PEO), polyethylene glycol (PEG), hyper-branched polyester, hydroxypropyl Methyl cellulose phthalate ester, hypromellose phthalate, hydroxypropyl methyl cellulose or hypromellose Plain (HMPC), hydroxypropyl methyl cellulose succinate or hydroxypropyl methyl cellulose acetate succinate (HPMCAS) are gathered Lactide-copolymer of poly lactic acid (PLGA), carbomer, polyvinyl-polyvinylacetate copolymer, ethane-acetic acid ethyenyl ester are total Polymers, polyethylene (PE) and polycaprolactone (PCL), hydroxy propyl cellulose (HPC), the castor oil of the hydrogenation of polyoxyethylene 40, first Base cellulose (MC), ethyl cellulose (EC), poloxamer, hydroxypropyl methylcellulose phthalate (HPMCP) moor Lip river Sha Mu, rilanit special, 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.

4. pharmaceutical formulation as described in any one of claims 1-3, which is characterized in that the drug matrices are with form of nanoparticles In the presence of.

5. pharmaceutical formulation as described in any one of claims 1-3, which is characterized in that the drug matrices are deposited in the form of micropin ?.

6. pharmaceutical formulation as described in any one of claims 1-3, which is characterized in that the drug matrices formed reticular structure or Porous structure.

7. pharmaceutical formulation as described in claim 1, zero-order dissolution profile is presented in the active pharmaceutical ingredient, makes constant dosage Drug is within an extension period by sustained release.

8. pharmaceutical formulation as described in claim 1, described matrix includes closing off multiple compartments of the multiple compartment, And the multiple compartment has different thickness.

9. pharmaceutical formulation as described in claim 1, drug matrices and compartment are at covalent key connection.