CN107157991A - Alleviating prolongation delivery formulations and its application method for alleviating frequent micturition - Google Patents

Alleviating prolongation delivery formulations and its application method for alleviating frequent micturition Download PDF

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Publication number
CN107157991A
CN107157991A CN201710373440.5A CN201710373440A CN107157991A CN 107157991 A CN107157991 A CN 107157991A CN 201710373440 A CN201710373440 A CN 201710373440A CN 107157991 A CN107157991 A CN 107157991A
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release
analgestic
polymer
acid
pharmaceutical composition
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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 US13/424,000 external-priority patent/US8236857B2/en
Priority claimed from US13/487,348 external-priority patent/US20120244221A1/en
Application filed by Wellesley Pharmaceuticals LLC filed Critical Wellesley Pharmaceuticals LLC
Publication of CN107157991A publication Critical patent/CN107157991A/en
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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
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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
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    • A61K31/18—Sulfonamides
    • 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
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus

Abstract

The invention discloses the method and composition for alleviating frequent micturition.A kind of method includes the pharmaceutical composition for including analgestic prepared with alleviating prolongation delivery formulations that a kind of effective dose is applied to subject in need.Another method includes the pharmaceutical composition for including various active composition for being formulated into extension release that a kind of effective dose is applied to subject in need.

Description

Alleviating prolongation delivery formulations and its application method for alleviating frequent micturition
The application is the division Shen of " being used for the alleviating prolongation delivery formulations and its application method for alleviating frequent micturition " application for a patent for invention Please, the national applications number of female case is that " 2013800150623 ", PCT international filing dates are March 13, PCT international applications in 2013 Number be PCT/US2013/030901.
This application claims enjoy the U.S. Patent application for the serial number 13/424,000 submitted on March 19th, 2012 (i.e. Present U.S. Patent number 8,236,857) and the United States Patent (USP) Shen of serial number 13/847,348 submitted on June 4th, 2012 Priority please.By reference to mode patent application mentioned above is fully incorporated the application.
Technical field
Present application relates generally to the method and composition for suppressing contraction of muscle, in particular it relates to for suppressing bladder Smooth muscle contraction method and composition.
Background technology
Detrusor is one layer of the bladder wall, and it is by being arranged with spiral fiber bundle, longitudinal fiber bundle and fibrae circulares bundle What smooth muscle fibers was constituted.When bladder is stretched, this can transmit signal to shrink detrusor to parasympathetic.This promotees Enter bladder and urine is excluded by urethra.
To make urine discharge bladder, the arbitrarily internal sphincter of autonomous control (autonomically controlled) and control It must be open to make the external sphincter of (voluntarily controlled).These muscle, which go wrong, may result in mistake Prohibit.If urine volume reaches the 100% of the absolute capacity of bladder, random sphincter is changed into nonvoluntary, and urine can be arranged at once Go out.
The bladder of adult can generally accommodate 300 to 350ml urine (swept volume), but according to individual not Together, an one-tenth human bladder being full of, which can be accommodated, is up to about 1000ml (absolute volume).With the increase of urine, because of the folding of the bladder wall Bladder wall flattens formed by folded (gauffer), and the bladder wall stretches and thinning with it, so that bladder stores a greater amount of urines and interior Portion's pressure is not dramatically increased.
For most individuals, generally urination is begun with when the volume of the urine in bladder reaches about 200ml Desire.In this stage, if individual need, he is easy to suppress urination impulsion.As bladder continues to be full of, urination desire becomes Obtain increasingly stronger and be more difficult to ignore.Finally, when bladder will be filled to the degree that impulsion of urinating can not be resisted, individual can not Ignore it again.For some individuals, begin to generate this row when bladder is filled relative to its swept volume less than 100% The desire of urine.This enhanced urination desire may interfere with normal activity, including provide the sleep of sufficient uninterrupted rest Ability.In some cases, it is this it is enhanced urination desire may be related to internal medicine situation, such as male's benign prostatic hyperplasis or Prostate cancer, or women gestation.However, enhanced urination desire also occur in the male that is not influenceed by other internal medicine situation and In female individual.
Accordingly, it would be desirable to be stranded for being less than 100% compared with its swept volume by bladder full of urination desire is produced when urinating Composition and method that the sex patient disturbed is treated.The composition and method are required for suppressing muscle receipts Contracting, so that the patient just begins with urination desire when the volume of urine in bladder exceedes the 100% of about its swept volume Hope.
The content of the invention
The one side of the application is related to a kind of method for alleviating frequent micturition.Methods described is included to subject in need Using a kind of pharmaceutical composition, described pharmaceutical composition is included：Active component, the active component is with every dose of 50-400mg amount Comprising one or more analgestics, wherein, one or more analgestics are selected from aspirin, brufen, naproxen, Nabumetone Raw sodium, Indomethacin, Nabumetone and paracetamol, wherein, described pharmaceutical composition is formulated into extension release so that The active component is continuously released by within the period of 5-24 hours.Methods described can be used for treatment bed-wetting or bladder excessive to live Dynamic disease.
Further aspect of the application is related to a kind of method for alleviating frequent micturition.Methods described include to have this need it is tested Person applies a kind of pharmaceutical composition, and described pharmaceutical composition is included：Active component, the active component is with every dose of 50-400mg's Amount includes one or more analgestics, wherein, one or more analgestics are selected from aspirin, brufen, naproxen, naphthalene General raw sodium, Indomethacin, Nabumetone and paracetamol, wherein, described pharmaceutical composition is formulated into two sections of releases Extension release with the characteristics of curve, in the release profiles, the 20-60% of the active component is released in two hours applying Put, and the remainder of the active component is continuously released by within the period of 5-24 hours.Methods described can be used for treatment night Urinate disease or overactive bladder.
Further aspect of the application is related to a kind of method for alleviating frequent micturition, and it includes：Applied to subject in need With the botulin toxin of effective dose, wherein, the botulin toxin is applied by being expelled to bladder muscle；With to A kind of pharmaceutical composition of subject's oral administration, described pharmaceutical composition is included：Active component, the active component is with every Agent 50-400mg amount includes one or more analgestics, wherein, one or more analgestics are selected from aspirin, Bu Luo Sweet smell, naproxen, naproxen sodium, Indomethacin, Nabumetone and paracetamol, wherein, described pharmaceutical composition is formulated Into extension release.Methods described can be used for treatment bed-wetting or overactive bladder.
Further aspect of the application is related to a kind of method for alleviating frequent micturition, and it includes applying to subject in need The one or more analgestics and the zolpidem of effective dose of effective dose.Methods described can be used for treatment bed-wetting or bladder excessive to live Dynamic disease.
Further aspect of the application is related to a kind of method for alleviating frequent micturition, and it includes applying to the subject for having this demand A kind of pharmaceutical composition, described pharmaceutical composition is included：One or more analgestics；And antidiuretic, wherein, it is described a kind of or A variety of analgestics are formulated into sustained release, and wherein, the antidiuretic is formulated into be discharged immediately.Methods described can use In treatment bed-wetting or overactive bladder.
Further aspect of the application is related to a kind of pharmaceutical composition, and it is included：Contain one or more analgestics, azoles pyrrole Smooth active component and pharmaceutically acceptable carrier.
Further aspect of the application is related to a kind of pharmaceutical composition, and it is included：One or more analgestics and antidiuresis Agent, wherein, one or more analgestics are formulated into sustained release, and wherein, the antidiuretic is formulated establishment Discharge.
Brief description of the drawings
Figure 1A and Figure 1B be shown in lack under LPS (Figure 1A) or exist under LPS (Figure 1B) analgestic regulation Raw 264 it is huge The figure of the expression of the costimulatory molecules of phagocyte.Cell is in analgestic individualism or and salmonella typhimurium Cultivated 24 hours in the presence of (Salmonella typhimurium) LPS (0.05 μ g/ml) is common.Result is CD40+CD80+ thin The mean relative percentages of born of the same parents.
Embodiment
Following detailed description is proposed so that those skilled in the art implements and using the present invention.For the mesh of explanation , concrete term set forth below is to fully understand the present invention.It will be apparent, however, to one skilled in the art, that these have The details of body need not simultaneously be implemented in the present invention.The statement for providing concrete application is used only as typical embodiment.The present invention is simultaneously Shown embodiment is not intended to be limited to, and is desirable to include consistent with feature with principle disclosed herein possible most wide Scope.
Term " effective dose " as used herein refers to reach the amount needed for selected result.
Term " analgestic " as used herein refer to the reagent for pain of alleviation and comprising anti-inflammatory compound, compound or Medicine.Exemplary analgesia and/or anti-inflammatory agents, compound or medicine include but is not limited to following material：NSAIDs (NSAIDs), salicylate, aspirin, salicylic acid, gaultherolin, Diflunisal, salsalate, Olsalazine, willow nitrogen Sulphur pyridine, the derivative of para-aminophenol, antifebrin, paracetamol, phenacetin, fenamic acid ester, mefenamic acid, first chlorine go out Acid esters, meclofenamate sodium, heteroaryl acetic acid derivative, tolmetin, ketorolac, Diclofenac, propanoic derivatives, brufen, naphthalene General raw sodium, naproxen, fenoprofen, Ketoprofen, Flurbiprofen, olsapozine；Bmap acid, former times health (oxicam) derivative, pyrrole Sieve former times health, Meloxicam, tenoxicam, Ampiroxicam, drogelor, a Fu Xikang (pivoxicam), e derivatives, Phenylbutazone, crovaril, antipyrine, aminopyrine, analgin, examine former times class medicine, celecoxib, rofecoxib, naphthalene fourth U.S. ketone, apazone, Indomethacin, sulindac, Etodolac, IB, Prexige (lumiracoxib), Etoricoxib, parecoxib, valdecoxib, for drawing examine former times (tiracoxib), Etodolac, darbufelone, Dexketoprofen, vinegar Chlorine sweet smell acid, Licofelone (licofelone), Bromfenac, loxoprofen, pranoprofen, piroxicam, aulin, western azoles come Spit of fland, 3- Formylamino -7- Methylsulfonylamino -6- phenoxy group -4H-1- benzopyran-4-ones, Meloxicam, chlorine promise former times Health, right-handed indobufen, Mofezolac, Amtolmetin Guacil (amtolmetin), pranoprofen, Tolfenamic Acid, Flurbiprofen, relax Ibuprofen, olsapozine, Zaltoprofen, alminoprofen, Tiaprofenic Acid, and its pharmaceutical salts, its hydrate and its solvate.
