CN108348487A - Delayed release preparation, preparation method and use - Google Patents

Delayed release preparation, preparation method and use Download PDF

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Publication number
CN108348487A
CN108348487A CN201680050660.8A CN201680050660A CN108348487A CN 108348487 A CN108348487 A CN 108348487A CN 201680050660 A CN201680050660 A CN 201680050660A CN 108348487 A CN108348487 A CN 108348487A
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China
Prior art keywords
component
analgesic
pharmaceutical composition
coating
sustained release
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CN201680050660.8A
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Chinese (zh)
Inventor
大卫·A·迪尔
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Wellesley Pharmaceuticals LLC
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Wellesley Pharmaceuticals LLC
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Priority claimed from US14/842,539 external-priority patent/US10278925B2/en
Application filed by Wellesley Pharmaceuticals LLC filed Critical Wellesley Pharmaceuticals LLC
Publication of CN108348487A publication Critical patent/CN108348487A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/06—Anti-spasmodics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention discloses the manufacturing methods of a kind of composition for reducing micturition frequency and the composition.A kind of manufacturing method includes the following steps：Form the first mixture for including the first active constituent containing one or more analgesic, first mixture is coated with to form the first component with the first sustained release coating, form the second mixture for including the second active constituent containing one or more analgesic, second mixture is coated with the second sustained release coating to form the second component, and by first component to merge to form third mixture with second component.

Description

Delayed release preparation, preparation method and use
This application claims the priority for the Application U.S. Serial No 14/842,539 submitted for 1st in September in 2015.Above-mentioned Shen Full content please is incorporated herein by reference.
Technical field
Present application relates generally to inhibit bladder for inhibiting the method and composition of contraction of muscle also, being more particularly to used for The method and composition of smooth muscle contraction.
Background technology
Detrusor is one layer of the bladder wall being made of the smooth muscle fibers for arranging helical beam, longitudinal beam and circular beam. When bladder stretching, this instruction parasympathetic makes detrusor contractions.This makes bladder that urine be discharged by urethra.
In order to make urine that bladder be discharged, it is necessary to open the internal sphincter of spontaneous control and the external sphincter of autonomous control.This A little muscle go wrong and can lead to the urinary incontinence.If urine volume reaches the 100% of bladder absolute capacity, autonomous sphincter becomes non- Autonomous and urine will be discharged at once.
The bladder of adult usually accommodates the urine (swept volume) of about 300-350ml, but full one-tenth human bladder can accommodate It is up to about the urine of 1000ml (absolute volume), is had differences between individual.As urine is gathered, the bladder wall folds the crestal line generated (gauffer) flattens and the bladder wall is thinning with its stretching so that bladder store a large amount of urine and internal pressure will not significantly on It rises.
In most of individuals, the urine volume usually in bladder begins with urine intention when reaching about 200ml.In this stage, If desired, subject is easy to resist urination impulsion.As bladder continues to fill, urine intention becomes stronger and is more difficult to ignore. Finally, bladder can fill to urination irresistible point of getting excited, and subject will be unable to ignore at this time.In some individuals, Start to generate this urine intention when the urine in bladder is less than the 100% of its swept volume.The urine intention of this enhancing may be done Disturb the sleep ability during normal activity, including sufficient uninterrupted rest.In some cases, the urine intention of this enhancing may It is related with medical conditions, such as male's benign prostatic hyperplasis or prostate cancer or women gestation.However, the urine intention of enhancing is also sent out Life is in the male and female individual not influenced by another medical conditions.
Therefore, it is necessary to for treat the urine in bladder be less than its swept volume 100% when just have urine intention male and The composition and method of female subjects.The composition and method is needed to inhibit contraction of muscle, to work as urine in bladder Volume makes the subject begin with urine intention when being more than about the 100% of its swept volume.
Invention content
The one side of the application is related to the method for manufacturing the pharmaceutical composition for reducing micturition frequency.This method Include the following steps：Form the first mixture for including the first active constituent containing one or more analgesic；Prolonged with first Slowbreak puts coating and is coated with first mixture to form the first component, wherein the first sustained release coating is to be administered orally 1-4 hours lag times discharge first mixture afterwards；It is formed comprising the second activity containing one or more analgesic Second mixture of ingredient；Second mixture is coated with to form the second component with the second sustained release coating, wherein described Second sustained release coating discharged second mixture with 4-6 hours after being administered orally lag times；And by described first Component merges with second component to form third mixture.
In another embodiment, it the described method comprises the following steps：Formed includes to contain one or more analgesic The first active constituent the first mixture；The first sustained release coating with body fluid to be in direct contact latter 1-4 hours slow The stagnant time discharges first mixture；Nuclear structure is coated with to form the nuclear structure of coating with the second mixture, wherein described the Two mixtures include the second active constituent containing one or more analgesic；And described in the coating of the second sustained release coating The nuclear structure of coating is to form the nuclear structure of double coatings, wherein the second sustained release coating is small with 1-4 after oral administration When lag time discharge second mixture.
Further aspect of the application is related to the pharmaceutical composition manufactured using the present processes.
Description of the drawings
Figure 1A and 1B is shown in LPS there is no (Figure 1A) or when there is (Figure 1B), and analgesic is thin by 264 macrophages of Raw Born of the same parents adjust the figure of costimulatory molecules expression.Analgesic individualism or with Salmonella typhymurium LPS (0.05 μ G/ml) together in the presence of culture cell 24 hours.The result is that the average opposite % of CD40+CD80+ cells.
Specific implementation mode
Following detailed description is presented so that those skilled in the art can implement and utilize the present invention.It is old for task of explanation Specific term is stated to provide the complete understanding to the present invention.However, it will be obvious to one skilled in the art that putting into practice this hair It is bright not need to these specific details.The description of specific application is only provided as representative embodiment.The present invention is directed to unrestricted The embodiment shown in, and with the broadest scope of the possibility consistent with principle disclosed herein and feature.
As used herein, term " effective quantity " means amount necessary to reaching selected result.
As used herein, term " analgesic " refers to for relieving pain and including the medicament of anti-inflammatory compound, compound Or drug.Medicament, compound or the drug of illustrative analgesic and/or anti-inflammatory include, but are not limited to following substance：Non- class is solid Alcohol anti-inflammatory drug (NSAID), salicylate (salicylate), aspirin (aspirin), salicylic acid (salicylic Acid), gaultherolin (methyl salicylate), Diflunisal (diflunisal), sasapyrin (salsalate), Olsalazine (olsalazine), salicylazosulfapyridine (sulfasalazine), para-aminophenol (para- Aminophenol) derivative, antifebrin (acetanilide), paracetamol (acetaminophen), phenaetin (phenacetin), fragrant that sour (fenamate), mefenamic acid (mefenamic acid), Meclofenamic Acid (meclofenamate), meclofenamate sodium (sodium meclofenamate), heteroaryl acetic acid (heteroayl Acetic acid) derivative, MCN 2559 (tolmetin), ketorolac (ketorolac), Diclofenac (diclofenac), third Sour (propionic acid) derivative, brufen (ibuprofen), naproxen sodium (naproxen sodium), naproxen (naproxen), fenoprofen (fenoprofen), Ketoprofen (ketoprofen), Flurbiprofen (flurbiprofen), Austria Husky general piperazine (oxaprozin)；Bmap acid (enolic acids), former times health (oxicam) derivative, piroxicam (piroxicam), Meloxicam (meloxicam), tenoxicam (tenoxicam), Ampiroxicam (ampiroxicam), bend Former times health (droxicam), pyrrole irrigate former times health (pivoxicam), pyrazolone (pyrazolon) derivative, bute (phenylbutazone), crovaril (oxyphenbutazone), antipyrine (antipyrine), aminopyrin (aminopyrine), analgin (dipyrone), former times dry goods (coxibs), celecoxib (celecoxib), rofecoxib (rofecoxib), Nabumetone (nabumetone), apazone (apazone), Indomethacin (indomethacin), relax Woods acid (sulindac), Etodolac (etodolac), isobutylphenylpropionic acid (isobutylphenyl propionic Acid), lumiracoxib (lumiracoxib), etoricoxib (etoricoxib), SC 69124 (parecoxib), Valdecoxib (valdecoxib), it replaces and draws former times cloth (tiracoxib), Etodolac (etodolac), Da Bufeilong (darbufelone), the right side Revolve Ketoprofen (dexketoprofen), Aceclofenac (aceclofenac), Licofelone (licofelone), Bromfenac (bromfenac), pranoprofen (pranoprofen), loxoprofen (loxoprofen), piroxicam (piroxicam), Buddhist nun Mei Shuli (nimesulide), western azoles profit quinoline (cizolirine), 3- formamido -7- methylsulfonyl amido -6- phenoxy groups -4H- 1- benzo piperazines are muttered -4- ketone (3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1- Benzopyran-4-one), Meloxicam (meloxicam), Lornoxicam (lornoxicam), d- Indobufens (d- Indobufen), Mofezolac (mofezolac), piperazine ammonia MCN 2559 (amtolmetin), pranoprofen (pranoprofen), Tolfenamic Acid (tolfenamic acid), Flurbiprofen (flurbiprofen), suprofen (suprofen), oxaprozin (oxaprozin), Zaltoprofen (zaltoprofen), Alminoprofen (alminoprofen), Tiaprofenic Acid (tiaprofenic Acid), their pharmacology salt, their hydrate and their solvate.
As used herein, term " former times cloth " and " COX inhibitor " refer to inhibit activity or the expression of COX2 enzymes, or can Inhibit or mitigate the composition of the compound of the severity (including pain and swelling) of extensive inflammation reaction.
There are two critical functions for bladder tool：Storage of urine and emptying.Storage of urine under low pressure, it means that detrusor exists Relaxation during full.Empty bladder needs detrusor to coordinate to shrink and sphincter urethrae relaxation.The disorder of storage function may be led Lower urinary tract symptom, such as urgent urination, frequent micturition and urge incontinence are caused, they are the component parts of overactive bladder.Bladder Over-activity disease, may be due to smooth muscle of bladder (detrusor) during storage not spontaneous contractions and cause, be one often The problem of seeing and being rarely reported, illness rate are only just evaluated recently.
The one side of the application is related to the pharmaceutical composition by being configured to delayed release preparation to people in need application Object is come the method that reduces micturition frequency.Described pharmaceutical composition includes one or more analgesic also, optionally, a kind of or more Kind muscarine antagonist.
As used herein, term " sustained release " refers to that will not decompose the medicine for entering body with discharge active component immediately Object.In some embodiments, term " sustained release " is for referring to drug release releasing there are predetermined delay after administration Put the pharmaceutical preparation of curve.In some embodiments, the delayed release preparation includes enteric coating, is to be applied to oral medicine The barrier of object prevents drug from being discharged before reaching small intestine.Delayed release preparation (such as enteric coating) prevents having stimulation to stomach Drug (such as aspirin) dissolve in the stomach.This coating is also used for protecting the unstable drug of acid from exposure to hydrochloric acid in gastric juice, And they are delivered to alkaline pH environment (5.5 or more intestinal pH), keep its non-degradable, and play their expected effects.
Term " pulsed release (pulsatile-release) " is a kind of sustained release, in this paper, we refer to A kind of pharmaceutical preparation, the pharmaceutical preparation provide quick and of short duration drug release in a short time at once after the predetermined lag phase, Thus " pulsed " blood plasma distribution of drug is generated after medicament administration.Preparation was designed to after application with the scheduled time Interval provides the release of single pulse formula or the release of multiple pulses formula.
Most of enteric coatings are worked by the surface stablized under the peracidity pH found under one's belt is presented, but in acidity It is decomposed rapidly under weaker (relatively alkaline) pH.Therefore, enteric coating ball will not dissolve in hydrochloric acid in gastric juice liquid (pH~3), but they It can be dissolved in alkaline (pH 7-9) environment present in small intestine.The example of enteric coating material includes but not limited to acrylic acid first Ester-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, acetic acid succinic acid Hydroxypropyl methyl cellulose (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl Acrylate-methacrylic acid copolymer, sodium alginate and stearic acid.
In some embodiments, described pharmaceutical composition is by being designed as the various pharmaceutical preparations for providing sustained release Oral medication.It includes such as tablet, capsule, caplet to postpone peroral dosage form, and can also include it is a variety of can with or cannot be by Particle, bead, powder or the pill of encapsulating.The peroral dosage form of tablet and Capsules representative most convenient, in this case using solid Body pharmaceutical carrier.
In delayed release preparation, one or more screen-wall coatings can be applied to pill, tablet or capsule to promote Simultaneously concomitant drugs are discharged into intestines drug slow mechanism dissolved.Typically, the screen-wall coating include encapsulating, around therapeutic combination or Active nucleus, or one or more polymer of forming layer or film around therapeutic combination or active nucleus.
In some embodiments, delivering activating agent provides sustained release with the predetermined time upon administration in the formulation. The delay can be grown of about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 Hour, about 6 hours or longer.
Delayed release compositions can include the 100% of the given activating agent accumulated dose being administered with single unit dose.Or Person, the delayed release compositions for including as component in combining release profiles preparation can be provided to be delivered by the pharmaceutical preparation Activating agent accumulated dose about 30-95%.For example, the component of release at once can provide the activity delivered by the pharmaceutical preparation The about 5-70% of agent accumulated dose or about 50%.In an alternative embodiment, the sustained release component offer is passed by said preparation About the 30% of the activating agent accumulated dose sent, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.
Delayed release preparation generally comprises the screen-wall coating of delay active constituent release.The screen-wall coating is depending on target It can be made of various different materials.In addition, preparation may include multiple screen-wall coatings to promote in a manner of of short duration (temporal) Release.The coating can be sugared coating, membrane coat (for example, based on hydroxypropyl methyl cellulose, methylcellulose, methyl hydroxyl second Base cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymer, polyethylene glycol and/or polyvinylpyrrolidine Ketone), or based on methacrylic acid copolymer, cellulose acetate phthalate, Hydroxypropyl Methylcellulose Phathalate, second Sour succinic acid hydroxypropyl methyl cellulose (hydroxypropyl methylcellulose acetate succinate) is gathered Vinyl acetate phthalic acid ester (polyvinyl acetate phthalate), shellac (shellac) and/or ethyl cellulose The coating of element.In addition, the preparation can include additionally time delay material, such as glycerin monostearate or distearin (glyceryl distearate)。
In some embodiments, the delayed release preparation includes enteric coating, and the enteric coating includes to promote activating agent The one or more polymer discharged in the proximal end region or remote locations of gastrointestinal tract.As used herein, " enteric polymer applies term Layer " refers to comprising the coating with pH dependences or one or more polymer of pH-independent release curve.In general, described Coating resistant to dissolution in the acid medium of stomach, but dissolving or erosion in the more distal area of gastrointestinal tract (such as small intestine or colon). Enteric polymer coating usually prevents activating agent release after administration when some until about 3-4 hours gastric emptying lag phase Between.
PH dependence enteric coating includes one or more pH dependences or pH sensitive polymers, (is such as existed at a low ph In stomach) its structural intergrity is kept, but dissolved in the higher pH environment of gastrointestinal tract more distal area (such as small intestine), it discharges there Drug substance contents.For the purpose of the present invention, " pH dependences (pH dependent) " is defined as having to be changed according to environment pH Feature (for example, dissolving).Illustrative pH dependent polymers include, but are not limited to methacrylic acid copolymer；Methyl-prop Olefin(e) acid-methylmethacrylate copolymer (methacrylic acid-methyl methacrylate copolymer) (example Such as,L100 (A types),S100 (Type B), German Rohm Co., Ltd (Rohm GmbH,Germany))；EUDRAGIT L100-55 (methacrylic acid-ethyl Acrylatecopolymer) (for example,L100-55 (c-type) andL30D-55 is copolymerized Object dispersion liquid, German Rohm Co., Ltd (Rohm GmbH, Germany))；Methacrylic acid-methyl methacrylate with The copolymer of methyl methacrylateMethacrylic acid, methacrylate and ethyl acrylate Terpolymer (terpolymer)；Cellulose acetate phthalate (cellulose acetate phthalates, CAP)；Hydroxypropyl Methylcellulose Phathalate (hydroxypropyl methylcellulose phthalate, HPMCP) (for example, HP-55, HP-50, HP-55S, Japanese chemical company of SHIN-ETSU HANTOTAI (Shinetsu Chemical, Japan))；It is poly- Vinyl acetate phthalic acid ester (PVAP) (for example,Enteric solubility white OY-P- 7171)；Succinic acid cellulose acetate (cellulose acetate succinates, CAS)；Hydroxypropylmethylcellulose acetate methylcellulose Succinate (hydroxypropyl methylcellulose acetate succinate, HPMCAS) is (for example, HPMCAS LF grades, MF grades and HF grades, includingLF andMF, Japanese chemical company of SHIN-ETSU HANTOTAI (Shin-Etsu Chemical,Japan))；Shellac (shellac) is (for example, MARCOATTM125 and MARCOATTM125N)；Sodium carboxymethylethyl Cellulose (carboxymethyl ethylcellulose, CMEC, Japanese Freund company (Freund Corporation, Japan))；Cellulose acetate phthalate (CAP) (for example,), cellulose acetate trimellitate (cellulose acetate trimellitates, CAT)；And the weight ratio wherein more than the two or both is about 2:1 to about 5:Mixture between 1, if weight ratio is about 3:1 to about 2:1L 100-55 with The mixture or weight ratio of S 100 is about 3:1 to about 5:1L 30D-55 withFS Mixture.
PH dependent polymers usually characteristic pH optimum value of the displaying for dissolving.In some embodiments, The pH dependent polymers are illustrated between about 5.0 and 5.5, between about 5.5 and 6.0, between about 6.0 and 6.5 or about 6.5 with PH optimum values between 7.0.In other embodiments, pH dependent polymers displaying >=5.0, >=5.5, >=6.0, >= 6.5 or >=7.0 pH optimum values.
In other embodiments, the enteric coating can include one or more non-TCP friendly flow polymer.These are poly- The release that object provides drug after a certain time is closed, and it is unrelated with pH.For the purposes of the present invention, " non-TCP friendly flow " is defined For with the feature (such as dissolving) not influenced by pH substantially.Non-TCP friendly flow polymer usually in " time is controlled " or It is mentioned in the context of " time dependence " release profiles.
Non-TCP friendly flow polymer can be water-soluble or water-soluble with right and wrong.Illustrative water-insoluble non-TCP friendly flow is poly- It includes but not limited to contain a small amount of MethacryloyloxyethylTrimethyl Trimethyl Ammonium Chloride (trimethylammonioethyl to close object Methacrylate chloride) neutral methacrylic acid esters (such asRS and RL)；Without any functional group neutral ester dispersion (such asNE30D andNE30)； Cellulosic polymer, such as ethyl cellulose, hydroxyethyl cellulose, cellulose acetate or mixture and other non-TCP friendly flows Coating product.Illustratively water solubility non-TCP friendly flow polymer includesamb。
In some embodiments, the non-TCP friendly flow polymer contains one or more resisted in stomach and intestines and invades The polysaccharide of erosion.This polymer is only degraded in colon, and big microbiologic population is contained in colon, contains and for example decomposes polysaccharide The biodegradable enzyme of coating, to which with controlled, time dependent mode discharges drug substance contents.
In some embodiments, coating method, which uses, makes one or more pH dependences and one or more non-TCP friendly flows Property polymer be blended.Once soluble polymer reaches its best dissolving pH value, pH dependences and non-TCP friendly flow polymer Blending can reduce the rate of release of active constituent.
In some embodiments, " time is controlled " or " time dependence " release profiles can be used containing a kind of or more The water-insoluble capsule body of activating agent is planted to obtain, wherein one end of the capsule body is with insoluble but tool permeability and swellability Hydrogel plug (plug) close.When being contacted with gastrointestinal fluid or dissolving medium, plug swelling releases its own The capsule and drug is discharged after scheduled lag time, this can be controlled by the positions and dimensions of such as plug.The capsule Body can further be coated with external pH dependence enteric coating, and capsule is made to keep complete before reaching small intestine.Suitable plug material Including, such as polymethacrylates, erodible comperession polymer (for example, HPMC, polyvinyl alcohol), condensation (congealed) molten polymer (for example, glyceryl monooleate (glycerl mono oleate)) and enzymatic controls easy Weather polymer (for example, polysaccharide, as amylose, arabogalactan, chitosan, chondroitin sulfate, cyclodextrin, Glucan, guar gum, pectin and xylan).
In other embodiments, capsule or bilayer tablet can be formulated containing drug containing core (drug-containing Core), insoluble but the semi-permeable polymer coating of tool or film coat by swell layer and outside.Sluggishness before rupture Time can be controlled by the permeability of polymer coating with the swelling behavior of mechanical property and swell layer.In general, the swell layer Including one or more swellers, such as swelling and the in its structure swellable hydrophilic polymer of reservation water.
Illustrative water-swellable material includes but not limited to, polyethylene glycol oxide (have such as 1,000,000 and 7,000, Average molecular weight between 000, such as)；Methylcellulose；Hydroxypropyl cellulose；Hydroxypropyl methyl cellulose；Tool The polyalkylene oxide (polyalkylene oxides) for having 100,000 to 6,000,000 weight average molecular weight, includes, but are not limited to Poly- (methylene oxide) (poly (methylene oxide)), poly- (epoxy butane) (poly (butylene oxide))；Tool There are poly- (hydroxyalkyl methacrylates) (poly (hydroxy alkyl of 25,000 to 5,000,000 molecular weight methacrylate))；With low-shrinkage aldehyde residue (low acetal residue) and with glyoxal, formaldehyde or glutaraldehyde cross-linking And with poly- (ethylene) alcohol (poly (vinyl) alcohol) of 200 to 30,000 degree of polymerization；Methylcellulose, crosslinked fine jade The mixture of fat and carboxymethyl cellulose；By formed maleic anhydride (maleic anhydride) with styrene, ethylene, Hydrogel caused by the dispersion of the copolymer fine crushing (finely divided copolymer) of propylene, butylene or isobutene Copolymer is formed, the copolymer fine crushing is handed over every mole of maleic anhydride in copolymer with 0.001 to 0.5 mole of saturation Join agent crosslinking；With 450,000 to 4,000,000 molecular weightAcid carboxyl polymer；Polyacrylamide；Crosslinked water-swellable indenes maleic anhydride (indenemaleic anhydride) Polymer；With 80,000 to 200,000 molecular weightPolyacrylic acid；Starch graft copolymer (starch graft copolymers)；The AQUA- being made of polyglucose unitAcrylate polymer is more Sugar, such as diester crosslinking polydextrose (diester cross-linked polyglucan)；With 3,000 to 60,000mPa.s Viscosity, and in mass volume ratio (w/v) be 0.5% to 1% aqueous solution carbomer (carbomer)；Cellulose ether, such as With about 1000 to 7000mPa.s viscosity, and the hydroxypropyl fibre for the aqueous solution (25 DEG C) for being 1% in weight/weight ratio (w/w) Dimension element；With about 1000 or higher, preferably 2,500 or higher to the viscosity of 25,000mPa.s of maximum, and in w/v it is The hydroxypropyl methyl cellulose of 2% aqueous solution；With about 300 to 700mPa.s viscosity at 20 DEG C, and it is in bulking value Than the polyvinylpyrrolidone for the aqueous solution that (w/v) is 10%；And combinations thereof.
The enteric layer can further include antiplastering aid, such as talcum and glycerin monostearate.The enteric layer can be into one Step includes one or more plasticizer, includes, but are not limited to triethyl citrate, CitroflexA-2, acetyl group lemon Lemon acid tributyl, polyethylene glycol acetylated monoglyceride (polyethylene glycol acetylated Monoglycerides), glycerine, glyceryl triacetate, propylene glycol, phthalic acid ester (for example, diethyl phthalate, Dibutyl phthalate), titanium dioxide, iron oxide, castor oil, D-sorbite and dibutyl sebacate.
In another embodiment, the delayed release preparation closes work using the membrane coat of water penetration but non-solubility Property ingredient and bleeding agent.When the water from enteron aisle slowly diffuses in core through this film, core swelling is until film spalling, thus discharges Active constituent.The membrane coat can be adjusted to allow various water penetration rates or release time.
Optionally, can the release time of drug be controlled by disintegration lag time (disintegration lag time), This depends on the tolerance level and thickness that contain the non-water-soluble polymer film (such as ethyl cellulose, EC) of predetermined micropore in bottom part body Balance between degree and the amount of swellable excipient (such as low substituted hydroxypropyl cellulose (L-HPC) and sodium glycollate).It is oral Later, GI fluids cause swellable excipient to be swollen through micropore permeation, this generation makes the internal pressure that capsule component is detached from, the capsule Component includes the first capsule body containing swellable material, the second capsule body containing drug and is attached to first glue The outer cover of capsule main body.
In other embodiments, drug can be discharged by permeating mechanism.For example, can be matched with single permeation unit Glue capsule or its can be introduced into 2 be encapsulated in hard gelatin capsule, 3,4,5 or 6 plug-type units (push-pull unit), by This each double-layer push-pull unit, which contains, permeates push layer (osmatic push layer) and medicine layer (drug layer), and two Person is surrounded by semipermeable membrane.Pair film adjacent with medicine layer drills out one or more holes.This film can be relied on additionally with pH Property enteric coating cladding so that until gastric emptying after just discharged.Gelatine capsule dissolves at once upon intake.In plug-type list When member enters small intestine, enteric coating decomposes, and can then pass the fluid through and be flowed out by semipermeable membrane, and osmotic pressure is made to push compartment swelling, with Drug is driven to be released through aperture to convey the rate that the rate of water accurately controls through semipermeable membrane.The release of drug can be in constant speed Carried out under rate up to 24 hours or longer time.
It includes one or more bleeding agents to permeate push layer, to generate driving force for water to be delivered to through semipermeable membrane In the core for delivering mediator (delivery vehicle).A kind of bleeding agent includes water-swellable hydrophilic polymer, also known as " is oozed Saturating polymer (osmopolymer) " and " hydrogel (hydrogel) " comprising, but it is not limited to hydrophilic ethylene and acrylic acid Polymer, polysaccharide (such as calcium alginate), polyethylene glycol oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly- (methyl-prop Olefin(e) acid 2- hydroxyl ethyl esters) (poly (2-hydroxyethyl methacrylate)), poly- (propylene) acid, poly- (metering system) acid, it is poly- Vinylpyrrolidone (PVP), polyvinyl alcohol (PVA), PVA/PVP copolymers, contains hydrophobic monomer such as methyl at crosslinked PVP The PVA/PVP copolymers of methyl acrylate and vinyl acetate, the hydrophilic polyurethane containing big PEO blocks, crosslinking carboxylic first are fine The plain sodium of dimension, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxylic Methylcellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthans and ethyl alcohol acid-starch Sodium.