Term " examining former times (coxib) " as used herein and " COX inhibitor " refer to containing can suppress the activity of COX-2 enzymes Or expression or can suppress or alleviate serious inflammatory reaction the order of severity (including pain and swelling) compound Composition.
Term " derivative " as used herein refers to the compound of chemical modification, wherein the modification is by common skilled Chemist is considered customary means, for example, the ester or acid amides of acid, protection group (such as benzyl for alcohol or mercaptan and right In the tertbutyloxycarbonyl of amine).
Term " analog " as used herein refers to include specific compound or the chemical modification form of its class and holding The compound of pharmacy the and/or pharmacological living features of the compound or that class compound.
" pharmaceutically acceptable salt " as used herein refers to the derivative of disclosed compound, wherein, parent chemical combination Thing is modified by forming its acid or alkali salt.The example of pharmaceutically acceptable salt includes, but not limited to alkaline residue (example Such as amine) mineral salt or acylate；The alkali salt or organic salt of acidic residues (such as carboxylic acid)；Etc..It is described pharmaceutically to connect The salt received include the conventional non-toxic salt of parent compound that (for example, by atoxic inorganic acid or organic acid) formed or Quaternary ammonium salt.For example, so conventional non-toxic salt includes：The salt obtained by inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, It is sulfamic acid, phosphoric acid, nitric acid etc.；And the salt prepared by organic acid, such as acetic acid, propionic acid, butanedioic acid, hydroxyl Acetic acid, stearic, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, Malaysia Acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic, p-aminobenzene sulfonic acid, 2- acetyl oxygen It is yl benzoic acid, fumaric, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid etc..
Phrase " pharmaceutically acceptable " as used herein is that same compound, material, composition and/or formulation make together With it is adapted to contact with the tissue of human and animal to use, with rational interests/wind in rational medical judgment scope Danger than and without too high toxicity, excitant, allergic reaction or other problems or complication.
Term " subject " as used herein or " patient " include mammal.On the one hand, the mammal refers to people Class.On the other hand, the mammal is non-human primates, such as chimpanzee and other apes and monkey class.On the one hand, it is described to feed Newborn animal is domestic animal, for example rabbit, dog or cat.On the other hand, the mammal is farm-animals, such as ox, horse, sheep, goat Or pig.On the other hand, the mammal is laboratory animal, and it includes rodent, such as rat, mouse and cavy Deng.
Bladder has two important functions：Storage of urine and emptying.Storage of urine occurs at low pressures, it means that Filling stage detrusor relaxes.The emptying of bladder needs the contraction and the relaxation of sphincter urethrae for the detrusor coordinated.Store work( The disorder of energy can cause lower urinary tract symptoms, such as urgent urination, frequent micturition and urge incontinence, the composition of bladder excessive activities syndrome Part.Bladder excessive activities syndrome (this is probably due to the non-autonomous contraction in storage stage smooth muscle of bladder (detrusor)) It is a kind of common and the problem of underestimated, its illness rate is just being assessed recently.
The one side of the application is related to a kind of method for alleviating frequent micturition, and methods described is applied by the people needed to there is this The pharmaceutical composition prepared with alleviating prolongation delivery formulations.Described pharmaceutical composition includes one or more analgestics, and not necessarily, One or more muscarine antagonists, one or more antidiuretics, one or more antispastics and/or zolpidem.Methods described It can be used for the treatment of bed-wetting and/or overactive bladder.
" extension release ", also known as sustained release (sustained-release, SR), continuous action (sustained- Action, SA), limited release (time-release, TR), control release (controlled-release, CR), improvement release (modified release, MR) or sustained release (continuous-release, CR), is that one kind makes in medicinal tablet or capsule To slow mechanism dissolved over time and the mechanism of discharge active component.The advantage of the tablet or capsule that extend release exists In, they usually can than the less frequency of immediate release formulation of same medicine administration, moreover, they keep more in blood flow Stable levels of drugs, so as to extend the pharmaceutically-active duration and reduce peak volume of the medicine in blood flow.For example, prolonging The analgestic of long release can make one to sleep peacefully whole night without getting up in the night to urinate.
In one embodiment, described pharmaceutical composition passes through insoluble matter (such as esters of acrylic acid or chitin) Embedding active component in matrix and be formulated into extension release.Extension releasing pattern is designed to by being tieed up in specific time period Hold constant levels of drugs and at a predetermined rate release analgesic compound.This can be realized by different preparation, including, But it is not limited to, liposome and drug-polymer conjugated body, such as hydrogel.
The preparation of extension release be designed at a predetermined rate release bioactive agent to maintain the period specifically extended Interior constant levels of drugs, for example, being up to about 24 after application or after the lag phase related to medicine sustained release Hour, about 20 hours, about 16 hours, about 12 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 Hour, about 4 hours, about 3 hours, about 2 hours or about 1 hour.
It is some preferred embodiment in, activating agent quilt during the time interval between about 2 hours to about 10 hours Release.Or, activating agent can about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, it is about 9 small When, about 10 hours, about 12 hours, about 16 hours, be released in about 20 hours or about 24 hours.In some other embodiment In, activating agent is released in the period after application between about 3 hours to about 8 hours.
In some embodiments, alleviating prolongation delivery formulations include active nucleus, and the active nucleus is by one or more inertia grain Son composition, each to be coated with medicine on its surface (for example, (use example in the form of the coating or film-forming composition of drug containing Such as fluidization or other method well known to those skilled in the art)) pearl, pill, pill, granule particles, microcapsules, Microballoon, microparticle, the form of Nano capsule or nanosphere.The inert particle can be different size of, as long as its is sufficiently large To keep not readily dissolving.Or, the active nucleus by the granulation of the polymer composition containing drug ingedient and can mill And/or prepared by extrusion with round as a ball.
The activating agent can be by being introduced in inert carrier, such as medicine point well known to a person skilled in the art technology Layer, powder coating, extrusion/round as a ball, rolling are granulated.The amount of medicine in the core by depending on required dosage, and Usually change from about 5 to 90wt%.Generally, based on the weight of coated bead, according to required lag time and/or selected Polymer and coating solvent, polymer coating on active nucleus is 1 to 50%.Those skilled in the art is possible to selection The proper amount of medicine of core is coated with or introduces on core to realize required dosage.In one embodiment, inactive core can To be sugar ball or buffered crystal or encapsulation buffered crystal, such as calcium carbonate, sodium acid carbonate, fumaric acid, tartaric acid, they change medicine The microenvironment of thing is to promote it to discharge.
Various extension releases can be used to be coated or contribute to activating agent gradually to be discharged with the time for the preparation of the extension release Mechanism.In some embodiments, the preparation of extension release includes the polymer of control release by control dissolving release. In special embodiment, activating agent is merged in containing insoluble polymer and coated by the polymeric material of different-thickness In the matrix of drug particle or particle.Polymeric material may include the lipid barrier containing wax-like materials, such as Brazil wax, honeybee Wax, spermaceti, candelila wax, shellac wax (shellac wax), cocoa butter, cetostearyl alcohol (cetostearyl Alcohol), partially hydrogenated vegetable oil, ceresine, paraffin, ceresine, myristyl alcohol, stearyl alcohol, cetanol and stearic acid, simultaneously What is existed also has surfactant, such as polyoxyethylene 20 sorbitan monooleate (polyoxyethylene sorbitan monooleate).When being contacted with aqueous medium (such as biological fluid), according to the thickness of polymer coating, predetermined delayed After time, polymer coating is emulsified or corroded.The lag time and gastrointestinal peristalsis, pH value or the holdup time in stomach (gastric residence) is unrelated.
In other embodiments, the preparation of extension release includes the polymer substrate for realizing control dispersal events.It is described Matrix can include the polymer of one or more hydrophilic and/or water-swellable formation matrix, the polymer dependent on pH value And/or the polymer independent of pH value.
In one embodiment, the preparation of the extension release includes water miscible or water-swellable formation matrix Polymer, not necessarily comprising one or more solubilized auxiliary materials and/or promotion delivery formulations.With the solubilising of water-soluble polymer Effect, activating agent dissolving (if solvable), and gradually being spread containing water section by matrix.Because more water penetrate into matrix In core, gel layer grows with the time, adds the thickness of gel layer and there is provided the diffusion barrier of insoluble drug release.As outer layer becomes Complete aquation, polymer chain is unfolded completely, and can not keep the integrality of gel layer again, causes on the surface of the substrate outer The polymer of layer aquation is untied entanglement and corroded.Water continues through gel layer and penetrated into core, until it is etched completely.Solvable Medicine is discharged by this diffusion and the synergy corroded, and for insoluble drugs, no matter dosage, erosion is all main Want mechanism.
Similarly, water-swellable polymer aquation and is swelled to form homogeneous matrix knot generally in biological fluid Structure, the structure keeps its shape during insoluble drug release, and is used as carrier, solubilizer and/or the discharge accelerator for medicine. Initial matrix polymer hydration stage result in the slow release (lag stage) of medicine.Once water-swellable polymer is complete It is hydrated and is swelled, the water in matrix can similarly dissolve drug substance, and be passed to matrix coating and diffuses out.
Further, since relying on the leaching of the discharge accelerator of pH value, the porosity of matrix can increase, so that with faster Speed discharges medicine.Then, drug release rate is changed into constant, and it turns into the drug diffusion of the polymer gel by being hydrated Function.Different parameters, including polymer type and grade are depended on from the rate of release of matrix；Drug solubility and agent Amount；The ratio of polymer and medicine；Wire feeding and grade；The ratio of polymer and filler；The particle diameter of medicine and polymer；With And the porosity and shape of matrix.
The polymer of exemplary hydrophilic and/or water-swellable formation matrix includes, but not limited to cellulose and gathered Compound, including hydroxy alkyl cellulose and carboxyl alkyl cellulose, such as hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), methylcellulose (MC), carboxymethyl cellulose (CMC), powdered cellulose, such as crystallite are fine Tie up element, cellulose acetate, ethyl cellulose, its salt, and combinations thereof；Alginates, natural gum, including heteroglycan glue and homopolysaccharide Glue, such as xanthans, tragacanth, pectin, Arabic gum, karaya, alginates, agar, guar gum, HPG, silicic acid Magnalium, carrageenan, carob gum, gelling carbohydrate gum and its derivative；Acrylic resin, including acrylic acid, methacrylic acid, third The polymer and copolymer of e pioic acid methyl ester and methyl methacrylate, and the polyacrylic acid derivative being crosslinked, such as carbomer (example Such as,Such as, including71G NF, with different molecular weight grade, from Noveon companies, Ohio The state city of Cincinnati)；Antler glue；Polyvinyl acetate (for example,SR)；Polyvinylpyrrolidone and its derivative Thing, such as Crospovidone；Polyethylene glycol oxide；And polyvinyl alcohol.It is preferred that hydrophily and water-swellable polymer include cellulose Polymer, particularly HPMC.