Another kind of bleeding agent includes that infiltration is former (osmogen), can be absorbed water to influence the osmotic pressure across semipermeable membrane Gradient.Illustrative infiltration original includes, but are not limited to inorganic salts, as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, Potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium sulphate；Carbohydrate, as dextrose (dextrose), Fructose, glucose, inositol (inositol), lactose, maltose, mannitol, gossypose (raffinose), D-sorbite, sugarcane Sugar, trehalose and xylitol；Organic acid, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, the last of the ten Heavenly stems two Acid, sorbic acid, adipic acid, ethylenediamine tetra-acetic acid (edetic acid), glutamic acid, p-methyl benzenesulfonic acid, succinic acid and tartaric acid； Urea；And its mixture.
The material that can be used to form semipermeable membrane is included under physiology correlation pH and has water penetration and water-insoluble or be easy to By chemical modification (as be crosslinked) have the acrylic compounds of water-insoluble various grades, vinyl, ethers, it is polyamide-based, Polyesters and cellulose derivative.
In another embodiment, the delayed release preparation uses fluid-tight tablet coating, and water is through controlled whereby The hole of system enters in coating until core spalling.When tablet spalling, drug substance contents are discharged or are released through longer period at once It puts.These technologies and other technologies can be improved with allow start discharge drug before there are scheduled lag times.
Various coating skills can be applied to the particle containing activating agent, bead, powder or pill, tablet, capsule or combinations thereof Art is to generate different and unique release profiles.In some embodiments, the pharmaceutical compositions are to contain signal layer coating Tablet or capsule form.In other embodiments, the pharmaceutical compositions are tablet or capsule form containing laminated coating.
In some embodiments, described pharmaceutical composition includes a variety of selected from analgesic, muscarine antagonist, antidiuretic With the active constituent of antispastic.The example of antispastic includes but not limited to carisoprodol, benzodiazepine drug, Baclofen, ring benzene bundle Woods, metaxalone, methocarbamol, clonidine, clonidine analog and Dantrolene.In some embodiments, the medicine group It includes one or more analgesic to close object.In other embodiments, described pharmaceutical composition includes (1) one or more analgesics Agent, and (2) one or more other active components selected from muscarine antagonist, antidiuretic and antispastic.In another implementation In mode, described pharmaceutical composition includes (1) one or two kinds of analgesic and (2) one or two kinds of muscarine antagonists.Another In a embodiment, described pharmaceutical composition includes (1) one or two kinds of analgesic and (2) one or two kinds of antidiuretics. In another embodiment, described pharmaceutical composition includes (1) one or two kinds of analgesic and (2) one or two kinds of antispastics. In yet another embodiment, described pharmaceutical composition includes (1) one or two kinds of analgesic, (2) one or two kinds of antitoxin gill fungus Alkaline agent, and (3) one or two kinds of antidiuretics.
In one embodiment, described a variety of active ingredients is formulated into discharges at once.In other embodiments, described A variety of active ingredients is formulated into sustained release.In other embodiments, described a variety of active ingredients is formulated into discharges at once With both sustained releases (for example, the first part of each active constituent be formulated into discharge at once and the of each active constituent Two parts are formulated into sustained release).In another other embodiment, some in described a variety of active ingredients are formulated At discharging at once and some in described a variety of active ingredients are formulated into sustained release (for example, active components A, B, C are formulated At discharging at once and active constituent C and D are formulated into sustained release).
In some embodiments, the pharmaceutical compositions include to discharge component and sustained release component at once.It is described to be It carves release component and may include one or more active constituents in analgesic, muscarine antagonist, antidiuretic and antispastic. The sustained release component may include one or more work in analgesic, muscarine antagonist, antidiuretic and antispastic Property ingredient.In some embodiments, the release component at once has identical activity with the sustained release component Ingredient.In other embodiments, the release component at once has different active constituents from the sustained release component. In other other embodiment, the release component at once has one or more common work with the sustained release component Property ingredient.
In one embodiment, described pharmaceutical composition includes a kind of two kinds of active components (such as two kinds of analgesic, or The mixture of analgesic and a kind of muscarine antagonist or antidiuretic or antispastic), it is configured at about discharge at once.Another In one embodiment, described pharmaceutical composition includes two kinds of active components, is configured at about sustained release.At another In embodiment, described pharmaceutical composition includes to be formulated as the two kinds of active components of two kinds of sustained release components, each is provided not Same sustained release curve.For example, the first sustained release component discharges the first active constituent in first time point, and second prolongs Slowbreak puts component and discharges the second active constituent at the second time point.In another embodiment, described pharmaceutical composition includes Two kinds of active components, one kind is formulated into be discharged at once, and another kind is formulated into sustained release.
In other embodiments, described pharmaceutical composition include two kinds of active constituents for being configured to discharge at once (such as The mixture of two kinds of analgesic or a kind of analgesic and a kind of muscarine antagonist or antidiuretic or antispastic), and (2) two kinds It is configured to active constituent (such as two kinds of analgesic or a kind of analgesic and a kind of muscarine antagonist or the antidiuresis of sustained release The mixture of agent or antispastic).In other embodiments, described pharmaceutical composition is configured to the work discharged at once comprising three kinds Property ingredient, and (2) three kinds of active constituents for being configured to sustained release.In other embodiments, described pharmaceutical composition includes Four kinds of active constituents for being configured to discharge at once, and (2) four kinds of active constituents for being configured to sustained release.In these embodiments In, the active constituent in discharging component at once can be identical or different with the active constituent in sustained release component.
Term " discharging (immediate-release) at once " is used to refer to the drug for controlling material without solution rate herein Preparation.After the preparation that application discharges at once, the release of activating agent does not postpone substantially.At once release coating may include applying It is dissolved at once afterwards to discharge the suitable material of drug substance contents therein.Illustratively at once release coating material include gelatin, Polyvinyl alcohol polyethylene glycol (PVA-PEG) copolymer (such as) and it is well known by persons skilled in the art various Other materials.
At once release composition can include the 100% of the given activating agent accumulated dose applied with single unit dose.Or Person, discharges component and can be used as and merge component in release profiles preparation by comprising can provide through the pharmaceutical preparation at once About the 1% to about 50% of the activating agent accumulated dose of delivering.For example, the component of release at once can be provided and be delivered by said preparation At least about the 5% of activating agent accumulated dose, or about 10% to about 30%, or about 45% to about 50%.Remaining activating agent can be It is delivered in delayed release preparation.In alternative embodiments, the component of release at once provides the work delivered by said preparation About the 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45 or 50% of property agent accumulated dose.The sustained release component carries For use by said preparation delivering activating agent accumulated dose about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55 or 50%.
In some embodiments, the release at once or delayed release preparation include by one or more inert particle groups At active nucleus (active core), the particle be respectively bead, pill, tablet, particle, microcapsules (microcapsule), Microsphere (microsphere), fine granule (microgranule), Nano capsule (nanocapsule) or nanosphere body (nanosphere) form uses such as liquid bed technology (fluid bed techniques) or this field skill on surface Other methods known to art personnel are coated with the drug in the form of the film-forming composition of such as drug containing.The inert particle can have There are various sizes, as long as its is sufficiently large to keep not readily dissolving.Optionally, it by granulation (granulating) and can grind It grinds and/or the activity is prepared by extrusion and the round as a ball polymer composition of (spheronization) containing drug substance Core.
The amount of drug in core usually changes in the range of about 5 to 90 weight % by depending on required dosage.One As for, depending on the lag time of required release profiles and type and/or selected polymer and coating solvents, on active nucleus Polymer coating would be about 1 to 50% based on the weight meter for being applied particle.Those skilled in the art will select suitably The drug of amount is for being applied on core or being incorporated in core to reach desired dosage.In one embodiment, nonactive core The buffer crystal that can be sugar ball body or buffer crystal or be encapsulated, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid Deng making the microenvironment of drug change to promote its release.
In some embodiments, the delayed release preparation can be by with non-soluble polymer and enteric polymer Mixture coating water soluble/dispersible drug containing particle (such as bead) formed, wherein the non-soluble polymer with it is described Enteric polymer can be with 4:1 to 1:1 weight ratio exists, and the total weight of coating with the total weight of be coated with bead for 10 To 60 weight %.The bead of drug lamination optionally includes the ethyl cellulose of the internal rate of dissolution of control.Outside polymeric membrane The composition and internal layer and the respective weight of outer layer of layer are optimized, reach desired circadian rhythm for given activity (circadian rhythm) release profiles, the correlation based in vitro/in vivo are predicted.
In other embodiments, the preparation includes to discharge drug containing particle at once (no rate of dissolution controls polymer film) With the mixture of sustained release bead (such as lag time of displaying 2 to 4 hours after oral administration), dipulse is thus provided Discharge (two-pulse profile) curve.In other other embodiment, the preparation includes two kinds of delay Discharge the mixture of bead：First type shows 1 to 3 hour lag time and second type shows 4 to 6 hours slow The stagnant time.
In some embodiments, the active nucleus is coated with the polymer of one or more layers control rate of dissolution, to obtain Obtain the desired release profiles with or without lag time.Inner layer film can be in very great Cheng after water or body fluid suck in core The rate of release of drug is controlled on degree, and outer membrane can provide desired lag time and (suck rear nothing in core in water or body fluid Drug release or drug release few period).Inner layer film may include non-soluble polymer or non-soluble polymer and water The mixture of soluble polymer.
Largely control may include as described above up to the polymer suitable for outer membrane of 6 hours lag times Enteric polymer and 10 to 50 weight % non-soluble polymer.The ratio of non-soluble polymer and enteric polymer Rate can be 4:1 to 1:Change in the range of 2, these polymer are preferably with about 1:1 ratio exists.Usually used is water-insoluble Polymer is ethyl cellulose.
Illustrative non-soluble polymer includes ethyl cellulose, the polyvinyl acetate (Kollicoat from BASF SR#0D the neutral copolymer), based on ethyl acrylate and methyl methacrylate, the acrylate with quaternary ammonium group and methyl-prop The copolymer of olefin(e) acid ester, such asNE, RS and RS30D, RL or RL30D etc..Illustrative water-soluble polymer packet Include low molecular weight HPMC, HPC, methylcellulose, polyethylene glycol (molecular weight>3000 PEG), thickness regards activating agent in water Solubility and the coating formulation used based on solvent or latex suspension depending on, 1 weight %'s up to 10 weight % In range.The ratio of the non-soluble polymer and water-soluble polymer usually can be 95:5 to 60:40, preferably 80:20 to 65:Change in the range of 35.
Preferably, the preparation is configured to have release profiles of the limitation to peaceful sleep interference, wherein when individual is logical When can often be waken up by urination impulsion, the preparation discharges drug.For example, it is contemplated that starting to sleep for 11 points at night to individual, usually At night 12:30,3:00 and 6:00 wakes up urination.The carrier of sustained release can be at night 12:15 delivering drugs, to arrange General 2-3 hours of the needs delay of urine.
Described pharmaceutical composition can be applied or be applied as needed daily.In some embodiments, the medicine group It closes object and is applied to subject before sleeping.In some embodiments, described pharmaceutical composition is applied immediately before sleeping.In some realities It applies in mode, described pharmaceutical composition is applied before sleeping in about 2 hours, is applied in about 1 hour preferably before sleeping.In another reality It applies in mode, described pharmaceutical composition is applied for about 2 hours before sleeping.In another embodiment, described pharmaceutical composition exists It applies at least 2 hours before sleeping.In another embodiment, described pharmaceutical composition is applied for about 1 hour before sleeping.At another In embodiment, described pharmaceutical composition is applied at least 1 hour before sleeping.In yet another embodiment, the pharmaceutical composition Object was applied before sleeping less than 1 hour.In yet another embodiment, described pharmaceutical composition is applied immediately before sleeping.Preferably, Described pharmaceutical composition oral administration.
At once the release component or the suitable dosage (" therapeutically effective amount ") of the active constituent in sustained release component will Depending on the seriousness and the course of disease of such as disease, administration mode, the bioavilability of particular agent (bioavailability), The age of patient and weight, the clinical medical history of patient and the judgement etc. to the reaction of activating agent, doctor.
It is described to discharge component or the therapeutically effective amount of the activating agent in the sustained release component at once as general recommendations It is applied with the range in about 100 μ g/ kg body weights/day to about 100mg/ kg body weights/day, regardless of being applied by one or many With.In some embodiments, the daily application of each activating agent ranging from about 100 μ g/ kg body weights/day to about 50mg/ thousand Gram body weight/day, 100 μ g/ kg body weights/day to about 10mg/ kg body weights/day, 100 μ g/ kg body weights/day is to about 1mg/ kilograms Body weight/day, 100 μ g/ kg body weights/day to about 10mg/ kg body weights/day, 500 μ g/ kg body weights/day is to about 100mg/ kilograms Body weight/day, 500 μ g/ kg body weights/day to about 50mg/ kg body weights/day, 500 μ g/ kg body weights/day to about 5mg/ kilograms body Weight/day, 1mg/ kg body weights/day to about 100mg/ kg body weights/day, 1mg/ kg body weights/day to about 50mg/ kg body weights/ It, 1mg/ kg body weights/day to about 10mg/ kg body weights/day, 5mg/ kg body weights/time dosage to about 100mg/ kg body weights/ It, 5mg/ kg body weights/time dosage to about 50mg/ kg body weights/day, 10mg/ kg body weights/day to about 100mg/ kilograms body Weight/day and 10mg/ kg body weights/day to about 50mg/ kg body weights/day.
Activating agent as described herein may include in discharging component or sustained release component or combinations thereof at once for every Day oral medication, single dose or unitized dose ranging from 1mg to 2000mg, 5mg to 2000mg, 10mg to 2000mg, 50mg to 2000mg, 100mg are to 2000mg, and 200mg to 2000mg, 500mg to 2000mg, 5mg to 1800mg, 10mg are extremely 1600mg, 50mg are to 1600mg, 100mg to 1500mg, 150mg to 1200mg, 200mg to 1000mg, 300mg to 800mg, 325mg to 500mg, 1mg are to 1000mg, and 1mg to 500mg, 1mg to 200mg, 5mg to 1000mg, 5mg to 500mg, 5mg is extremely 200mg, 10mg are to 1000mg, and 10mg to 500mg, 10mg to 200mg, 50mg to 1000mg, 50mg to 500mg, 50mg is extremely 200mg, 100mg are to 250mg, 100mg to 500mg, 250mg to 1000mg, 250mg to 500mg, 500mg to 1000mg, 500mg to 2000mg.As expected, dosage will be depending on the disease of patient, size, age and the state of an illness.
In some embodiments, the pharmaceutical compositions include single analgesic.In one embodiment, the list One analgesic is aspirin.In another embodiment, the single analgesic is brufen.In another embodiment In, the single analgesic is naproxen sodium.In another embodiment, the single analgesic is Indomethacin.Another In one embodiment, the single analgesic is Nabumetone.In another embodiment, the single analgesic is pair Paracetamol.
In some embodiments, the dosage that is administered daily of the single analgesic is 1mg to 2000mg, and 5mg is extremely 2000mg, 20mg are to 2000mg, and 5mg to 1000mg, 20mg to 1000mg, 50mg to 500mg, 100mg to 500mg, 250mg is extremely 500mg, 250mg are to 1000mg or 500mg to 1000mg.In some embodiments, described pharmaceutical composition includes acetyl water Poplar acid, brufen, naproxen sodium, Indomethacin, Nabumetone or paracetamol as single analgesic and it is described only The daily qf oral administration dosage of pain agent is in 5mg to 2000mg, 20mg to 2000mg, 5mg to 1000mg, 20mg to 1000mg, 50mg to 500mg, 100mg are to 500mg, in the range of 250mg to 500mg, 250mg to 1000mg or 500mg to 1000mg. In some embodiments, the dosage that is administered daily of the second analgesic is 1mg to 2000mg, and 5mg to 2000mg, 20mg are extremely 2000mg, 5mg are to 1000mg, and 20mg to 1000mg, 50mg to 500mg, 100mg to 500mg, 250mg to 500mg, 250mg is extremely 1000mg or 500mg to 1000mg.
In other embodiments, the pharmaceutical compositions include a pair of of analgesic.The example packet of this pairs of analgesic It includes, but is not limited to acetylsalicylic acid and brufen, acetylsalicylic acid and naproxen sodium, acetylsalicylic acid and naphthalene fourth U.S. Ketone, acetylsalicylic acid and paracetamol, acetylsalicylic acid and Indomethacin, brufen and naproxen sodium, brufen With Nabumetone, brufen and paracetamol, brufen and Indomethacin, naproxen sodium and Nabumetone, naproxen sodium With paracetamol, naproxen sodium and Indomethacin, Nabumetone and paracetamol, Nabumetone and Indomethacin, With paracetamol and Indomethacin.The pairs of analgesic is with 0.1:1 to 10:1、0.2:1 to 5:1 or 0.3:1 to 3:1 Weight ratio mixing in range, mixing dosage is in 5mg to 2000mg, and 20mg to 2000mg, 100mg to 2000mg, 200mg is extremely 2000mg, 500mg are to 2000mg, 5mg to 1500mg, 20mg to 1500mg, 100mg to 1500mg, 200mg to 1500mg, 500mg to 1500mg, 5mg are to 1000mg, and 20mg to 1000mg, 100mg to 1000mg, 250mg to 500mg, 250mg are extremely 1000mg, 250mg are to 1500mg, and 500mg to 1000mg, 500mg to 1500mg, 1000mg to 1500mg and 1000mg are extremely In the range of 2000mg.In one embodiment, the pairs of analgesic is with 1:1 weight ratio mixing.
In some other implementations, the pharmaceutical compositions of the application further include one or more Antimuscarinics Agent.The example of the muscarine antagonist includes, but are not limited to oxybutynin, Solifenacin, darifenacin, Fesoterodine, support Special Luoding, bent department's chloramines and atropine.The daily dosage of muscarine antagonist is in 0.01mg to 100mg, 0.1mg to 100mg, 1mg To 100mg, 10mg to 100mg, 0.01mg to 25mg, 0.1mg to 25mg, 1mg to 25mg, 10mg to 25mg, 0.01mg are extremely 10mg, 0.1mg are to 10mg, in the range of 1mg to 10mg, 10mg to 100mg and 10mg to 25mg.
Further aspect of the application is related to a kind of medicine by being configured to delivery formulations at once to people in need application Compositions are come the method that reduces micturition frequency.In some embodiments, described pharmaceutical composition includes one or more stops Pain agent and one or more muscarine antagonists.In other embodiments, described pharmaceutical composition includes one or more analgesics Agent and one or more antidiuretics.In other embodiments, described pharmaceutical composition include one or more analgesic, one Kind or a variety of muscarine antagonists and one or more antidiuretics.
In other embodiments, the pharmaceutical compositions of the application further include one or more antispastics.Antispastic Example include, but are not limited to carisoprodol, benzodiazepine drug, Baclofen, cyclobenzaprine, metaxalone, methocarbamol, cola Rather, clonidine analog and Dantrolene.In some embodiments, the antispastic is with 1mg to 1000mg, 1mg to 100mg, 10mg to 1000mg, 10mg are to 100mg, 20mg to 1000mg, 20mg to 800mg, 20mg to 500mg, 20mg to 200mg, 50mg to 1000mg, 50mg are to 800mg, 50mg to 200mg, 100mg to 800mg, 100mg to 500mg, 200mg to 800mg, It is used with the daily dosage of 200mg to 500mg.The antispastic can individually prepare or with other in described pharmaceutical composition Active constituent is formulated for discharging at once together, sustained release or combinations thereof.
In some embodiments, described pharmaceutical composition includes two or more analgesic.In other embodiment In, described pharmaceutical composition includes one or more analgesic and one or more muscarine antagonists and/or antidiuretic.It is described Pharmaceutical compositions can be formulated into tablet, capsule, sugar-coat ingot (dragee), powder, granule, liquid, gel or emulsion form. The liquid, gel or lotion (naked form) or can be taken in included in capsule by subject in the form of naked.
In some embodiments, the analgesic is selected from salicylate (salicylate), aspirin (aspirin), salicylic acid (salicylic acid), gaultherolin (methyl salicylate), Diflunisal (diflunisal), sasapyrin (salsalate), Olsalazine (olsalazine), salicylazosulfapyridine (sulfasalazine), para-aminophenol (para-aminophenol) derivative, antifebrin (acetanilide), to second Acylamino- phenol (acetaminophen), phenaetin (phenacetin), fragrant that sour (fenamate), mefenamic acid (mefenamic acid), Meclofenamic Acid (meclofenamate), meclofenamate sodium (sodium Meclofenamate), heteroaryl acetic acid (heteroayl acetic acid) derivative, MCN 2559 (tolmetin), ketone are coughed up Sour (ketorolac), Diclofenac (diclofenac), propionic acid (propionic acid) derivative, brufen (ibuprofen), naproxen sodium (naproxen sodium), naproxen (naproxen), fenoprofen (fenoprofen), Ketoprofen (ketoprofen), Flurbiprofen (flurbiprofen), oxaprozin (oxaprozin)；Bmap acid (enolic Acids), former times health (oxicam) derivative, piroxicam (piroxicam), Meloxicam (meloxicam), tenoxicam (tenoxicam), Ampiroxicam (ampiroxicam), E-3128 (droxicam), pyrrole irrigate former times health (pivoxicam), pyrazoline Ketone (pyrazolon) derivative, bute (phenylbutazone), crovaril (oxyphenbutazone), peace Come for pyrrole quinoline (antipyrine), aminopyrin (aminopyrine), analgin (dipyrone), former times dry goods (coxibs), plug Former times cloth (celecoxib), rofecoxib (rofecoxib), Nabumetone (nabumetone), apazone (apazone), Buddhist nun Mei Shuli (nimesulide), Indomethacin (indomethacin), sulindac (sulindac), Etodolac (etodolac) And isobutylphenylpropionic acid (isobutylphenyl propionic acid).The muscarine antagonist is selected from oxybutynin, rope Li Naxin, darifenacin and atropine.
In some embodiments, the pharmaceutical compositions include the single analgesic and single muscarine antagonist. In one embodiment, the single analgesic is aspirin.In another embodiment, the single analgesic is cloth Ibuprofen.In another embodiment, the single analgesic is naproxen sodium.In another embodiment, described single Analgesic is Indomethacin.In another embodiment, the single analgesic is Nabumetone.In another embodiment In, the single analgesic is paracetamol.The analgesic and muscarine antagonist can be in range described earlier agent Amount application.
The another aspect of the application is related to by applying (1) one or more analgesic and (2) to subject in need The method that one or more antidiuretics carry out treatment bed-wetting.In some embodiments, antidiuretic plays the role of following： (1) increase inappropriate secretion；(2) increase vasopressin receptor activation；(3) atrial natriuretic peptide (ANP) or c-type natriuretic peptide are reduced (CNP) secretion；Or (4) reduce ANP and/or CNP receptor activations.
Illustrative antidiuretic includes, but are not limited to antidiuretic hormone (ADH), angiotonin II, aldosterone, blood Pipe pitressin, vasopressing are similar to object (for example, amine pitressin, arginine vasopressin, lypressin, benzene is gone to rely pressurization Element, ornipressin, terlipressin)；Vasopressin receptor agonist, atrial natriuretic peptide (ANP) and c-type natriuretic peptide (CNP) receptor (also that is, NPR1, NPR2 and NPR3) antagonist is (for example, HS-142-1, isatin, [Asu7,23'] b-ANP- (7- 28)], Annan spit of fland (a kind of cyclic peptide from streptomyces coelicolor) and 3G12 monoclonal antibodies)；2 receptor of amicine Antagonist (for example, amicine) and pharmaceutically acceptable derivates and its analog, salt, hydrate and solvate.
In some embodiments, one or more analgesic and one or more antidiuretics are formulated into delay Release.
Further aspect of the application is related to a kind of by applying the first medicine group comprising diuretics to people in need Object is closed, then application carrys out the method for the treatment of bed-wetting comprising the second pharmaceutical composition of one or more analgesic.Described first Kind pharmaceutical composition is taken and is configured to applying with diuresis in 6 hours, and at least 8 hours before sleeping apply. Second of pharmaceutical composition is applied before sleeping in 2 hours.
The example of diuretics includes, but are not limited to be acidified salt, such as CaCl2And NH4Cl；Arginine vasopressin receptor 2 is short of money Anti-agent, such as amphotericin B (amphotericin B) and lithium citrate；Water discharge agent (aquaretics), such as Goldenrod (Goldenrod) and needle juniper (Junipe)；Na-H exchanges antagonist (Na-H exchanger antagonist), such as dopamine (dopamine)；Carbonic anhydrase (carbonic anhydrase) inhibitor, such as acetyl azo amine (acetazolamide) and Du Fill in amide (dorzolamide)；Ring diuretics (loop diuretics), such as bumetanide (bumetanide), ethacrynic acid (ethacrynic acid), frusemide (furosemide) and Torasemide (torsemide)；Osmotic diuresis agent, such as glucose And mannitol；Potassium-sparing diuretic (potassium-sparing diuretics), in amiloride (amiloride), spiral shell Ester (spironolactone), dyrenium (triamterene), Canrenoate Potassium (potassium canrenoate)；Thiazine Class (thiazides), such as bendroflumethiazide (bendroflumethiazide) and Hydrochioro (hydrochlorothiazide)； And xanthine (xanthines), such as caffeine (caffeine), theophylline (theophylline) and theobromine (theobromine)。
In some embodiments, second pharmaceutical compositions further include one or more muscarine antagonists.Institute The example for stating muscarine antagonist includes, but are not limited to oxybutynin, Solifenacin, darifenacin, Fesoterodine, Tuo Teluo Fixed, bent department's chloramines and atropine.Second pharmaceutical composition can configure in delivery formulations at once or delayed release preparation. In one embodiment, first pharmaceutical composition is configured to discharge at once, and second pharmaceutical composition by with Sustained release is made.
In some other implementations, second pharmaceutical composition also includes one or more antidiuretics.
The another aspect of the application is related to a kind of medicine group including a variety of active ingredients and pharmaceutically acceptable carrier Close object.In some embodiments, described a variety of active ingredients includes two or more analgesic.In other embodiment In, described a variety of active ingredients includes one or more analgesic and one or more muscarine antagonists.In other embodiment In, described a variety of active ingredients includes one or more analgesic and one or more antidiuretics.In other embodiments, Described a variety of active ingredients includes one or more analgesic, one or more antidiuretics and one or more Antimuscarinics Agent.In other embodiments, at least one of described a variety of active ingredients is configured to sustained release.