The alleviating prolongation delivery formulations can further include at least one adhesive, and the adhesive can make hydrophilic compounds Crosslinking is with the formation hydrophilic polymer base (that is, gel-type vehicle) in aqueous medium (including biological fluid).
Exemplary adhesive includes homopolysaccharide, such as galactomannan gum, guar gum, HPG, hydroxypropyl Cellulose (HPC；Such as Klucel EXF) and carob gum.In other embodiments, described adhesive be alginic acid derivative, HPC or microcrystalline cellulose (MCC).Other adhesives include, but not limited to starch, microcrystalline cellulose, hydroxypropyl cellulose, Hydroxyethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone.
In one embodiment, introducing method is by the suspension to injection activating agent and adhesive on inert carrier Medicine layering.
Described adhesive can in pearl type preparation with about 0.1wt% to about 15wt%, and preferably from about 0.2wt% is to about 10wt% amount is present.
In some embodiments, hydrophilic polymer base can further include ionomer, non-ionic polymers Or water insoluble hydrophobic polymer, with the more powerful gel layer of offer and/or the quantity and size of reduction matrix mesopore, So as to slow down the release of diffusion and erosive velocity and adjoint activating agent.This can additionally suppress initially break out effect, and produce " Zero order release " of raw more stable activating agent.
The exemplary ionomer for being used to slow down dissolution rate includes anionic polymer and cationic polymer.Show The anionic polymer of example property includes, for example, sodium carboxymethylcellulose (Na CMC), sodium alginate, acrylic acid or carbomer Polymer (such as934、940、974P NF)；Enteric polymer (enteric polymer), such as polyvinyl acetate Phthalic acid ester (PVAP), methacrylic acid copolymer are (such asL100, L 30D55, A and FS 30D), hydroxyl Propyl methocel acetate succinate (AQUAT HPMCAS)；And xanthans.Exemplary cationic polymer includes, For example, copolymer of dimethylaminoethyl methacrylate (for example,E 100).With only hydrophilic polymer Compare, anionic polymer, especially the introducing of enteric polymer is for forming for weakly alkaline medicine independent of pH The release profiles of value are useful.
The exemplary non-ionic polymers for being used to slow down dissolution rate include, for example, hydroxypropyl cellulose (HPC) and gathering Ethylene oxide (PEO) is (for example, POLYOXTM)。
Exemplary hydrophobic polymer includes ethyl cellulose (for example, ETHOCELTM,), acetic acid Cellulose, methacrylic acid copolymer (for example,NE 30D), ammonio methacrylate copolymer (e.g.,RL 100 or PO RS100), polyvinyl acetate, glyceryl monostearate, aliphatic acid, such as citric acid acetyl Base tributyl, and combinations thereof and derivative.
The swelling polymer can be with 1wt% to 50wt%, and preferably 5wt% to 40wt%, most preferably 5wt% are extremely 20wt% ratio is incorporated in preparation.The swellable polymer and adhesive can be incorporated to system before granulation or after granulation In agent.The polymer can also be dispersed in organic solvent or aqueous alcoholic and be sprayed during granulating.
Exemplary releasing agent includes the enteric polymer dependent on pH value, and the enteric dependent on pH value polymerize Thing keeps complete when pH value is below about 4.0, and is higher than 4.0, preferably above 5.0 in pH value, is dissolved when most preferably higher than 6.0, And think that it is in the present invention useful as releasing agent.The polymer of exemplary dependence pH value includes, but does not limit In methacrylic acid copolymer, EUDRAGIT L100 are (such as Rohm limited companies of GermanyL100 (A types),S100 (Type B))；EUDRAGIT L100-55 (such as moral Rohm limited companies of stateL100-55 (c-type) andL30D-55 copolymers disperse)； Methacrylic acid-methyl methacrylate and methyl methacrylate copolymer (FS)；Methacrylic acid, The terpolymer of methacrylate and ethyl acrylate；Cellulose acetate phthalate (CAP)；Hydroxypropyl methyl fiber Plain phthalic acid ester (HPMCP) (for example, HP-55, HP-50, HP-55S of Japanese SHIN-ETSU HANTOTAI's chemistry)；Polyvinyl acetate neighbour's benzene two Formic acid esters (PVAP) (for example,White (enteric white) OY-P-7171 of enteron aisle)；Poly- second Sour vinyl butyrate；Cellulose acetate succinate (CAS)；Hydroxypropyl methyl cellulose acetate succinate (HPMCAS), For example, LF grades of HPMCAS, MF grades, HF grades, includingLF andMF (Japanese SHIN-ETSU HANTOTAI's chemistry)；Japanese SHIN-ETSU HANTOTAI Chemistry)；Shellac is (for example, MARCOATTM125 and MARCOATTM125N)；Vinyl acetate-copolymer-maleic anhydride；Styrene- Malaysia monoester copolymer (styrene-maleic monoester copolymer)；Carboxymethylethylcellulose (CMEC, Freund companies, Japan)；Cellulose acetate phthalate (CAP) (for example,)；Acetic acid -1,2,4- benzene Three acid celluloses (CAT)；And weight ratio is about 2:1 to about 5:1 its two or more mixture, for example, such as weight ratio It is about 3:1 to about 2:1L 100-55 andS 100 mixture, or weight ratio are about 3: 1 to about 5:1L 30D-55 andFS mixture.
These polymer may be used singly or in combin, or be used together with polymer other than the above.It is excellent The enteric polymer of the dependence pH value of choosing is pharmaceutically acceptable methacrylic acid copolymer.These copolymers are based on methyl The anionic polymer of acrylic acid and methyl methacrylate, and it preferably has about 135,000 mean molecule quantity.At these In copolymer, the scope of the ratio of the carboxyl of free carboxyl group and esterification is, for example, 1:1 to 1:3, e.g., about 1:1 or 1:2. This polymer commercially withTrade (brand) name is on sale, such as Eudragit L series, for example, Eudragit L Eudragit LEudragitEudragit LEudragitEudragit L-30EudragitSeries, for example, Eudragit SEudragit SEudragitRelease Accelerator is not limited to the polymer dependent on pH value.Other rapid dissolvings and the rapid parent for leaching formulation and leaving loose structure Aqueous molecule can also be used for identical purpose.
In some embodiments, the matrix may include the combination of releasing agent and solubilizer.The solubilizer can To be ionic or nonionic surface active agent, complexing agent, hydrophilic polymer, pH value regulator (such as acidulant and alkalization Agent) and by molecule embedding increase insoluble drug solubility molecule.Several solubilizer can be used simultaneously.
The solubilizer may include surfactant, such as docusate sodium, sodium lauryl sulfate, sodium stearyl fumarate, TweensWith spans (Spans) (sorbierite monoesters and fatty acid sorbitol ester that PEO is modified), poly- (epoxy second Alkane)-PPOX-poly- (oxirane) block copolymer (also known as PLURONICSTM)；Complexing agent, such as low molecular weight polyethylene Pyrrolidones and low-molecular-weight hydroxypropyl methyl cellulose；Contribute to the molecule of solubility, such as cyclodextrin by molecule embedding； And pH value regulator, including acidulant, such as citric acid, fumaric acid, tartaric acid and hydrochloric acid；And basifier, such as meglumine and Sodium hydroxide.
The solubilizer typically comprises the 1wt% to 80wt% of formulation, and preferably 1wt% to 60wt%, more preferably 1wt% are extremely 50wt%, and it can be incorporated in a different manner.They can be incorporated in preparation before granulation in the way of drying or moistening. They can also be added in preparation after other materials granulation or other techniques.During granulating, solubilizer can be to add Plus or sprayed without the solution form of adhesive.
In one embodiment, the alleviating prolongation delivery formulations are coated or base comprising water insoluble permeable polymer Matter, it includes forming one or more water insoluble water permeable membranes on active nucleus.The coating can additionally include it is a kind of or A variety of water miscible polymer and/or one or more plasticizer.Water insoluble polymer coating, which is included, to be used to discharge in core Activating agent isolation coat, wherein, compared with viscosity higher grade, lower molecular weight (viscosity) grade is shown to be released faster Put speed.
In a preferred embodiment, water insoluble film forming polymer includes one or more alkyl cellulose ethers, such as Ethyl cellulose and its mixture, (for example, grade is PR100, PR45, PR20, PR10 and PR7 ethyl cellulose；Dow companies).
Exemplary water-soluble polymer, such as polyvinylpyrrolidoneHydroxypropyl methyl cellulose, Hydroxypropyl cellulose and its mixture.
In some embodiments, water insoluble polymer provides suitable property in the case where not needing plasticizer Energy (for example, extending release characteristics, mechanical performance and coating performance).It is, for example, possible to use the coating containing following material and nothing Need plasticizer：Polyvinyl acetate (PVA), the neutral copolymer of acrylate/methacrylate are (e.g., by Evonik Industries commercially available Eudragit NE30D), ethyl cellulose and hydroxypropyl cellulose apply jointly, wax etc..
In another embodiment, water insoluble polymer substrate can further comprise plasticizer.Required plasticising The content of agent depends on the performance of plasticizer, the performance of water insoluble polymer and final required coating.Relative to coating Gross weight, the suitable level of plasticizer is about 1wt% to about 20wt%, about 3wt% to about 20wt%, about 3wt% to about 5wt%, about 7wt% to about 10wt%, about 12wt% to about 15wt%, about 17wt% to about 20wt% or about 1wt%, about 2wt%, about 3wt%, about 4wt%, about 5wt%, about 6wt%, about 7wt%, about 8wt%, about 9wt%, about 10wt%, about 15wt% or about 20wt%, including all scopes therein and subrange.