In some embodiments, described pharmaceutical composition includes selected from cetyl salicylic acid, brufen, naproxen Two kinds of analgesic of sodium, Nabumetone, paracetamol and Indomethacin.In other embodiments, the pharmaceutical composition Object includes one selected from cetyl salicylic acid, brufen, naproxen sodium, Nabumetone, paracetamol and Indomethacin Kind or a variety of analgesic；With the antimuscarinic agent selected from oxybutynin, Solifenacin, darifenacin and atropine.
As used herein, " pharmaceutically acceptable carrier " includes any and all solvents, decentralized medium, coating, resists carefully Microbial inoculum and antifungal agent, isotonic agent and absorption delaying agent, sweetener etc..The pharmaceutically acceptable carrier can be by a variety of materials It prepares, including but not limited to corrigent, sweetener and various miscellaneous materials (miscellaneous material), such as in order to Prepare buffer and absorbent that particular treatment composition may need.This medium and medicament containing pharmaceutically active substance Using being well known in the present art.In addition to any conventional media or the medicament situation incompatible with the active constituent it Outside, it is also considered that use it in the therapeutic combination.
Another aspect of the present invention relates to one kind by alternately applying two or more analgesics to subject in need Agent is to prevent the method to develop immunity to drugs to reduce micturition frequency.In one embodiment, the method includes applying first Analgesic continues first time period and then continues second time period using the second analgesic.In another embodiment, institute The method of stating is further included continues the third period using third analgesic.First analgesic, the second analgesic and third Analgesic is different from each other and can be selected from salicylate (salicylate), aspirin (aspirin), salicylic acid (salicylic Acid), gaultherolin (methyl salicylate), Diflunisal (diflunisal), sasapyrin (salsalate), Olsalazine (olsalazine), salicylazosulfapyridine (sulfasalazine), para-aminophenol (para- Aminophenol) derivative, antifebrin (acetanilide), paracetamol (acetaminophen), phenaetin (phenacetin), fragrant that sour (fenamate), mefenamic acid (mefenamic acid), Meclofenamic Acid (meclofenamate), meclofenamate sodium (sodium meclofenamate), heteroaryl acetic acid (heteroayl Acetic acid) derivative, MCN 2559 (tolmetin), ketorolac (ketorolac), Diclofenac (diclofenac), third Sour (propionic acid) derivative, brufen (ibuprofen), naproxen sodium (naproxen sodium), naproxen (naproxen), fenoprofen (fenoprofen), Ketoprofen (ketoprofen), Flurbiprofen (flurbiprofen), Austria Husky general piperazine (oxaprozin)；Bmap acid (enolic acids), former times health (oxicam) derivative, piroxicam (piroxicam), Meloxicam (meloxicam), tenoxicam (tenoxicam), Ampiroxicam (ampiroxicam), bend Former times health (droxicam), pyrrole irrigate former times health (pivoxicam), pyrazolone (pyrazolon) derivative, bute (phenylbutazone), crovaril (oxyphenbutazone), antipyrine (antipyrine), aminopyrin (aminopyrine), analgin (dipyrone), former times dry goods (coxibs), celecoxib (celecoxib), rofecoxib (rofecoxib), Nabumetone (nabumetone), apazone (apazone), aulin (nimesulide), indoles Mei Xin (indomethacin), sulindac (sulindac), Etodolac (etodolac) and isobutylphenylpropionic acid (isobutylphenyl propionic acid)。
In one embodiment, first analgesic is paracetamol, and second analgesic is brufen, The third analgesic is naproxen sodium.The visual subject of length in each period is different to the reaction of each analgesic.One In a little embodiments, each period continues 3 days to 3 weeks.In another embodiment, first analgesic, the second analgesic It is configured to sustained release with one or more in third analgesic.
Further aspect of the application is related to a kind of pharmaceutical composition, includes one or more analgesic it includes (1) First component, wherein first component is configured to 1-4 hours after oral administration lag time sustained releases；With (2) include the second component of one or more analgesic, wherein second component be configured to it is small with 4-6 after oral administration When lag time sustained release.
In some embodiments, one or more analgesic in first component or the second component are selected from Ah Si Woods, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and paracetamol.
In some embodiments, second component includes the analgesic of 5-2000mg amounts, such as paracetamol.
In some embodiments, described pharmaceutical composition is coated with enteric coating.
In some embodiments, first component is further included selected from muscarine antagonist, antidiuretic and spasmolysis The medicament of agent.
In some embodiments, second component is further included selected from muscarine antagonist, antidiuretic and spasmolysis The medicament of agent.
In some embodiments, first and second component both further includes selected from muscarine antagonist, resists The medicament of diuretics and antispastic.
In some embodiments, second component is coated with non-soluble polymer (WIP) and enteric polymer (EP) WIP:EP ratios are 4:1 to 1:2 blend.
In some embodiments, second component is coated with multiple dope layers.
In some embodiments, second component is by swell layer and outside be insoluble but the semi-permeable polymerization of tool Object coating is coated.In some related embodiments, the swell layer includes fine selected from hydroxypropyl methyl cellulose, methyl Tie up element, methyl hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymer, polyethylene glycol, poly- second Alkene pyrrolidone, methacrylic acid copolymer, cellulose acetate phthalate, Hydroxypropyl Methylcellulose Phathalate, Acetic acid succinic acid hydroxypropyl methyl cellulose (hydroxypropylmethylcellulose acetate succinate) gathers Vinyl acetate phthalic acid ester (polyvinyl acetatephthalate), shellac (shellac) and ethyl cellulose Material.
In some embodiments, second part formulation includes water-insoluble capsule body, wherein the one of the capsule body End is with insoluble but have the hydrogel plug (plug) of permeability and swellability and close, wherein the plug includes selected from poly- Methacrylate, erodible comperession polymer, the molten polymer of condensation (congealed) and enzymatic control it is easy by The material of eroding polymer.
Further aspect of the application is related to a kind of pharmaceutical composition, and it includes the analgesic that (1) includes 5-2000mg amounts First component of (such as paracetamol), wherein first component is formulated into and discharges at once；(2) include it is a kind of or Second component of a variety of analgesic, wherein second component is formulated into 1-4 hours after oral administration lag times Sustained release；(3) include the third component of one or more analgesic, wherein first component is formulated into oral 4-6 hours lag time sustained releases after administration.
In some embodiments, one or more analgesic in second component or third component or both are selected from Aspirin, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and paracetamol.
In some embodiments, second component includes the analgesic of 5-2000mg amounts, such as paracetamol.
In some embodiments, second component is coated with enteric coating.
In some embodiments, the third component includes the analgesic of 5-2000mg amounts, such as paracetamol.
In some embodiments, first component is further included selected from muscarine antagonist, antidiuretic and spasmolysis The medicament of agent.
In some embodiments, second component is further included selected from muscarine antagonist, antidiuretic and spasmolysis The medicament of agent.
In some embodiments, the third component is further included selected from muscarine antagonist, antidiuretic and spasmolysis The medicament of agent.
In some embodiments, first and second component respectively contain selected from muscarine antagonist, antidiuretic and The medicament of antispastic.
In some embodiments, described first and third component respectively contain selected from muscarine antagonist, antidiuretic and The medicament of antispastic.
In some embodiments, described second and third component respectively contain selected from muscarine antagonist, antidiuretic and The medicament of antispastic.
In some embodiments, first, second, and third component is respectively contained selected from muscarine antagonist, antidiuresis The medicament of agent and antispastic.
In some embodiments, second component is coated with enteric coating.
In some embodiments, second component or third component are coated with WIP:EP ratios are 4:1 to 1:2 it is non- Water-soluble polymer (WIP) and enteric polymer (EP).
In some embodiments, the third component is coated with multiple dope layers.
Further aspect of the application is related to a kind of pharmaceutical composition for reducing micturition frequency, and it includes (1) to include First component of the paracetamol of 5-2000mg amounts, wherein first component is formulated into and discharges at once；(2) include Second component of one or more analgesic, wherein second component be formulated into it is slow with 1-4 hours after oral administration Stagnant time delay release；(3) include the third component of one or more analgesic, wherein first component be formulated into 4-6 hours lag time sustained releases after oral administration, wherein described pharmaceutical composition reduce the row of patient in need Frequent micturition rate.
In some embodiments, one or more analgesic choosing in second component or third component or both From aspirin, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and paracetamol.
Manufacturing method
The another aspect of the application is related to the side for manufacturing the delayed release medicine composition for reducing micturition frequency Method.In some embodiments, it the described method comprises the following steps：It is formed and is lived comprising first containing one or more analgesic First mixture of property ingredient；It is coated with first mixture to form the first component with the first sustained release coating, wherein institute It states the first sustained release coating and first mixture was discharged with 1-4 hours after being administered orally lag times；Formation contains There is the second mixture of the second active constituent of one or more analgesic；It is mixed with the second sustained release coating coating described second Object is closed to form the second component, wherein the second sustained release coating was with lag time release in 4-6 hour after being administered orally Second mixture；And first component is merged with second component to form third mixture.
In some embodiments, described first, second and/or third mixture include pharmaceutically acceptable carrier, Such as excipient.
In some embodiments, one or more analgesic in second component or third component or both are selected from Aspirin, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and paracetamol.
In some embodiments, at least one of described first and second active constituent containing 5mg to 2000mg's Analgesic, such as paracetamol.In some embodiments, first active constituent contains stopping for 5mg to 2000mg Pain agent, such as paracetamol.In other embodiments, second active constituent contains the analgesic of 5mg to 2000mg Agent, such as paracetamol.In other embodiments, first and second active constituent respectively contains 5mg extremely The analgesic of 2000mg, such as paracetamol.
In some embodiments, at least one of described first and second active constituent also includes to be selected from Antimuscarinic Agent, antidiuretic and antispastic medicament.In some embodiments, first active constituent also includes to be selected from Antimuscarinic Agent, antidiuretic and antispastic medicament.In other embodiments, second active constituent also includes to be selected from Antimuscarinic Agent, antidiuretic and antispastic medicament.In other embodiments, first and second active constituent respectively contains and is selected from The medicament of muscarine antagonist, antidiuretic and antispastic.
In some embodiments, the first sustained release coating is enteric coating.In some embodiments, described Two sustained release coatings include WIP:EP ratios are 4:1 to 1:2 non-soluble polymer (WIP) and enteric polymer (EP) Blend.In some embodiments, the second sustained release coating includes multiple dope layers.
In some embodiments, the second sustained release coating includes swell layer and outside is insoluble but tool partly oozes The polymer coating of permeability.In some related embodiments, the swell layer includes selected from hydroxypropyl methyl cellulose, first Base cellulose, methyl hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymer, polyethylene glycol, Polyvinylpyrrolidone, methacrylic acid copolymer, cellulose acetate phthalate, phthalic acid hydroxypropyl methyl fiber Element, acetic acid succinic acid hydroxypropyl methyl cellulose (hydroxypropylmethylcellulose acetate Succinate), polyvinyl acetate phthalate (polyvinyl acetatephthalate), shellac (shellac) and The material of ethyl cellulose.
In some embodiments, the second sustained release coating includes water-insoluble capsule body, the wherein capsule body One end with insoluble but have the hydrogel plug (plug) of permeability and swellability and close, wherein the plug includes choosing It is controlled from polymethacrylates, erodible comperession polymer, the molten polymer of condensation (congealed) and enzymatic The material of erodible polymer.
In some embodiments, the method further includes third mixture being suppressed or being molded as the step of tablet form Suddenly.
In some embodiments, it is formed by merging first component and second component with third component The third mixture, wherein the third component includes the third active constituent containing one or more analgesic.At some In embodiment, one or more analgesic be selected from aspirin, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and paracetamol.
In some embodiments, first, second, and third active constituent respectively contains one or more analgesic. In some embodiments, one or more analgesic are selected from aspirin, brufen, naproxen, naproxen sodium, indoles Mei Xin, Nabumetone and paracetamol.In some embodiments, first, second, and third active constituent is respectively Including 5-2000mg paracetamol.In some embodiments, one of described first, second, and third active constituent includes 5-2000mg paracetamol.In some embodiments, two kinds in first, second, and third active constituent include 5-2000mg paracetamol.
In some embodiments, it the described method comprises the following steps：Formed includes containing one or more analgesic First mixture of the first active constituent；With the first sustained release coating coating first mixture to form nuclear structure, Described in the first sustained release coating discharge first mixture to be in direct contact rear 1-4 hours of lag time with body fluid； Be coated with the nuclear structure with the second mixture to form the nuclear structure of coating, wherein second mixture include containing a kind of or Second active constituent of a variety of analgesic；And the nuclear structure of the coating is coated with to form double paintings with the second sustained release coating The nuclear structure of cloth, wherein the second sustained release coating is with 1-4 hours after oral administration lag times release described the Two mixtures.In some embodiments, first mixture is just straight with body fluid after second mixture is released Contact.
In some embodiments, one or more analgesic choosing in first active constituent or the second active constituent From aspirin, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and paracetamol.
In some embodiments, the second sustained release coating is enteric coating.
In some embodiments, first active constituent or second active constituent or both further include choosing From the medicament of muscarine antagonist, antidiuretic and antispastic.
In some embodiments, first active constituent or second active constituent or both include to acetyl ammonia Base phenol.
In some embodiments, the method further includes the nuclear structure of double coatings is coated with third coating Step, wherein the third coating includes the third active constituent containing one or more analgesic.In some embodiments, One or more analgesic in the third active constituent are selected from aspirin, brufen, naproxen, naproxen sodium, indoles Mei Xin, Nabumetone and paracetamol.In some embodiments, the third active constituent includes 5mg to 2000mg Analgesic.In some embodiments, the third active constituent includes 5mg to 2000mg paracetamol.
In some related embodiments, the third active constituent also include selected from muscarine antagonist, antidiuretic and The medicament of antispastic.In other related embodiments, first, second, and third active constituent is respectively contained to acetyl ammonia Base phenol.
In some embodiments, the first sustained release coating includes the non-TCP friendly flow containing one or more polysaccharide Property polymer, wherein the non-TCP friendly flow polymer equal resistant to corrosion in stomach and intestines, but can degrade in colon.
In other embodiments, the first sustained release coating or the second sustained release coating or both include water Permeability but insoluble film coating is active constituent and bleeding agent to be encapsulated in the nuclear structure or the nuclear structure of the coating. When the water from enteron aisle is slowly diffused to through this insoluble film in the nuclear structure, core swelling is until film spalling, thus discharges Active constituent.The membrane coat can be adjusted to allow various water penetration rates or release time.As previously mentioned, can be slow by being disintegrated Stagnant time (disintegration lag time) controls the release time of drug, this depends on containing in bottom part body pre- Determine the non-water-soluble polymer film (such as ethyl cellulose, EC) of micropore tolerance level and thickness and swellable excipient it is (such as low to take The hydroxypropyl cellulose (L-HPC) and sodium glycollate in generation) amount between balance.After oral, GI fluids are caused through micropore permeation Swellable excipient is set to be swollen, this generation makes the internal pressure that capsule component is detached from.
In other embodiments, drug is by permeating mechanism release.In some embodiments, first delay is released It includes semi-permeable membrane to put coating or the second sustained release coating or both.In some embodiments, the semi-permeable membrane additionally uses pH Dependence enteric coating, which is coated with, prevents release until after gastric emptying.
Following embodiment further illustrates the present invention, which should not be construed as limiting the invention.It is quoted in the present invention All reference papers, the content of patent and Patent Application Publication it is incorporated herein by reference.
Embodiment 1：The inhibition of urination impulsion
20 trial volunteers that men and women participates in are recruited, they each experienced premature urination impulsion or urination and need It asks, this disturbs the ability that they are enough the sleep for a period of time for feeling fully to rest.Every subject is before bedtime with list Dosage takes in 400 to 800mg brufen.At least 14 subjects reporteds are said, because not called out by frequent urination impulsion It wakes up, they can preferably rest.
There are several subjects reporteds to say, after night use brufen several weeks, can no longer realize urination impulsion not Too frequent benifit.However, all these subjects further report, after abandoning taking medicament several days, and obtain Such benifit.
Embodiment 2：Analgestic, botulic neurotoxin and muscarine antagonist are to macrophage to inflammation and non-inflammation The influence of the reaction of stimulation
Experimental design
This research be intended to determine analgestic and muscarine antagonist control macrophage to by COX2 and prostaglandin (PGE, PGH etc.) mediate inflammation and non-inflammation stimulation reaction in dosage and vitro efficacy.It is established to scorching in bladder cells The reaction of the baseline (dosage and dynamics) of disease and non-inflammation effector.In short, being not present or there are various effectors In the case of, so that culture cell is exposed to analgestic and/or muscarine antagonist.
The effector includes：Lipopolysaccharides (LPS), inflammatory agent and Cox2 inducers, as inflammatory stimulus；Kappa courage Alkali or acetylcholine, smooth muscle contraction stimulant, as non-inflammation stimulus；Botulic neurotoxin A, one kind known to The inhibitor of acetylcholine release, as positive control；Arachidonic acid (AA), gamma linolenic acid (DGLA) or eicosapentaenoic Sour (EPA), as the precursor of prostaglandin, they are by cyclooxygenase (COX1 and COX2) and terminal prostaglandin synthase It is generated after oxidation AA, DGLA or EPA successively in the cell.
The analgestic includes：Salicylate, such as aspirin, isobutyl group propionic acid phenolic acid derivative (brufen) such as refined dimension (Advil), Motrin (Motrin), sulfamethazole (Nuprin) and Medipren；Naproxen sodium, such as naproxen sodium (Aleve), naproxen preparation (Anaprox), Antalgin, Feminax Ultra, naproxen (Flanax), Inza, Midol Extended Relief, Nalgesin, Naposin, Naprelan (Naprelan), Naprogesic, naproxen (Naprosyn), naproxen (Naprosyn) suspension, EC- naproxens (EC-Naprosyn), Narocin, naproxen (Proxen), Synflex and Xenobid；Acetic acid derivative, such as Indomethacin (Indocin)；1- naphthylacetic acid derivants, such as naphthalene Fourth U.S. ketone or Relafen；N-acetyl p-aminophenol (APAP) derivative, such as paracetamol or paracetamol (Tylenol Woods) and celecoxib.
The muscarine antagonist includes：Oxybutynin, solifenacin, darifenacin and atropine.
Macrophage is set to be stimulated by short-term (1-2 hours) of following substance or long-term (24-48 hours)：
(1) each individual analgestic of various dose.
(2) in the presence of LPS various dose each analgestic.
(3) in the presence of carbachol or acetylcholine various dose each analgestic.
(4) in the presence of AA, DGLA or EPA various dose each analgestic.
(5) the individual botulic neurotoxin A of various dose.
(6) in the presence of LPS various dose botulic neurotoxin A.
(7) in the presence of carbachol or acetylcholine various dose botulic neurotoxin A.
(8) in the presence of AA, DGLA or EPA various dose botulic neurotoxin A.
(9) each individual muscarine antagonist of various dose.
(10) in the presence of LPS various dose each muscarine antagonist.
(11) in the presence of carbachol or acetylcholine various dose each muscarine antagonist.
(12) in the presence of AA, DGLA or EPA various dose each muscarine antagonist.
Then the PGH of cell is analyzed2、PGE、PGE2, prostacyclin, thromboxane, IL-1 β, IL-6, TNF-α release, COX2 activity, the generation of cAMP and cGMP, IL-1 β, IL-6, TNF-α and COX2mRNA generation and CD80, CD86 and MHC The surface expression of II class molecules.
Material and method
Macrophage
Muridae RAW264.7 or J774 macrophage (being obtained by ATCC) are used in this research.By cell be maintained at containing In the culture medium of RPMI 1640, and it is supplemented with 10% fetal calf serum (FBS), 15mM HEPES, 2mM l-glutamines, 100U/ The streptomysin of ml penicillin and 100 μ g/ml.By cell at 37 DEG C, 5% CO2It is cultivated under atmosphere, and separation (passage) per week Once.
Macrophage is with the external treatment of analgestic
By RAW264.7 macrophages with 1.5x105The cell density of a cells/well (in 100 μ l culture mediums) is seeded in In 96 orifice plates.The following substance of cell is handled：(1) analgestic (paracetamol, aspirin, the Bu Luo of various concentration Fragrant or naproxen), the lipopolysaccharides (LPS) of (2) various concentration, it is the effector to the inflammation sexual stimulus of macrophage, (3) no With the carbachol or acetylcholine of concentration, they are the effector of non-inflammation stimulation, (4) analgestic and LPS or (5) analgesia Agent and carbachol or acetylcholine.In short, analgestic is dissolved in the culture medium of no FBS (that is, being supplemented with 15mM The RPMI 1640 of the streptomysin of HEPES, 2mM l-glutamine, 100U/ml penicillin and 100 μ g/ml), and by with identical The serial dilution of medium is diluted to required concentration.For the cell handled with analgestic in the presence of no LPS, to every The culture medium without FBS of the analgestic solution and 50 μ l of 50 μ l is added in a hole.For in the presence of having LPS with analgesia The cell of agent processing, the LPS being added into each hole in the analgestic solution of 50 μ l and the culture medium in no FBS of 50 μ l (come From salmonella typhimurium (Salmonella typhimurium)).All condition retests are twice.
Culture 24 or 48 hours after, collect 150 μ l culture supernatant, rotated at 4 DEG C, under 8,000rpm 2 minutes with Cell and fragment are removed, and is stored at -70 DEG C for passing through the reaction of elisa assay cell factor.Pass through the phosphorus in 500 μ l Centrifugation in phthalate buffer (PBS) (at 4 DEG C, 1,500rpm lower 5 minutes) is collected and washing cell.Then the cell of half is existed Quick freezing in liquid nitrogen, and stored at -70 DEG C.Remaining cell fluorescent monoclonal antibody is dyed and passes through fluidic cell Meter analysis.
The Flow Cytometry of costimulatory molecules expression
For Flow Cytometry, the FACS buffer solution by macrophage in 100 μ l (has 2% bovine serum albumin (BSA) and 0.01%NaN in vain3Phosphate buffer (PBS)) in dilution, and pass through add FITC- combine anti-CD40, PE- In conjunction with anti-CD80, PE- combine anti-CD86 antibody, anti-MHC II classes (I-Ad) PE (BD bioscience) and dyed at 4 DEG C 30 minutes.Then by cell by centrifuging (at 4 DEG C, 1,500rpm lower 5 minutes) cleaning in the FACS buffer solution of 300 μ l. After second is washed, cell is resuspended in the FACS buffer solution of 200 μ l, and (BD gives birth to by Accuri C6 flow cytometries Object science) analyze the percentage that expression gives the cell for the combination (double positives) for marking (single positive) or label.
Pass through the reaction of elisa assay cell factor
Cytokine ELISA is carried out to culture supernatant, to determine individually being handled with analgestic, LPS or IL-1 β, IL-6 in the culture of LPS and the macrophage of analgestic combination processing and TNF-α reaction.These measurement be with Anti-mouse IL-6, the TNF-α mAbs (BD bioscience) of the 100 μ l in the sodium bicarbonate buffer liquid (pH 9.5) of 0.1M or It is carried out on the overnight Nunc MaxiSorp Immunoplates (Nunc) of IL-1 β mAb (R＆D systems) coatings.With PBS After (per 200 μ l of hole) cleaning twice, to the PBS 3%BSA of 200 μ l of addition in each hole (area), and it is incubated at room temperature plate 2 Hour.200 μ l are added by every hole, clean plate twice, repeats cytokine standards product and the serial dilution of adding 100 μ l again Culture supernatant, and the plate is incubated overnight at 4 DEG C.Finally, twice by plate cleaning, it is used in combination 100 μ l biotinylated The secondary antibody of anti-mouse IL-6, TNF α mAbs (BD bioscience) or IL-1 β (R＆D systems) then use the sheep of peroxidase labelling Antibiotin mAb (laboratories Vector) is incubated.It is bis- (3- Ethylbenzyl thiazoline -6- sulfonic acid) by adding 2,2 '-azines - (ABTS) substrate and H2O2(Sigma) chrominance response is made to develop, and absorbance usesV multiple labeling microwell plates detect Instrument (PerkinElmer) measures at 415nm.
The generation of the determination of activity of COX2 and cAMP and cGMP
The activity of COX2 in the macrophage of culture is determined by COX2 determinations of activity.The generation of cAMP and cGMP is logical CAMP is crossed to measure and cGMP measure to determine.These measurement usually carry out in the art.
As a result
Table 1 summarize the experiment carried out by 264 macrophage strains of Raw and analgestic to costimulatory molecules CD40 and Main discovery in terms of the influence of the cell surface expression of CD80.The expression of these molecules is pierced by COX2 and inflammatory signals Sharp, and the expression of these molecules is therefore assessed to determine the functional consequence of the inhibition of COX2.
1. experimental summary of table
As shown in table 2, in addition to maximum dose level is (that is, 5x106NM) (it shows to enhance, rather than inhibits costimulatory molecules Expression) other than, paracetamol, aspirin, brufen and naproxen are in all proof loads (that is, 5x105nM、 5x104nM、5x103nM、5x102NM, 50nM and 5nM) under inhibit macrophage costimulatory molecules CD40 and CD80 underlying table It reaches.As shown in Figure 1A and 1B, it is observed to CD40 and CD50 tables when analgestic dosage is down to 0.05nM (that is, 0.00005 μM) The such inhibition reached.This discovery supports such viewpoint：The control release of low dose of analgestic is than large dosage Acute delivering it is more preferable.Experiment is it is also shown that paracetamol, aspirin, brufen and naproxen induced LPS CD40 has similar inhibition with the expression of CD80.
The summary that table 2. is mainly found
*ND：It does not carry out (toxicity)
Table 3 summarize several research as a result, these researchs measure analgestic of the adult after oral medication dosage Serum levels.As shown in table 3, after oral medication dosage the maximum serum levels of analgestic 104To 105Within the scope of nM.Cause This, the analgesia agent dose of the testing in vitro in table 2 covers achievable concentration range in human body.
The serum levels of analgestic after 3. oral medication dosage of table in human blood
Embodiment 3：Analgestic, botulic neurotoxin and muscarine antagonist are to bladder smooth muscle cells to inflammation and non- The influence of the reaction of inflammation sexual stimulus
Experimental design
How the optimal dosage that this research is intended to the analgestic that explanation determines in example 2 influences in cell culture or group Knit culture in bladder smooth muscle cells, and discuss inhomogeneous analgestic whether can cooperate with more effectively inhibit COX2 and PGE2 reacts.
Effector, analgestic and muscarine antagonist are described in example 2.
Make short-term (1-2 hour) or long-term (24- of the primary culture of mouse bladder smooth muscle cell by following substance 48 hours) stimulation：
(1) each individual analgestic of various dose.