Exemplary plasticizer includes, but not limited to glyceryl triacetate, acetylated monoglyceride, oil (castor oil, Rilanit special, rapeseed oil, sesame oil, olive oil etc.)；Citrate, triethyl citrate, acetyl triethyl citrate, Acetyl tributyl citrate, ATBC, citric acid acetyl three N-butyl, diethyl phthalate, adjacent benzene two Formic acid dibutyl ester, dioctyl phthalate, methyl p-hydroxybenzoate, propylparaben, P-hydroxybenzoic acid third Ester, butyl p-hydroxybenzoate, diethyl sebacate, dibutyl sebacate, glycerin tributyrate, the ester of substituted glycerol three and glycerine Fat, monoacylated and diacetyl glyceride are (such as9-45), glycerin monostearate, glycerin tributyrate, poly- PS80, polyethylene glycol (such as PEG-4000, PEG-400), propane diols, 1,2- propane diols, glycerine, sorbierite, oxalic acid two Ethyl ester, diethyl malate, diethyl fumarate, diethylmalonate, dibutyl succinate, aliphatic acid, glycerine, sorb Alcohol, diethy-aceto oxalate, diethyl malate, diethyl maleate, diethyl fumarate, diethyl succinate, malonic acid Diethylester, dioctyl phthalate, dibutyl sebacate and its mixture.The plasticizer can have surfactant Property, so that it can be used as release regulator.It is, for example, possible to use non-ionic detergent, such as (polyoxyethylene of Brij 58 (20) cetyl ether) etc..
Plasticizer can be the high boiling organic solvent for assigning other hard or crisp polymeric material elasticities, and It can influence the release profiles of activating agent.Plasticizer would generally cause subtracting along the intermolecular force of the cohesion of polymer chain It is few, so as to cause the change of multiple polymers performance, include the reduction of tensile strength, the increase of elongation and the glass of polymer The decline of glass transition temperature or softening temperature.The content of plasticizer and selection can influence the hardness of tablet, it might even be possible to shadow Ring its dissolving or disintegrating property, and its physics and chemical stability.Some plasticizer can increase the elastic of coating and/or can Flexibility, so as to reduce the fragility of coating.
In another embodiment, the alleviating prolongation delivery formulations include the group of at least two polymer for forming gel Close, the polymerization of its polymer for including at least one non-ionic formation gel and/or at least one anionic formation gel Thing.The gel formed by the combination for the polymer for forming gel provides control release so that when preparation is ingested and touches During gastro-intestinal Fluid, closest to the polymer hydration on surface to form viscogel layer.Due to high viscosity, viscous layer is only capable of gradually dissolving Fall, following material is exposed with identical process.Therefore, material slow mechanism dissolved is fallen, so that active component slowly is discharged into stomach Intestinal juice.The combination of the polymer of at least two formation gels causes the performance (such as viscosity) of the gel produced to be manipulated to carry For required release profiles.
In a specific embodiment, the preparation comprising at least one non-ionic formation gel polymer and The polymer of at least one anionic formation gel.In another embodiment, the preparation is different non-comprising two kinds The polymer of ionic formation gel.In another embodiment, the preparation is comprising identical chemical property but with difference Solubility, the polymer of the non-ionic formation gel of viscosity and/or molecular weight combination (such as different viscosities grade The combination of hydroxypropyl methyl cellulose, such as HPMC K100 and HPMC K15M or HPMC K100M).
The polymer of exemplary anionic formation gel includes but is not limited to, sodium carboxymethylcellulose (Na CMC)； Carboxymethyl cellulose (CMC)；Anionic polysaccharides, such as sodium alginate, alginic acid, pectin, poly- glucuronic acid (poly- α-and-β -1, 4- glucuronic acids), polygalacturonic acid (pectic acid), chondroitin sulfate, carrageenan, furcellaran (furcellaran)；Anion glue, such as xanthans；The polymer of acrylic acid or carbomer is (such as934、940、 974P NF)；Copolymer；Polymer；Polycarbophil etc..
The polymer of exemplary non-ionic formation gel includes, but not limited to PVP (PVP, polyvinyl pyrrole Alkanone), polyvinyl alcohol, the copolymer of PVP and polyvinyl acetate, HPC (hydroxypropyl cellulose), (hydroxypropyl methyl is fine by HPMC Dimension element), hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, PEO, gum arabic, dextrin, starch, poly- methyl-prop Olefin(e) acid hydroxyl ethyl ester (PHEMA), water-soluble nonionic polymethacrylates and its copolymer, modified cellulose, modification of polysaccharides, Non-ionic glue, non-ionic polysaccharide and/or its mixture.
The preparation can not necessarily include above-mentioned enteric polymer, and/or at least one excipient, such as filler, viscous Mixture (as described above), disintegrant, and/or flow aid or glidant.
Exemplary filler includes but is not limited to, lactose, glucose, fructose, sucrose, Dicalcium Phosphate, sugar alcohol, also referred to as " sugar Polyol ", such as sorbierite, mannitol (manitol), Lactitol, xylitol, isomalt (isomalt), antierythrite It is fine with hydrogenated starch hydrolysate (mixtures of a variety of sugar alcohols), cornstarch, farina, sodium carboxymethylcellulose, ethyl Tie up element, cellulose acetate, enteric polymer, or its mixture.
Exemplary adhesive includes but is not limited to, water-soluble hydrophilic polymer, such as PVP (PVP：Polyvinyl pyrrole Alkanone), copolyvidone (copolymer of polyvinylpyrrolidone and polyvinyl acetate), the HPC (hydroxy propyl celluloses of low molecule amount Element), the HPMC (hydroxypropyl methyl cellulose) of low molecule amount, the carboxymethyl cellulose of low molecule amount, ethyl cellulose, gelatin, PEO, gum arabic, dextrin, aluminium-magnesium silicate, starch and polymethacrylate, such as Eudragit NE 30D, Eudragit RL, Eudragit RS, Eudragit E, polyvinyl acetate and enteric polymer, or its mixture.
Exemplary disintegrant includes but is not limited to, low substituted sodium carboxymethylcellulose, Crospovidone (crosslinked polyethylene Pyrrolidones), sodium carboxymethyl starch (Explotab), Ac-Di-Sol (Croscarmellose), pre- paste Change starch (starch 1500), microcrystalline cellulose, water insoluble starch, calcium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, And magnesium silicate or alumina silicate.
Exemplary glidant includes but is not limited to, magnesium, silica, talcum, starch, titanium dioxide etc..
In another embodiment, the alleviating prolongation delivery formulations by using capsulating material and nonessential pore shaping object and Other excipient are coated with the particle containing water solubility/water dispersible medicine and formed, (as above institute of the particle such as pearl or pearl colony State).(e.g., the capsulating material is preferably selected from cellulosic polymer, such as ethyl cellulose), Methyl cellulose Element, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate and cellulose acetate phthalate；Polyvinyl alcohol；Third Alkene acids polymers, such as polyacrylate, polymethacrylates and its copolymer；And it is other based on water or based on solvent Capsulating material.Control release coating for the colony of given pearl can be by least one parameter of control release coating And control, performance, coating level, pore shaping object type and the concentration of such as coating, technological parameter with and combinations thereof.Thus, lead to Cross change parameter (such as pore shaping object concentration) or condition of cure, it is allowed to change activating agent and discharged by the colony of any given pearl, So as to allow preparation to be selectively adjusted as predetermined release profiles.
Here, the pore shaping object being suitable for use in control release coating can be organic or inorganic reagent, and including that can make With the material in environment from coating dissolving, extraction or leaching.Exemplary pore former includes but is not limited to, organic compound, such as Monose, oligosaccharides and polysaccharide, including sucrose, glucose, fructose, mannitol, mannose, galactolipin, sorbierite, amylopectin, Glucan；Solvable polymer, such as water soluble hydrophilic polymer in use environment, hydroxy alkyl cellulose, carboxyalkyl are fine Dimension element, hydroxypropyl methyl cellulose, cellulose ether, acrylic resin, polyvinylpyrrolidone, crosslinked polyethylene pyrrolidines Ketone, PEO, carbowax (Carbowaxes), carbopol etc., glycol, polyalcohol, polyalcohol, PAG gathers Ethylene glycol, polypropylene glycol, or its block polymer, polyglycols, poly- (α-Ω) aklylene glycol；Inorganic compound, such as alkali metal Salt, lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate, appropriate calcium salt, its Composition etc..
The control release coating can further include other additives well known in the art, such as plasticizer, antiplastering aid, help Flow agent (or flow aid) and defoamer.
In some embodiments, coated particle or pearl may comprise additionally in " outer coatings ", to provide for example, it is moistureproof, Minimizing electrostatic, taste masked, seasoning, coloring and/or polishing or other decoration functions to pearl.For such outer coatings, close Suitable coating material is it is known in the art that and including, but not limited to cellulosic polymer, such as hydroxypropyl methyl cellulose, hydroxyl Propyl cellulose and microcrystalline cellulose or its combination are (for example, a variety ofCoating material).
Coated particle or pearl can additionally include reinforcing agent, for example, its can it is exemplary but without limitation for enhancing lytic agent, Strengthen dissolution agent, sorbefacient, penetration enhancer, stabilizer, complexing agent, enzyme inhibitor, P- glycoprotein inhibitors and many Medicine drug-resistant protein inhibitor.Or, the preparation can also include the reinforcing agent separated with the particle of coating, such as in single pearl Colony in or be used as powder.In another embodiment, the single layer that reinforcing agent may be embodied on coating particle In, can control release coating below or above.
In other embodiments, the alleviating prolongation delivery formulations are formulated into by permeating mechanism release bioactive agent.For example, Capsule can be made into single permeation unit, or its can comprising 2, the push-and-pull unit that 3,4,5 or 6 are encapsulated in hard gelatin capsule, by This, each bilayer push-and-pull unit pushes away layer and medicine layer comprising infiltration, and is both surrounded by pellicle.Adjacent with medicine layer One or more holes are drilled through on film.This tunic can be relied on the enteric coating covering of pH value in addition, to prevent release, until stomach row After sky.Gelatine capsule dissolves immediately upon intake.As push-and-pull unit enters small intestine, enteric coating is decomposed, and then allows liquid flow Move by pellicle, to make infiltration push away portion swells, so as to force medicine with given pace by aperture, the speed is led to by water The speed of semi-permeable membrane and accurately control.The release of medicine can carry out being up to more than 24 hours with constant rate of speed.
The infiltration pushes away layer and produced comprising one or more for passing water through pellicle into the drive of the core of delivery vector The bleeding agent of power.One class bleeding agent includes water-swellable hydrophilic polymer, also referred to as " osmopolymer (osmopolymers) " and " hydrogel ", it includes but is not limited to, hydrophilic ethylene base and acrylate copolymer, such as alginic acid The polysaccharide of calcium, polyethylene glycol oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly- (HEMA), Poly- (acrylic acid), poly- (methacrylic acid), polyvinylpyrrolidone (PVP), cross-linked pvp, polyvinyl alcohol (PVA), PVA/PVP are common Polymers, the PVA/PVP copolymers of hydrophobic monomer with such as methyl methacrylate and vinylacetate, contain big PEO blocks Hydrophilic polyurethane, AC-DI-SOL, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, poly- Ka Bofei, gelatin, xanthans and primojel.
Another kind of bleeding agent includes proenzyme, and it can absorb water to realize the osmotic pressure gradient through pellicle.Proenzyme Example include but is not limited to, inorganic salts, such 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；Sugar, such as dextrose (dextrose), fructose, glucose (glucose), inositol, lactose, maltose, mannitol, gossypose, sorbierite, sucrose, trehalose and xylitol；Organic acid, such as Ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, decanedioic acid, sorbic acid, adipic acid, edetic acid(EDTA), glutamic acid, to first Benzene sulfonic acid, butanedioic acid and tartaric acid；Urea；And their mixture.
The material to form pellicle is contributed to include acrylic resin, vinyl, ethers, the polyamide of different stage Class, polyesters and cellulose derivative, these materials are permeable and water insoluble under the related pH value of physiology, or, these materials Material is easy to by chemical modification, for example, be crosslinked and water insoluble performance is presented.
In some embodiments, the alleviating prolongation delivery formulations may include many sweet tablets for resisting the erosion of stomach and enteral. This polymer can only degrade in the colon for containing substantial amounts of microorganism, and the microorganism contains biodegradable enzyme, The biodegradable enzyme decomposes for example many sweet tablets, so as to discharge drug substance contents in the way of controllable Time-Dependent. Exemplary many sweet tablets may include, for example, amylose, arabogalactan, chitosan, chondroitin sulfate, cyclodextrin, Glucan, guar gum, pectin, xylan and combinations thereof or derivative.
In some embodiments, described pharmaceutical composition is formulated into the extension release of delay.Term as used herein " sustained release " refers to a kind of to be at once disintegrated and be discharged into internal drug therapy active component.In some embodiments In, term " the extension release of delay " is used with reference to the pharmaceutical preparation with such release profiles：In the release profiles, There is presetting delay in the release of medicine after application.In some embodiments, the alleviating prolongation delivery formulations of delay include By the coated alleviating prolongation delivery formulations of enteric coating, this is the isolation applied to oral drugs, with prevent medicine reach small intestine it Preceding release.Delayed release preparation such as enteric coating prevents that the medicine (such as aspirin) for having stimulation to stomach is molten under one's belt Solution.This coating is additionally operable to the protection medicine unstable to acid, prevents it in the sour environment of stomach, but delivered Into alkaline pH environment (pH value of enteron aisle be more than 5.5), its is non-degradable under the alkaline environment, and needed for giving them Effect.
Term " pulsed release " is one kind of sustained release, and it is herein with reference to used below：The predetermined lag phase with Afterwards, the pharmaceutical preparation of rapid and instantaneous insoluble drug release is provided immediately in the short term, so as to produce the medicine after medicine is applied " pulse " blood plasma distribution.Preparation can be designed as providing single-impulse release or many under time interval predetermined after application Pulsed release, or extension release (for example, continuous release of active component remainder) in period provide arteries and veins afterwards Rush formula release (for example, 20-60% of active component).
Sustained release or pulsatile release formulations generally include one or more elements covered by isolation coat, and it is one Dissolve, corrode or rupture after the individual specific lag phase.In some embodiments, the pharmaceutical composition of the application is formulated into Extension release or the extension release of delay, and its accumulated dose for being included in the given activating agent applied in single unit dose 100%.In other embodiments, described pharmaceutical composition includes extension/sustained release component and immediate-release component. In some embodiments, the immediate-release component and extension/sustained release component contain identical active component.Other one In a little embodiments, the immediate-release component and extension/sustained release component contain different active components (for example, one It is analgestic in individual component, and is muscarine antagonist in another component).In some embodiments, described first and Each self-contained analgestic of two components, it is selected from aspirin, brufen, naproxen sodium, Indomethacin, Nabumetone and to acetyl Amino phenols.In other embodiments, the extension/sustained release component is coated with by enteric coating.In other embodiments, The immediate-release component and/or the extension/sustained release component further include muscarine antagonist, and it is selected from former times cloth difficult to understand Rather, solifenacin, darifenacin and atropine.In other embodiments, the analgestic in each component is with daily oral Dosage 5mg is applied to 2000mg, 20mg to 1000mg, 50mg to 500mg or 250mg to 1000mg.In other embodiments, The immediate-release component and/or the extension/sustained release component are further comprising antidiuretic, muscarine antagonist or both Have.In other embodiments, the treatment method be included in before target time point (such as bedtime) at least 8 or 7 hours to Subject applies diuretics, and applies comprising immediate-release component and/or prolong to subject in 2 hours before target time point The pharmaceutical composition of length/sustained release component.
In other embodiments, total agent that component provides the activating agent that will be delivered by pharmaceutical preparation " is discharged " immediately About the 5 to 50% of amount, and " extension release " component can provide the accumulated dose for the activating agent that will be delivered by pharmaceutical preparation About 50 to 95%.For example, immediate-release component provide about the 20 of the accumulated dose of activating agent that will be delivered by pharmaceutical preparation to 60%, or about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%.Prolongation release component can provide by Will by the accumulated dose of the activating agent of formulation delivered about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75 or 80%.In some embodiments, prolongation release component further comprises isolation coat, to postpone the release of activating agent.
According to purpose, the isolation coat for sustained release can be made up of a variety of materials.In addition, preparation can be wrapped Multiple isolation coats are included to discharge to help with time mode.The coating can be sweet tablet, film coating (for example, based on hydroxypropyl Ylmethyl cellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate are common Polymers, polyethylene glycol and/or polyvinylpyrrolidone) or based on methacrylic acid copolymer, cellulose acetate The adjacent benzene of element, HPMCP, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate The coating of dicarboxylic acid esters, shellac and/or ethyl cellulose.In addition, the preparation can comprise additionally in time delay material, for example, Glycerin monostearate or distearin.
In some embodiments, the alleviating prolongation delivery formulations of the delay include enteric coating, and the enteric coating is included The one or more polymer for contributing to activating agent to be discharged in the near-end or remote area of intestines and stomach.Term as used herein " enteric polymer coatings " refer to comprising with the one or more polymer for relying on pH or the release profiles independent of pH value Coating.The pill of enteric coating will not be dissolved in acidic gastric juice (pH value~3), but they can be dissolved in small intestine or colon and exist Alkalescence (pH value 7-9) environment in.The usual inhibitory activity agent release of enteric polymer coatings, until about 3~4 hours after administration Gastric emptying lag phase after some time.
The enteric coating for relying on pH value relies on pH value or the polymer to pH sensitive comprising one or more, its can compared with Keep their structural integrity under conditions of low ph value (such as in stomach), and intestines and stomach more distal end region (such as small intestine) compared with Dissolved in the environment of high ph-values, so as to discharge drug substance contents.For the purpose of the present invention, " dependence pH value " is defined as tool With good grounds environmental pH and the characteristic (for example, dissolving) changed.The polymer of exemplary dependence pH value includes, but not limited to Methacrylic acid copolymer, EUDRAGIT L100 are (such as Rohm limited companies of GermanyL100 (A types),S100 (Type B))；EUDRAGIT L100-55 (such as moral Rohm limited companies of stateL100-55 (c-type) andL30D-55 copolymers disperse Body)；Methacrylic acid-methyl methacrylate and methyl methacrylate copolymer (FS)；Methyl-prop The terpolymer of olefin(e) acid, methacrylate and ethyl acrylate；Cellulose acetate phthalate (CAP)；Hydroxypropyl first Base cellulose phthalate (HPMCP) (for example, HP-55, HP-50, HP-55S of Japanese SHIN-ETSU HANTOTAI's chemistry)；Polyvinyl acetate Phthalic acid ester (PVAP) (for example,White (enteric white) OY-P- of enteron aisle 7171)；Cellulose acetate succinate (CAS)；Hydroxypropyl methyl cellulose acetate succinate (HPMCAS), for example, LF grades of HPMCAS, MF grades, HF grades, includingLF andMF (Japanese SHIN-ETSU HANTOTAI's chemistry)；Japanese SHIN-ETSU HANTOTAI's chemistry)； Shellac is (for example, MarcoatTM125 and MarcoatTM125N)；Carboxymethylethylcellulose (CMEC, Freund company, Japan), Cellulose acetate phthalate (CAP) (for example,)；Acetic acid -1,2,4- benzenetricarboxylic acids cellulose (CAT)；With And weight ratio is about 2:1 to about 5:1 its mixture of two or more, for example, weight ratio is about 3:1 to about 2:1L 100-55 andS 100 mixture, or weight ratio are about 3:1 to about 5:1L 30D-55 andFS mixture.
The polymer for relying on pH value generally shows the distinctive optimum pH for dissolving.In some embodiments, The polymer for relying on pH shown 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 and Optimum pH between 7.0.In other embodiment, the polymer for relying on pH shows >=5.0, >=5.5, >=6.0, >=6.5 or >=7.0 optimum pH.
These polymer may be used singly or in combin, or be used together with polymer other than the above.It is excellent The enteric polymer of the dependence pH value of choosing is pharmaceutically acceptable methacrylic acid copolymer.These copolymers are based on methyl The anionic polymer of acrylic acid and methyl methacrylate, and it preferably has about 135,000 mean molecule quantity.At these In copolymer, the scope of the ratio of the carboxyl of free carboxyl group and esterification is, for example, 1:1 to 1:3, e.g., about 1:1 or 1:2. This polymer commercially withTrade (brand) name is on sale, such as Eudragit L series, for example, Eudragit L Eudragit LEudragitEudragit LEudragitEudragit L-30EudragitSeries, for example, Eudragit SEudragit SEudragitRelease Accelerator is not limited to the polymer dependent on pH value.Other rapid dissolvings and the rapid parent for leaching formulation and leaving loose structure Aqueous molecule can also be used for identical purpose.
In some embodiments, coating method relies on pH value and one or more independent of pH value using one or more Polymer mixing.Once soluble polymer reaches the optimum pH of its dissolving, pH value is relied on and independent of pH value The mixing of polymer can reduce the rate of release of active component.