(2) in the presence of LPS various dose each analgestic.
(3) in the presence of carbachol or acetylcholine various dose each analgestic.
(4) in the presence of AA, DGLA or EPA various dose each analgestic.
(5) the individual botulic neurotoxin A of various dose.
(6) in the presence of LPS various dose botulic neurotoxin A.
(7) in the presence of carbachol or acetylcholine various dose botulic neurotoxin A.
(8) in the presence of AA, DGLA or EPA various dose botulic neurotoxin A.
(9) each individual muscarine antagonist of various dose.
(10) in the presence of LPS various dose each muscarine antagonist.
(11) in the presence of carbachol or acetylcholine various dose each muscarine antagonist.
(12) in the presence of AA, DGLA or EPA various dose each muscarine antagonist.
Then the PGH of cell is analyzed2、PGE、PGE2, prostacyclin, thromboxane, IL-1 β, IL-6, TNF-α release, COX2 activity, the generation of cAMP and cGMP, IL-1 β, IL-6, TNF-α and COX2mRNA generation and CD80, CD86 and MHC The surface expression of II class molecules.
Material and method
The separation and purifying of mouse bladder cell
Bladder cells are taken out from the animal C57BL/6 mouse (8-12 week old) being euthanized, and cell is passed through into enzymic digestion Separation, it is then gradient-purified with Percoll.In short, by the bladder scissors obtained from 10 mouse chopping for 10ml's Digest the refined slurries in the buffer solution DNA enzymatic of 2% fetal calf serum, 0.5mg/ml clostridiopetidase As, 30 μ g/ml (RPMI 1640). By bladder slurries at 37 DEG C enzymic digestion 30 minutes.By indigested fragment by cell training aids (cell-trainer) into one Step dispersion.Make cell suspension liquid precipitate, and be added to discontinuous 20%, 40% and 75%Percoll gradients with purification Mononuclear Cell.Each experiment uses 50-60 bladder.
With RPMI 1640 clean after, bladder cells are re-suspended into be supplemented with 10% fetal calf serum, 15mM HEPES, In the RPMI 1640 of the streptomysin of 2mM l-glutamines, 100U/ml penicillin and 100 μ g/ml, and with 3x104A cells/well The cell density of (100 μ l) is inoculated into the 96 micro- culture plate of hole cell culture of black of clarification bottom.By cell at 37 DEG C, 5% CO2It is cultivated under atmosphere.
Cell is with the external treatment of analgestic
Bladder cells individually or with carbachol (10 moles, 50 holes μ l/) (are made with analgestic solution (50 holes μ l/) For the example of non-inflammation stimulus) it is jointly processed by, or lipopolysaccharides (LPS) (the 1 μ g/ml, 50 μ with salmonella typhimurium The holes l/) (example as non-inflammation stimulus) be jointly processed by.When there is no other effectors to be added in cell, Xiang Kongzhong The RPMI1640 without fetal calf serum of 50 μ l is added to adjust final volume as 200 μ l.
After 24 hours of incubation, the culture supernatant for collecting 150 μ l rotates 2 minutes at 4 DEG C, under 8,000rpm to remove Cell and fragment, and stored at -70 DEG C for passing through elisa assay prostaglandin E2 (PGE2) reaction.The cells are fixed, Permeabilization is simultaneously closed to use fluorogenic substrate to detect cyclooxygenase-2 (COX-2).In selected experiment, cell stimulates 12 in vitro The analysis that hour reacts for COX2.
COX2 response analysis
COX2 reactions are divided by the ELISA based on cell of the total COX2 immunoassays of user/mouse (R＆D systems) Analysis, the analysis carry out according to the manufacturer's instructions.In short, after cell fixation and permeabilization, to the black of clarification bottom Mouse is added in the hole of the 96 micro- culture plate of hole cell culture of color and resists total COX2 and the total GAPDH of rabbit-anti.After cultivation and cleaning, The anti-rabbit IgG that the anti-mouse IgG and AP that HRP is combined are combined is added in Xiang Kongzhong.After another cultivation and cleaning, it is glimmering that HRP- is added Light substrate and AP- fluorogenic substrates.Finally, it usesV multiple labeling micropore board detectors (PerkinElmer) are read The fluorescence sent out at 600nm (COX2 fluorescence) and 450nm (GAPDH fluorescence).As a result it is expressed as the relative level of total COX2, is led to It crosses Relative fluorescence units (RFUs) to determine, and is standardized as house keeping protein GAPDH.
PGE2 response analysis
The reaction of prostaglandin E2 is analyzed by sequential competition ELISA (R＆D systems).Specifically, small to being resisted by goat Culture supernatant or PGE2 standard samples are added in the hole of coated 96 porous polystyrene microporous plate of mouse polyclonal antibody.In microwell plate After being incubated one hour on oscillator, the PGE2 that HRP is combined is added, and plate is additionally incubated two hours at room temperature.Then it cleans Plate, and HRP substrate solutions are added into each hole.Allow colour developing 30 minutes, and by (correcting wave at 570nm in 450nm It is long) at read plate before sulfuric acid is added to stop reacting.As a result PGE2 is expressed as to be averaged pg/ml.
Other experiments
The release of PGH2, PGE, prostacyclin (Prostacydin), thromboxane, IL-1 β, IL-6 and TNF-α, cAMP With the generation of cGMP, IL-1 β, IL-6, TNF-α and the generation of COX2mRNA and the table of CD80, CD86 and MHC II class molecules Face expression is determined using method as described in example 2 above.
As a result
Analgestic inhibits mouse bladder cells to react the COX2 of inflammation sexual stimulus
To several analgestics (paracetamol, aspirin, brufen and naproxen) under 5 μM or 50 μM of concentration Mouse bladder cell is tested, to determine whether analgestic can induce COX2 reactions.24 hours culture analysis shows, institute The analgestic of test does not induce the COX2 in mouse bladder cell in vitro to react.
It is also tested for what these analgestics in vitro reacted carbachol or the LPS COX2 stimulated mouse bladder cell It influences.As shown in table 1, the dosage of the carbachol of test has no significant effect the COX-2 levels in mouse bladder cell. On the other hand, it is horizontal to dramatically increase total COX2 by LPS.It is worth noting that, paracetamol, aspirin, brufen and naphthalene General life can inhibit influences of the LPS to COX2 levels.When these drugs are tested at 5 μM or 50 μM, it can be seen that analgestic Inhibition (table 4).
Table 4. stimulates the COX2 expression with mouse bladder cell after analgestic processing in vitro
Analgestic inhibits mouse bladder cell to react the PGE2 of inflammation sexual stimulus
The secretion for measuring the PGE2 in mouse bladder cell culture supernatant, to determine because the mouse bladder of analgestic is thin The biological significance that born of the same parents' COX2 levels change.As shown in table 5, it is trained in the bladder cells not stimulated or in the presence of carbachol PGE2 is not detected in the culture supernatant of foster bladder cells.It reacts consistent with above-mentioned COX2, mouse is stimulated with LPS Bladder cells induce the high-level secretory of PGE2.The addition of analgestic paracetamol, aspirin, brufen and naproxen The influence for inhibiting LPS to secrete PGE2, and do not observed between the cell effect of the analgestic of 5 or 50 μM of dosage processing To difference.
Table 5. stimulates the PGE2 secretions with mouse bladder cell after analgestic processing in vitro
In short, these are statistics indicate that only use the COX2 that analgestic will not be in inducing mouse bladder cells under 5 μM or 50 μM It is reacted with PGE2.However, under 5 μM or 50 μM, it is thin that analgestic significantly inhibits the mouse bladder stimulated in vitro by LPS (1 μ g/ml) The COX2 and PGE2 of born of the same parents reacts.Do not observe analgestic to the COX2 of mouse bladder cell that is stimulated by carbachol (1mM) and PGE2 reactions significantly affect.
Embodiment 4：The influence that analgestic, botulic neurotoxin and muscarine antagonist shrink bladder smooth muscle cells
Experimental design
Make culture mouse or rat bladder smooth muscle cell with the bladder smooth muscle tissue of mouse or rat Bu Tong dense It is exposed to inflammatory stimulus and non-inflammation stimulus in the presence of the analgestic and/or muscarine antagonist of degree.Measure stimulation The contraction of muscle of induction is to assess the inhibition of analgestic and/or muscarine antagonist.
Effector, analgestic and muscarine antagonist are described in example 2.
Make short-term (1-2 hour) or long-term (24- of the primary culture of mouse bladder smooth muscle cell by following substance 48 hours) stimulation：
(1) each individual analgestic of various dose.
(2) in the presence of LPS various dose each analgestic.
(3) in the presence of carbachol or acetylcholine various dose each analgestic.
(4) in the presence of AA, DGLA or EPA various dose each analgestic.
(5) the individual botulic neurotoxin A of various dose.
(6) in the presence of LPS various dose botulic neurotoxin A.
(7) in the presence of carbachol or acetylcholine various dose botulic neurotoxin A.
(8) in the presence of AA, DGLA or EPA various dose botulic neurotoxin A.
(9) each individual muscarine antagonist of various dose.
(10) in the presence of LPS various dose each muscarine antagonist.
(11) in the presence of carbachol or acetylcholine various dose each muscarine antagonist.
(12) in the presence of AA, DGLA or EPA various dose each muscarine antagonist.
Material and method
Separation Primary mouse bladder cells as described in Example 3.In selected experiment, the culture of bladder body is used Object.It is shunk using Grass polygraphs (U.S. Quincy Mass) record bladder smooth muscle cells.
Embodiment 5：The influence of oral analgestic and muscarine antagonist to COX2 and the PGE2 reaction of bladder smooth muscle cells.
Experimental design
To normal mouse and the mouse with overactive bladder syndrome gives the aspirin of oral dose, naproxen Sodium, brufen, Indomethacin, Nabumetone, tylenol, celecoxib, oxybutynin, solifenacin, darifenacin, atropine And combinations thereof.Control group includes untreated normal mouse and the untreated OAB for not suffering from overactive bladder syndrome small Mouse.After final dose 30 (30) minute, collects bladder and stimulated in vitro with carbachol or acetylcholine.In selected experiment In, bladder uses botulic neurotoxin A processing before being stimulated with carbachol.Animal is retained in metabolic cage, and is commented Estimate micturition frequency (and volume).Bladder discharge rate is determined by monitoring water intake and cage litter weight (cage litter weight). Serum PG H is measured by ELISA2、PGE、PGE2, prostacyclin, thromboxane, IL-1 β, IL-6, TNF-α, cAMP and cGMP water It is flat.The expression of CD80, CD86, MHC II class in whole blood cells are detected by flow cytometry.
After the end of the experiment, it is shunk by animal euthanasia and with Grass polygraphs record in vitro bladder.By bladder Part is fixed in formalin, and is reacted by immunohistochemical analysis COX2.
Embodiment 6：Analgestic, botulic neurotoxin and muscarine antagonist to human bladder smooth muscle cell to inflammation and The influence of the reaction of non-inflammation stimulation
Experimental design
This research is designed to be characterized in how the optimal dosage of the analgestic determined in embodiment 1 to 5 influences to train in cell Human bladder smooth muscle cell in foster or tissue cultures, and discuss whether inhomogeneous analgestic can cooperate with more effectively to press down COX2 and PGE2 reaction processed.
Effector, analgestic and muscarine antagonist are described in example 2.
Make one bladder smooth muscle cells was stimulated by short-term (1-2 hours) of following substance or long-term (24-48 hours)：
(1) each individual analgestic of various dose.
(2) in the presence of LPS various dose each analgestic.
(3) in the presence of carbachol or acetylcholine various dose each analgestic.
(4) in the presence of AA, DGLA or EPA various dose each analgestic.
(5) the individual botulic neurotoxin A of various dose.
(6) in the presence of LPS various dose botulic neurotoxin A.
(7) in the presence of carbachol or acetylcholine various dose botulic neurotoxin A.
(8) in the presence of AA, DGLA or EPA various dose botulic neurotoxin A.
(9) each individual muscarine antagonist of various dose.
(10) in the presence of LPS various dose each muscarine antagonist.
(11) in the presence of carbachol or acetylcholine various dose each muscarine antagonist.
(12) in the presence of AA, DGLA or EPA various dose each muscarine antagonist.
Then the PGH of cell is analyzed2、PGE、PGE2, prostacyclin, thromboxane, IL-1 β, IL-6, TNF-α release, COX2 activity, the generation of cAMP and cGMP, IL-1 β, IL-6, TNF-α and COX2mRNA generation and CD80, CD86 and MHC The surface expression of II class molecules.
Embodiment 7：The shadow of analgestic, botulic neurotoxin and muscarine antagonist to human bladder smooth muscle cell contraction It rings
Experimental design
Make human bladder smooth muscle cell exposure in the presence of the analgestic of various concentration and/or muscarine antagonist of culture In inflammatory stimulus and non-inflammation stimulus.The contraction of muscle of stimulation induction is measured to assess analgestic and/or antitoxin gill fungus The inhibition of alkaline agent.
Effector, analgestic and muscarine antagonist are described in example 2.
Make one bladder smooth muscle cells was stimulated by short-term (1-2 hours) of following substance or long-term (24-48 hours)：
(1) each individual analgestic of various dose.
(2) in the presence of LPS various dose each analgestic.
(3) in the presence of carbachol or acetylcholine various dose each analgestic.
(4) in the presence of AA, DGLA or EPA various dose each analgestic.
(5) the individual botulic neurotoxin A of various dose.