In some embodiments, " time control " or " Time-Dependent " release profiles can use comprising a kind of or The water insoluble capsule body of multiple actives and obtain, wherein, the capsule body is in its one end with insoluble but permeable And swellable water-setting plug closing.When being contacted with gastro-intestinal Fluid or dissolving medium, the plug is swelled, by its own release glue Capsule, and after predetermined lag time (time can be by, for example, the positions and dimensions control of plug), discharge medicine.It is described Capsule body further can be coated with by the enteric coating of the dependence pH value of the complete outside of holding capsule, until it reaches small intestine. The material suitably filled in is included, for example, polymethacrylate, erodible comperession polymer are (for example, HPMC, polyethylene Alcohol), condense molten polymer (such as glycerin mono-fatty acid ester) and enzyme control erodible polymer (for example, polysaccharide, such as straight chain Starch, arabogalactan, chitosan, chondroitin sulfate, cyclodextrin, glucan, guar gum, pectin and xylan).
In other embodiment, capsule or double-layer tablets can be formulated into comprising the core containing medicine, and it is by being swelled Layer and outside insoluble but can semi permeable polymer coating or film covering.Lag time before rupture can pass through polymer bag The infiltration of clothing and mechanical performance, and the swelling behavior of swell layer are controlled.Generally, swell layer includes one or more swellabilities Agent, is such as swelled and retains in its structure the swellable hydrophilic polymer of moisture.
The exemplary water swellable material used in the coating of sustained release include, but are not limited to, polycyclic oxygen second Alkane is (for example, mean molecule quantity is 1,000,000 to 7,000,000, for example, such as), methylcellulose, hydroxypropyl Cellulose, hydroxypropyl methyl cellulose；Weight average molecular weight is 100,000 to 6,000,000 polyalkylene oxide, including but not limited to Polyformaldehyde (poly (methylene oxide)), polybutylene oxide；Molecular weight is 25,000 to 5,000,000 poly- (methyl-prop Olefin(e) acid hydroxy alkyl ester)；It is 200 to 30,000 with glyoxal, formaldehyde or glutaraldehyde cross-linking, with rudimentary acetal residue and the degree of polymerization Polyvinyl alcohol；The mixture of methylcellulose, Cross-linked Agar and carboxymethyl cellulose；The copolymer of hydrogel is formed, it leads to Cross following preparation：Form point of superfine separated maleic anhydride and the copolymer of styrene, ethene, propylene, butylene or isobutene Granular media, it is in the copolymer with the saturation cross-linking agents of every 0.001 to 0.5 mole of mol maleic anhydride；Molecular weight is 450, 000 to 4,000,000Acid carboxyl polymer；Polyacrylamide；What is be crosslinked can water The indenes maleic anhydride polymer being swelled；Molecular weight is 80,000 to 200,000Polyacrylic acid；It is starch-grafted Copolymer；By being constituted the glucose unit (such as the poly- glucan that diester is crosslinked) being condensedAcrylate gathers Compound polysaccharide；0.5% to viscosity under the 1%w/v aqueous solution be 3,000 to 60,000mPa carbomer；Cellulose ether, such as 1%w/ The hydroxypropyl cellulose of viscosity about 1,000 to 7,000mPa under the w aqueous solution (25 DEG C)；Viscosity is about 1000 under the 2%w/v aqueous solution More than, preferably more than 2,500, be up to 25,000mPa hydroxypropyl methyl cellulose；Glued under 20 DEG C, the 10%w/v aqueous solution Degree is about 300 to 700mPa polyvinylpyrrolidone；And their mixture.
Or, the release time of medicine can be controlled by being disintegrated lag time, and the disintegration lag time is depended on not It is dissolved in the balance between the tolerance of aqueous polymer film (such as ethyl cellulose, EC) and thickness, the water insoluble polymer film Included in the predetermined micropore of bottom part body, and a certain amount of swellable auxiliary material, such as rudimentary substituted hydroxypropyl cellulose And sodium glycollate (L-HPC).After oral administration, gastro-intestinal Fluid penetrates through micropore, causes being swelled for swellable auxiliary material, so produces Raw to make the internal pressure of capsule partial disintegration, the capsule part includes the first capsule body containing swellable material, contained Second capsule body of medicine and the enclosing cover being attached on the first capsule body.
Enteric layer can further include antiplastering aid, such as talcum or glyceryl monostearate and/or plasticizer.Enteric layer can enter One step includes one or more plasticizer, and the plasticizer is included but are not limited to, triethyl citrate, citric acid acetyl three Ethyl ester, acetyl tributyl citrate, the ester of polyethylene glycol acetylated glycerol one, glycerine, triacetyl glycerine, propane diols, adjacent benzene Dicarboxylic acid esters (such as diethyl phthalate, dibutyl phthalate), titanium dioxide, iron oxide, castor oil, sorbierite and Dibutyl sebacate.
In another embodiment, delayed release preparation employ permeable but insoluble film coating with encapsulate activity into Point, and bleeding agent.Core is slowly diffused into by film from enteron aisle with dampening, the core is swelled until film rupture, so as to release Put active component.Film coating can be adjusted, to obtain water penetration or the release time of different rates.
In another embodiment, delayed release preparation employs fluid-tight sheet coating, thereby, and water is by being coated In control hole enter, until core ruptures suddenly.When tablet ruptures suddenly, drug substance contents discharge immediately, or by compared with Long time release.These and other technologies can be changed, to allow to form the predetermined lag phase before medicine starts release.
In another embodiment, activating agent is delivered with dosage form, so as to provide sustained release and extension release (delay-continue).Term " delay-extension-release " is herein with reference to used below：Predetermined time after application or Lag phase discharges there is provided the pharmaceutical preparation of the pulsed release of activating agent, followed by the extension of activating agent.
In some embodiments, discharge immediately, extend release, sustained release or delay-alleviating prolongation delivery formulations including living Property core, the active nucleus is made up of one or more inert particles, each to be coated with medicine on its surface (for example, with pastille The form (using such as fluidization or other method well known to those skilled in the art) of the film-forming composition of thing) Pearl, pill, pill, granule particles, microcapsules, microballoon, microparticle, the form of Nano capsule or nanosphere.The inert particle It can be different size of, keep not readily dissolving as long as its is sufficiently large.Or, the active nucleus can by containing medicine into Point polymer composition granulation and mill and/or by extrusion and round as a ball prepare.
Medication amount in core will change depending on required dosage, and generally from about 5 to 90wt%.Generally, based on The weight of coated bead, it is molten according to the type and/or selected polymer of required lag time and release profiles and coating Agent, the polymer coating on active nucleus would be about 1 to 50%.It is proper amount of in core that those skilled in the art is possible to selection Upper coating introduces core with the medicine of the dosage needed for realizing.In one embodiment, inactive core can be sugar ball or Buffered crystal or encapsulation buffered crystal, such as calcium carbonate, sodium acid carbonate, fumaric acid, tartaric acid, they change the microenvironment of medicine To promote it to discharge.
In some embodiments, for example, sustained release or delay-extended-release composition are by with water insoluble The mixture of polymer and enteric polymer is coated with water-soluble/dispersible medicine-containing particle (such as pearl) and formed, wherein, do not dissolve in The polymer and enteric polymer of water can be with 4:1 to 1:1 weight ratio is present, and based on the gross weight of coated pearl, coating Gross weight is 10 to 60wt%.The pearl of medicine layering can not necessarily include the ethyl cellulose of dissolution rate in control.Optimization The composition of outer layer, and polymer film internal layer and the single weight of outer layer, it is preferable to be realized for given activity Circadian rhythm release profiles, this correlation based in vitro/in vivo and it is expected that obtaining.
In other embodiments, the preparation can include the particle containing the medicine discharged immediately and (not control molten Going out the polymer film of speed) (it shows, such as 2 to 4 hours after oral administration for the pearl of and delay-extension release Lag time) mixture, so as to provide dipulse release profiles.
In some embodiments, active nucleus is coated with by the layer of the polymer of one or more control dissolution rates, so that Obtain preferable release profiles (being with or without lag time).Inner layer film can be after extract water or body fluid enter core in very great Cheng Drug controlled release speed on degree, and the lag time needed for outer membrane can be provided (does not have after extract water or body fluid enter core Have or seldom insoluble drug release period).Inner layer film may include water insoluble polymer, or water insoluble polymer and water The mixture of soluble polymer.
As described above, the polymer for being suitable for outer membrane for largely controlling lag time to be for up to 6 hours includes Enteric polymer, and 10 to 50wt% water insoluble polymer.Water insoluble polymer and the ratio of enteric polymer Can be from 4:1 to 1:2 changes, preferably described polymer is with about 1:1 ratio is present.Usually used water insoluble polymer is Ethyl cellulose.
The example of water insoluble 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 first The copolymer of base acrylate is (such asNE, RS and RS30D, RL or RL30D etc.).The example of water-soluble polymer includes The HPMC of low molecule amount；HPC；Methylcellulose；Polyethylene glycol (molecular weight>3000 PEG), according to the work in water and solvent Property solubility, or the emulsion suspension based on used coating preparation, its scope is from 1wt% up to 10wt%.Do not dissolve in The polymer of water and the ratio of water-soluble polymer can be generally from 95:5 to 60:40, preferably from 80:20 to 65:35 changes.
In some embodiments, using AMBERLITETMThe carrier that IRP69 resins discharge as extension. AMBERLITETMIRP69 is a kind of insoluble highly acid sodium form cationic ion-exchange resin, and it is suitable as cation (alkalescence) thing The carrier of matter.In other embodiments, using DUOLITETMThe carrier that AP143/1093 resins discharge as extension. DUOLITETMAP143/1093 is a kind of insoluble strong-base anion-exchange resin, and it is suitable as anion (acidity) material Carrier.
When as pharmaceutical carrier in use, AMBERLITE IRP69 or/and DUOLITETMAP143/1093 resins are provided The method that medicament is bonded on to insoluble polymer matrix.By forming resin-drug complex (medical resin hydrochlorate (ester)) Realize extension release.As medicine and polyelectrolyte concentration reach balance, medicine discharges from resin in vivo, and this is typical Gastrointestinal drug discharges.Due to the hydrophobic interaction with the aromatic structure of cation exchange system, generally, more hydrophobicitys Medicine can be eluted with relatively low speed from resin.
In some embodiments, described pharmaceutical composition, which is formulated into, orally administers.Peroral dosage form includes, for example, piece Agent, capsule, lozenge, and can also include it is multiple can be by encapsulated or not by encapsulated particle, pearl, powder or ball Agent.The peroral dosage form of tablet and Capsules representative most convenient, in the case using the pharmaceutical carrier of solid.
In delayed release preparation, one or more isolation coats can be applied to pill, tablet or capsule, to help subtracting Slow dissolving and associated release of the medicine in enteron aisle.Under normal circumstances, isolation coat includes one or more polymer, in medicine Around composition or active nucleus, surround, surround or forming layer or film.
In some embodiments, activating agent is delivered in the formulation, so that the predetermined time after application provides and prolonged Slowbreak is put.Delay may be up to about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, it is about 4 small When, about 5 hours, about 6 hours or longer time.
Different packaging techniques can be applied to the particle containing activating agent, pearl, powder or pill, tablet, capsule or its knot Close, to produce different and difference release profiles.In some embodiments, pharmaceutical composition is with comprising single coatings The form of tablet or capsule.In other embodiments, pharmaceutical composition is with tablet or capsule comprising many coatings Form.
In some embodiments, described pharmaceutical composition is selected from analgestic, muscarine antagonist, antidiuresis comprising a variety of The active component of agent, antispastic and zolpidem.The example of muscarine antagonist includes, but are not limited to：Oxybutynin, solifenacin, Darifenacin and atropine.The example of antidiuretic includes, but not limited to antidiuretic hormone (ADH), angiotensinⅡ, aldehyde The similar thing of sterone, vasopressing, vasopressing (adds for example, minirin Argipressin, lypressin, benzene rely Press element, Ornipressin, terlipressin)；Vasopressin receptor activator, atrial natriuretic peptide (ANP) and c-type natriuretic peptide (CNP) acceptor (that is, NPR1, NPR2, NPR3) antagonist is (for example, HS-142-1, isatin, [Asu7,23 '] b-ANP- (7- 28)], Annan spit of fland (anantin), the cyclic peptide from streptomyces coelicolor (Streptomyces coerulescens), and 3G12 monoclonal antibodies)；The receptor antagonist of somatostatin 2 (e.g., somatostatin), and its can pharmaceutically connect Derivative, analog, salt, hydrate and the solvate received.The example of antispastic includes, but not limited to carisoprodol, benzene (simultaneously) diazepine, Baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine, clonidine analog and dantrolene. In some embodiments, described pharmaceutical composition includes one or more analgestics.It is described in some other embodiment Pharmaceutical composition is included：(1) one or more analgestics, and (2) one or more are conciliate selected from muscarine antagonist, antidiuretic The other active components of convulsion agent.In another embodiment, described pharmaceutical composition comprising (1) one or more analgestics and (2) one or more muscarine antagonists.In another embodiment, described pharmaceutical composition includes (1) one or more towns Pain agent and (2) one or more antidiuretics.In another embodiment, described pharmaceutical composition is a kind of or many comprising (1) Plant analgestic and (2) one or more antispastics.In another embodiment, described pharmaceutical composition comprising (1) it is a kind of or A variety of analgestics and (2) zolpidem.In another embodiment, described pharmaceutical composition includes the analgesia of (1) one or two Agent, (2) one or two muscarine antagonist, and (3) one or two kinds of antidiuretics.In another embodiment, the medicine Compositions include (1) one or more analgestics, (2) one or more antispastic, and (3) one or more antidiuretics. In another embodiment, described pharmaceutical composition includes (1) one or more analgestics, (2) one or more antidiuresis Agent, and (3) zolpidem.
In one embodiment, most active components are formulated into discharges immediately.It is many in other embodiment Number active component is formulated into extension release.In other embodiment, most active components are formulated into be discharged immediately With extension release (for example, the Part I of each active component is formulated into and discharged immediately, and second of each active component Divide and be formulated into extension release).In further embodiment, some in most active components are formulated into be discharged immediately, And some in most active components be formulated into extension release (for example, active components A, B, C is formulated into be discharged immediately, and Active component C and D are formulated into extension release).In some other embodiments, immediate-release component and/or extension are released Component is put by the upper delayed release coating (such as enteric coating) of further coating.
In some embodiments, described pharmaceutical composition includes immediate-release component and prolongation release component.This is immediately Discharging component can be comprising one or more active component selected from analgestic, muscarine antagonist, antidiuretic and antispastic.This prolongs Long release component can include one or more active components selected from analgestic, muscarine antagonist, antidiuretic and antispastic. In some embodiments, the immediate-release component and prolongation release component have identical active component just.In other In embodiment, the immediate-release component and prolongation release component have different active components.In other embodiment In, the immediate-release component and prolongation release component have one or more common active components.In some embodiments, Immediate-release component and/or prolongation release component are by the upper delayed release coating (such as enteric coating) of further coating.
In one embodiment, described pharmaceutical composition is formulated into when about the same comprising two or more Between discharge immediately active component (for example, the analgestic of two or more, or one or more analgestic and it is a kind of or The mixture of a variety of muscarine antagonists or antidiuretic or antispastic or zolpidem).In another embodiment, the medicine Composition is formulated into the active component in about the same time lengthening release comprising two or more.In another implementation In mode, described pharmaceutical composition includes two or more active components, and the active component is formulated into two kinds of extension releases Component, each prolongation release component provides different extension release profiles.For example, the first prolongation release component is in the first rate of release The first active component of lower release, and the second prolongation release component discharges the second active component under the second rate of release.Another In individual embodiment, described pharmaceutical composition is formulated into the active component of sustained release comprising two or more.Another In one embodiment, described pharmaceutical composition is formulated into the active component of sustained release comprising two or more.Another In one embodiment, described pharmaceutical composition comprising two or more be formulated into the activity of two kinds of sustained release components into Point, each sustained release component provides different sustained release curves.For example, the first sustained release component discharges in first time point First active component, and the second sustained release component discharges the second active component at the second time point.In another embodiment In, described pharmaceutical composition includes two or more active components, and one or more therein are formulated into be discharged immediately, and Remaining is formulated into extension release.In another embodiment, described pharmaceutical composition includes two or more activity Composition, a portion is formulated into be discharged immediately, and remainder is formulated into extension release.
In some other embodiment, described pharmaceutical composition includes the two kinds of active components for being formulated into and discharging immediately (for example, two kinds of analgestics, or a kind of analgestic and a kind of muscarine antagonist or antidiuretic or antispastic or zolpidem mixing Thing), and (2) be formulated into extension release two kinds of active components (for example, two kinds of analgestics, or a kind of analgestic and one kind it is anti- The mixture of poisonous fungus alkaline agent or antidiuretic or antispastic or zolpidem).In some other embodiment, the drug regimen Thing includes the three kinds of active components for being formulated into and discharging immediately, and (2) are formulated into three kinds of active components of extension release.At it In its some embodiment, described pharmaceutical composition includes the four kinds of active components for being formulated into and discharging immediately, and (2) are formulated Into four kinds of active components of extension release.In these embodiments, the active component in immediate-release component can with Active component in prolongation release component is identical or different.In some other embodiment, the immediate-release component and/or The prolongation release component can further be delayed by release and be coated (such as enteric coating) coating.
In some embodiments, described pharmaceutical composition includes one or more analgestics；With a kind of antidiuretic, its In, one or more analgestics are formulated into sustained release, and wherein, the antidiuretic is formulated into be released immediately Put.In some other embodiment, described pharmaceutical composition further includes and is selected from muscarine antagonist, antidiuretic, spasmolysis Agent and the additives of zolpidem, wherein, the additives are formulated into sustained release.In some embodiments, the delay Delivery formulations postpone the active component (for example, analgestic, muscarine antagonist, antidiuretic, antispastic and/or zolpidem) Release is up to 1,2,3,4 or 5 hours.
In this term " discharging immediately " with reference to the pharmaceutical preparation for not containing rate of dissolution control material.Using release system immediately After agent, the release of active agent does not postpone.Release immediately, which is coated, can include the suitable material dissolved immediately after administration, from And discharge the drug ingedient.Exemplary release coating material immediately includes gelatin, polyvinyl alcohol polyethylene glycol (PVA-PEG) Copolymer (for example,) and those skilled in the art known to various other materials.
Release composition can be included in the 100% of the accumulated dose for the given activating agent applied in single unit dose immediately. Or, can be comprising a kind of immediate-release component as the component in combination release profiles preparation, wherein the combination release system Agent can be provided about the 1% to about 60% of the accumulated dose of the activating agent delivered by pharmaceutical preparation, for example it is described immediately Release component can provide by by about the 5% to about 60% of the accumulated dose of the activating agent of formulation delivered, about 10% to about 60%th, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 60%th, about 20% to about 50%, about 20% to about 30%, about 30% to about 60%, about 30% to about 50%, about 40% to about 60%th, about 40% to about 50%, about 45% to about 60% or about 45% to about 50%.In other embodiment, immediately Discharge component provide will by the accumulated dose of the activating agent of formulation delivered about 2,4,5,10,15,20,25,30,35,40, 45th, 50,55 or 60%.
In some embodiments, release immediately or delayed release preparation include active nucleus, the active nucleus by a kind of or A variety of inert particles composition, the inert particle is each to be coated with medicine (for example, with the film forming combination of drug containing on its surface The form (use such as fluidization or other method well known to those skilled in the art) of thing) pearl, pill, pill, Granule particles, microcapsules, microballoon, microparticle, the form of Nano capsule or nanosphere.The inert particle can be different size , keep not readily dissolving as long as its is sufficiently large.Or, the active nucleus can pass through the polymer containing drug ingedient The granulation of composition and mill and/or by extrusion and round as a ball prepare.
Medication amount in the core will change depending on required dosage, and generally from about 5 to 90wt%.Generally, Weight based on coated bead, according to the type and/or selected polymer and bag of required lag time and release profiles Clothing solvent, the polymer coating on active nucleus would be about 1 to 50%.It is proper amount of that those skilled in the art is possible to selection The medicine of core is coated with or introduces on core to realize required dosage.In one embodiment, inactive core can be sugar Ball or buffered crystal or encapsulation buffered crystal, such as calcium carbonate, sodium acid carbonate, fumaric acid, tartaric acid, they change the micro- of medicine Environment is to promote it to discharge.
In some embodiments, delayed release preparation is by with the mixed of water insoluble polymer and enteric polymer Compound is coated with the particle (such as pearl) of water-soluble/dispersible drug containing and formed, wherein, water insoluble polymer and enteric are poly- Compound can exist with 4: 1 to 1: 1 weight ratio, and based on the gross weight of coated pearl, the gross weight of coating is 10 to 60wt%. The pearl of medicine layering can not necessarily include the ethyl cellulose of dissolution rate in control.Optimize the composition of outer layer, Yi Jiju The internal layer of compound film and the single weight of outer layer, to realize preferable circadian rhythm release profiles for given activity, this Correlation based in vitro/in vivo and it is expected that obtaining.