(6) in the presence of LPS various dose botulic neurotoxin A.
(7) in the presence of carbachol or acetylcholine various dose botulic neurotoxin A.
(8) in the presence of AA, DGLA or EPA various dose botulic neurotoxin A.
(9) each individual muscarine antagonist of various dose.
(10) in the presence of LPS various dose each muscarine antagonist.
(11) in the presence of carbachol or acetylcholine various dose each muscarine antagonist.
(12) in the presence of AA, DGLA or EPA various dose each muscarine antagonist.
It is shunk using Grass polygraphs (U.S. Quincy Mass) record bladder smooth muscle cells.
Embodiment 8：Influence of the analgestic to normal human bladder's smooth muscle cell to the reaction of inflammation and non-inflammation signal
Experimental design：
The culture of normal human bladder smooth muscle cell
Normal human bladder smooth muscle cell is detached by enzymic digestion from macroscopical normal segments of human bladder.Cell is existed In vitro by 37 DEG C in 5%CO2Atmosphere in be supplemented with the left-handed paddy acyl of 10% fetal calf serum, 15mM HEPES, 2mM It cultivates and expands in the RPMI 1640 of the streptomysin of amine, 100U/ml penicillin and 100mg/ml, and by at trypsase Reason to detach that cell then inoculates in new culture bottle and passage per week is primary.First week of culture, culture medium are mended Filled with 0.5ng/ml epidermal growth factor, 2ng/ml fibroblast growth factors and 5 μ g/ml insulin.
Normal human bladder smooth muscle cell is handled with analgestic in vitro
By by trypsin digestion, and with 3x104It is flat that the cell density of a cells/well (100 μ l) is seeded in micro- culture Bladder smooth muscle cells in plate with analgestic solution (50 holes μ l/) individually or with carbachol (10 moles, 50 holes μ l/) (example as non-inflammation stimulus) is jointly processed by, or with the lipopolysaccharides (LPS) of salmonella typhimurium (1 μ g/ml, 50 holes μ l/) (example as non-inflammation stimulus) be jointly processed by.When there is no other effectors to be added in cell, to The RPMI 1640 without fetal calf serum of 50 μ l is added in hole to adjust final volume as 200 μ l.
After 24 hours of incubation, the culture supernatant for collecting 150 μ l rotates 2 minutes at 4 DEG C, under 8,000rpm to remove Cell and fragment, and stored at -70 DEG C for passing through elisa assay prostaglandin E2 (PGE2) reaction.The cells are fixed, Permeabilization is simultaneously closed to use fluorogenic substrate to detect COX2.In selected experiment, cell stimulate in vitro 12 hours for The analysis of COX2, PGE2 and cell factor reaction.
COX2, PGE2 and cell factor response analysis
As described in embodiment 3, Analysis for CO X2 and PGE2 reaction.As described in example 2, analysis cell factor is anti- It answers.
As a result
Analgestic inhibit normal human bladder smooth muscle cell inflammatory and non-inflammation stimulus COX2 is reacted- Culture 24 hours later cells and culture supernatant analysis shows, induce normal human bladder without the analgestic individually tested COX2 reactions in smooth muscle cell.However, as table 6 is summarized, in normal human bladder smooth muscle cell, carbachol Low but significant COX2 is induced to react.On the other hand, LPS processing causes in normal human bladder smooth muscle cell compared with Gao Shui Flat COX2 reactions.Paracetamol, aspirin, brufen and naproxen can inhibit carbachol and LPS to COX2 Horizontal influence.When these drugs are tested at 5 μM or 50 μM, it can be seen that analgestic imitates the inhibition of the LPS reactions induced Fruit.
Normal human bladder is flat after table 6. is handled with inflammatory with non-inflammation stimulus stimulation and with analgestic in vitro The COX2 expression of sliding myocyte
#Data are expressed with the average value being repeated twice
Analgestic inhibit normal human bladder smooth muscle cell inflammatory and non-inflammation stimulus PGE2 is reacted-with The above-mentioned induction to COX2 reactions is consistent, and carbachol and LPS induce the PGE2's of normal human bladder smooth muscle cell It generates.It has also been found that paracetamol, aspirin, brufen and naproxen also inhibit LPS inductions under 5 μM or 50 μM PGE2 reacts (table 7).
Treated with the stimulation of inflammatory and non-inflammation stimulus and with the analgestic in vitro normal human bladder of table 7. The PGE2 of smooth muscle cell secretes
#Data are expressed with the average value being repeated twice
Analgestic inhibit normal human bladder cell to the cell factor of inflammatory stimulus reaction-culture 24 hours with Rear cell and culture supernatant analysis shows, induced in normal human bladder smooth muscle cell without the analgestic individually tested IL-6 or TNF α secretion.As shown in Table 8 and 9, the dosage of the carbachol of test is thin to normal human bladder smooth muscle Low but significant TNF α and IL-6 is induced to react in born of the same parents.On the other hand, LPS processing leads to these proinflammatory cell factors A large amount of inductions.Paracetamol, aspirin, brufen and naproxen can inhibit carbachol and LPS to TNF α and IL- The influence of 6 reactions.When these drugs are tested at 5 μM or 50 μM, it can be seen that analgestic imitates the inhibition of the LPS reactions induced Fruit.
Normal human bladder is flat after table 8. is handled with inflammatory with non-inflammation stimulus stimulation and with analgestic in vitro The TNF α secretion of sliding myocyte
#Data are expressed with the average value being repeated twice
Normal human bladder is flat after table 9. is handled with inflammatory with non-inflammation stimulus stimulation and with analgestic in vitro The IL-6 secretions of sliding myocyte
#Data are expressed with the average value being repeated twice
By primary normal human bladder smooth muscle cell separation, cultivate and evaluate its in non-inflammation (carbachol) and Reaction in the presence of inflammatory (LPS) stimulant to analgestic.The purpose of this research is to determine normal human bladder smooth muscle Whether cell can reappear the phenomenon that being obtained by Muridae bladder cells above-mentioned.
With sustained release or extended release dosage system or the analgestic and/or muscarine antagonist of delay and extended release dosage system Repeat above-mentioned experiment.
Description above is for instructing how those skilled in the art put into practice the object of the invention, being not intended to Detailed description has been read for those of ordinary skill in the art those of can be apparent after specification significantly repaiies Change and changes.But, it is intended to all apparent modifications and variations are included within the scope of the invention, this will pass through following power Profit requires definition.Opposite instruction unless the context clearly, claim are intended to covering can effectively realize in any order The required component and step of its required purpose.

Claims (33)

1. a kind of method of pharmaceutical composition of manufacture for reducing micturition frequency, this approach includes the following steps：
Form the first mixture for including the first active constituent containing one or more analgesic；
First mixture is coated with to form the first component with the first sustained release coating, wherein first sustained release applies Layer was with 1-4 hour after being administered orally lag time release first mixtures；
Form the second mixture for including the second active constituent containing one or more analgesic；
Second mixture is coated with to form the second component with the second sustained release coating, wherein second sustained release applies Layer was with 4-6 hour after being administered orally lag time release second mixtures；And
First component is merged with second component to form third mixture.
2. described in first active constituent and second active constituent according to the method described in claim 1, wherein One or more analgesic are selected from aspirin, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and to acetyl Amino phenols.
3. according to the method described in claim 1, wherein, the first sustained release coating is enteric coating.
4. according to the method described in claim 1, wherein, first active constituent or second active constituent or both into One step includes the medicament selected from muscarine antagonist, antidiuretic and antispastic.
5. according to the method described in claim 1, wherein, the second sustained release coating includes WIP:EP ratios are 4:1 to 1:The blend of 2 non-soluble polymer (WIP) and enteric polymer (EP).
6. according to the method described in claim 1, wherein, the second sustained release coating includes multiple dope layers.
7. according to the method described in claim 1, wherein, the second sustained release coating includes that swell layer and outside are insoluble But the semi-permeable polymer coating of tool.
8. according to the method described in claim 7, wherein, the swell layer includes fine selected from hydroxypropyl methyl cellulose, methyl Tie up element, methyl hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymer, polyethylene glycol, poly- second Alkene pyrrolidone, methacrylic acid copolymer, cellulose acetate phthalate, Hydroxypropyl Methylcellulose Phathalate, The material of acetic acid succinic acid hydroxypropyl methyl cellulose, polyvinyl acetate phthalate, shellac and ethyl cellulose.
9. according to the method described in claim 1, wherein, the second sustained release coating includes water-insoluble capsule body, In the capsule body one end with insoluble but have a hydrogel plug of permeability and swellability and close, wherein the plug packet It easy is invaded containing what is controlled selected from polymethacrylates, erodible comperession polymer, the molten polymer of condensation and enzymatic Lose the material of polymer.
10. according to the method described in claim 1, it further comprises the step of the tabletted form of third mixture Suddenly.
11. according to the method described in claim 1, wherein, the third mixture is by by first component and described Two components merge to be formed with third component, wherein the third component includes the third activity containing one or more analgesic Ingredient.
12. a kind of pharmaceutical composition manufactured using method described in claim 1.
13. a kind of method of pharmaceutical composition of manufacture for reducing micturition frequency, the method includes：
Form the first mixture for including the first active constituent containing one or more analgesic；
First mixture is coated with to form nuclear structure, wherein the first sustained release coating with the first sustained release coating First mixture is discharged to be in direct contact rear 1-4 hours of lag time with body fluid；
The nuclear structure is coated with to form the nuclear structure of coating with the second mixture, wherein second mixture includes containing choosing From the one or more of aspirin, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and paracetamol Second active constituent of analgesic；And
It is coated with the nuclear structure of the coating with the second sustained release coating to form the nuclear structure of double coatings, wherein described second prolongs Slowbreak puts coating and discharges second mixture with 1-4 hours after oral administration lag times.
14. according to the method for claim 13, wherein the second sustained release coating is enteric coating.
15. according to the method for claim 13, wherein the institute in first active constituent and second active constituent It states one or more analgesic and is selected from aspirin, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and to second Acylamino- phenol.
16. according to the method for claim 13, wherein first active constituent or second active constituent or both Further include the medicament selected from muscarine antagonist, antidiuretic and antispastic.
17. according to the method for claim 13, further comprising the nuclear structure for being coated with double coatings with third coating The step of, wherein the third coating include containing selected from aspirin, brufen, naproxen, naproxen sodium, Indomethacin, The third active constituent of one or more analgesic of Nabumetone and paracetamol.
18. according to the method for claim 17, wherein the third active constituent is further included selected from Antimuscarinic Agent, antidiuretic and antispastic medicament.
19. the pharmaceutical composition that a kind of method using described in claim 13 manufactures.
20. a kind of pharmaceutical composition, it includes：
Including selected from aspirin, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and paracetamol First component of one or more analgesic, wherein first component is configured to release with lag time delay in 1-4 hours It puts；And
Including selected from aspirin, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and paracetamol Second component of one or more analgesic, wherein second component is configured to release with lag time delay in 4-6 hours It puts.
21. pharmaceutical composition according to claim 20, wherein described pharmaceutical composition is coated with enteric coating.
22. pharmaceutical composition according to claim 20, wherein first component and/or second component are into one Step includes the medicament selected from muscarine antagonist, antidiuretic and antispastic.
23. pharmaceutical composition according to claim 20, wherein second component is coated with WIP:EP ratios are 4:1 To 1:The blend of 2 non-soluble polymer (WIP) and enteric polymer (EP).
24. pharmaceutical composition according to claim 20, wherein second component is coated with multiple dope layers.
25. pharmaceutical composition according to claim 20, wherein second component by swell layer and it is external insoluble but Has semi-permeable polymer coating cladding.
26. pharmaceutical composition according to claim 20, wherein the swell layer includes to be selected from hydroxypropyl methyl fiber Element, methylcellulose, methyl hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymer, poly- second Glycol, polyvinylpyrrolidone, methacrylic acid copolymer, cellulose acetate phthalate, phthalic acid hydroxypropyl first Base cellulose, acetic acid succinic acid hydroxypropyl methyl cellulose, polyvinyl acetate phthalate, shellac and ethyl cellulose Material.
27. pharmaceutical composition according to claim 20, wherein second part formulation includes water-insoluble capsule Body, wherein one end of the capsule body are with insoluble but have the hydrogel plug of permeability and swellability and close, wherein described insert Plug is comprising selected from the easy of polymethacrylates, erodible comperession polymer, the molten polymer of condensation and enzymatic control Weather the material of polymer.
28. a kind of pharmaceutical composition, it includes：
Include the first component of the paracetamol of 5-2000mg amounts, wherein first component is formulated into and discharges at once； And
Including selected from aspirin, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and paracetamol Second component of one or more analgesic is released wherein second component is formulated into lag time delay in 1-4 hours It puts；And
Including selected from aspirin, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone and paracetamol The third component of one or more analgesic is released wherein the third component is formulated into lag time delay in 4-6 hours It puts.
29. pharmaceutical composition according to claim 28, wherein second component is coated with enteric coating.
30. pharmaceutical composition according to claim 28, wherein first component and/or second component and/or The third component further includes the medicament selected from muscarine antagonist, antidiuretic and antispastic.
31. pharmaceutical composition according to claim 30, wherein second component is coated with enteric coating.
32. pharmaceutical composition according to claim 28, wherein second component or third component are coated with WIP:EP Ratio is 4:1 to 1:2 non-soluble polymer (WIP) and enteric polymer (EP).
33. pharmaceutical composition according to claim 28, wherein the third component is coated with multiple dope layers.
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