In other embodiments, the preparation includes the particle containing release medicine immediately and (does not control dissolution speed The polymer film of rate) and sustained release pearl (its show, such as the lag time of 2 to 4 hours after oral administration) Mixture, so as to provide dipulse release profiles.In other embodiments, the preparation, which includes two kinds of delay, to be released Put the mixture of pearl：Show the first type of 1 to 3 hour lag time and show the second of 4 to 6 hours lag times Type.
Preferably, preparation is configured to have such release profiles：Its interference to quiet sleep can be limited, its In, the preparation discharges medicine when individual is generally waken up by urination impulsion.For example, it is contemplated that starting to sleep to generally at night 11 points Sleep and generally in morning 12:30th, morning 3:00 and early morning 6:00 is waken up the individual of urination.The extension release vehicle of delay can Take for 10 points at night, and start delivering medicine 12 points of morning and little by little discharge medicine within the period of 5-8 hours, thereby Postpone or eliminate demand of urinating.
In other embodiment, preparation is configured to have such release profiles：So that a part for medicine (for example, 20-60%) discharges immediately or within 2 hours after application, and remainder discharges within the period of extension.The medicine Composition can be applied with daily administration or as needed.In some embodiments, described pharmaceutical composition is applied to before being slept Subject.In some embodiments, described pharmaceutical composition is applied immediately before sleeping.In some embodiments, the medicine Compositions before sleeping about two hours within, applied before preferably sleeping within about one hour.In another embodiment, institute Pharmaceutical composition is stated to apply about two hours before sleeping.In a further embodiment, described pharmaceutical composition is being slept Apply within first at least two hours.In another embodiment, described pharmaceutical composition is applied for about one hour before sleeping.At one In further embodiment, described pharmaceutical composition is applied at least one hour before sleeping.In a further embodiment party In formula, described pharmaceutical composition was applied before sleeping less than one hour.In another further embodiment, the medicine Composition is applied immediately before sleeping.Preferably, described pharmaceutical composition is orally administered.
The suitable dosage (" therapeutically effective amount ") of activating agent in immediate-release component or prolongation release component, will take Certainly in the order of severity and process of such as state of an illness, insecticide-applying way, the bioavilability of special preparation, the age of patient and body weight, The clinical medical history of patient and reaction to activating agent, doctor's advice, etc..
Generally suggestion, no matter it is one or many apply, immediate-release component, prolongation release component or delay-extension-release The therapeutically effective amount of activating agent in component is applied in the range of about 100 μ g/kg body weight/days to about 100mg/kg body weight/days. In some embodiments, the scope for each activating agent applied daily with single dose or multi-agent is in about 100 μ g/kg body weight/days to about 50mg/kg body weight/days, 100 μ g/kg body weight/days are to about 10mg/kg body weight/days, 100 μ g/kg body weight/days to about 1mg/kg bodies Weight/day, 100 μ g/kg body weight/days to about 10mg/kg body weight/days, 500 μ g/kg body weight/days to about 100mg/kg body weight/days, 500 μ g/kg body weight/days are to about 50mg/kg body weight/days, 500 μ g/kg body weight/days to about 5mg/kg body weight/days, 1mg/kg bodies Weight/day is to about 100mg/kg body weight/days, 1mg/kg body weight/days to about 50mg/kg body weight/days, 1mg/kg body weight/days to about 10mg/kg body weight/days, 5mg/kg body weight/days to about 100mg/kg body weight/days, 5mg/kg body weight/days to about 50mg/kg body weight/ Day, 10mg/kg body weight/days to about 100mg/kg body weight/days and 10mg/kg body weight/days to about 50mg/kg body weight/days.
Activating agent described herein can be comprised in immediate-release component or the extension that daily single dose or multi-agent are orally administered Discharge in component, delay-prolongation release component or its joint, the scope of the single dose or multi-agent is in 1mg to 2000mg, and 5mg is extremely 2000mg, 10mg are to 2000mg, 50mg to 2000mg, 100mg to 2000mg, 200mg to 2000mg, 500mg to 2000mg, 5mg to 1800mg, 10mg are to 1600mg, 50mg to 1600mg, 100mg to 1500mg, 150mg to 1200mg, and 200mg is extremely 1000mg, 300mg are to 800mg, 325mg to 500mg, 1mg to 1000mg, 1mg to 500mg, 1mg to 200mg, and 5mg is extremely 1000mg, 5mg are to 500mg, 5mg to 200mg, 10mg to 1000mg, 10mg to 500mg, 10mg to 200mg, and 50mg is extremely 1000mg, 50mg are to 500mg, 50mg to 200mg, 250mg to 1000mg, 250mg to 500mg, 500mg to 1000mg, 500mg To 2000mg.As expected, the dosage is by depending on the state of an illness of patient, size, age and the state of an illness.
In some embodiments, described pharmaceutical composition includes single analgestic.In one embodiment, the list One analgestic is aspirin.In another embodiment, the single analgestic is brufen.In another embodiment In, the single analgestic is naproxen or naproxen sodium.In another embodiment, the single analgestic is that indoles is beautiful It is pungent.In another embodiment, the single analgestic is Nabumetone.In another embodiment, the single town Pain agent is paracetamol.
In some embodiments, the single analgestic is with daily 1mg to 2000mg, 5mg to 2000mg, and 20mg is extremely 2000mg, 5mg are to 1000mg, 20mg to 1000mg, 50mg to 500mg, 100mg to 500mg, 250mg to 500mg, and 250mg is extremely 1000mg or 500mg to 1000mg dosage is given.In some embodiments, described pharmaceutical composition includes and is used as single town Acetylsalicylic acid, brufen, naproxen, naproxen sodium, Indomethacin, Nabumetone or the paracetamol of pain agent, and The analgestic is with 5mg to 2000mg, 20mg to 2000mg, 5mg to 1000mg, 20mg to 1000mg, 50mg to 500mg, 100mg to 500mg, 250mg to 500mg, 250mg to 1000mg or 500mg to 1000mg daily dosage scope are orally administered. In some embodiments, with 1mg to 2000mg, 5mg to 2000mg, 20mg to 2000mg, 5mg to 1000mg, 20mg is extremely 1000mg, 50mg are every to 500mg's, 100mg to 500mg, 250mg to 500mg, 250mg to 1000mg or 500mg to 1000mg Daily dose gives the second analgestic.
In other embodiments, described pharmaceutical composition includes a pair of analgestics.The example of the analgestic of this pairing Son includes, but not limited to, acetylsalicylic acid and brufen, acetylsalicylic acid and naproxen sodium, acetylsalicylic acid and Nabumetone, Acetylsalicylic acid and paracetamol, acetylsalicylic acid and Indomethacin, brufen and naproxen sodium, brufen and naphthalene fourth are beautiful Ketone, brufen and paracetamol, brufen and Indomethacin, naproxen, naproxen sodium and Nabumetone, naproxen sodium and Paracetamol, naproxen sodium and Indomethacin, Nabumetone and paracetamol, Nabumetone and Indomethacin, with And paracetamol and Indomethacin.The analgestic of the pairing is with 0.1: 1 to 10: 1,0.2: 1 to 5: 1 or 0.3: 1 to 3: 1 Weight than mixing, unitized dose scope is in 5mg to 2000mg, 20mg to 2000mg, 100mg to 2000mg, and 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, 20mg to 1000mg, 100mg to 1000mg, 250mg to 500mg, and 250mg is extremely 1000mg, 250mg are to 1500mg, 500mg to 1000mg, 500mg to 1500mg, 1000mg to 1500mg, and 1000mg is extremely 2000mg.In one embodiment, the analgestic of the pairing is mixed with 1: 1 weight ratio.
In other embodiments, the described pharmaceutical composition of the application is further comprising one or more Antimuscarinics Agent.The example of the muscarine antagonist includes, but are not limited to oxybutynin, solifenacin, darifenacin, fesoterodine, Tuo Te Luoding, trospium chloride and atropine.The daily dosage range of muscarine antagonist in 0.01mg to 100mg, 0.1mg to 100mg, 1mg to 100mg, 10mg are to 100mg, 0.01mg to 25mg, 0.1mg to 25mg, 1mg to 25mg, 10mg to 25mg, and 0.01mg is extremely 10mg, 0.1mg are to 10mg, 1mg to 10mg, 10mg to 10mg and 10mg to 25mg.
In some embodiments, described pharmaceutical composition, which is included, is selected from acetylsalicylic acid, brufen, naproxen, Nabumetone The analgestic of sodium, Nabumetone, paracetamol and Indomethacin is given birth to, and selected from oxybutynin, solifenacin, Da Feina The muscarine antagonist of new and atropine.
The another aspect of the application is related to a kind of by applying the medicine prepared with immediate release formulation to the people for having this needs Compositions are so as to alleviate the method for frequent micturition.Described pharmaceutical composition includes a variety of analgestics and/or muscarine antagonist.
In some embodiments, described pharmaceutical composition includes two or more analgestics.In some other implementation In mode, described pharmaceutical composition includes one or more analgestics and one or more muscarine antagonists.The medicine Composition can be formulated into the form of tablet, capsule, lozenge, pulvis, particle, liquid, gel or emulsion.It is the liquid, solidifying Glue or emulsion can be taken in by subject in the form of direct form or included in capsule.
In some embodiments, the analgestic is selected from following material：Salicylate, aspirin, salicylic acid, bigcatkin willow Sour methyl esters, Diflunisal, salsalate, Olsalazine, SASP, the derivative of para-aminophenol, antifebrin, to second Acylamino- phenol, phenaetin, fenamic acid ester, mefenamic acid, meclofenamic acid ester, meclofenamate sodium, heteroaryl acetic acid derivative, Tuo Mei Fourth, ketorolac, Diclofenac, propanoic derivatives, brufen, naproxen sodium, naproxen, fenoprofen, Ketoprofen, fluorine compare Lip river Fragrant, olsapozine；Bmap acid, former times health (benzo thiazides) derivative, piroxicam, Meloxicam, tenoxicam, peace pyrrole former times Health, drogelor, a Fu Xikang, e derivatives, phenylbutazone, Oxyphenbutazone, antipyrine, aminopyrine, analgin, examine former times Class medicine, celecoxib, rofecoxib, Nabumetone, apazone, aulin, Indomethacin, sulindac, Etodolac, Diflonid and IB.The muscarine antagonist is selected from oxybutynin, solifenacin, darifenacin and atropic Product.
In some embodiments, described pharmaceutical composition includes single analgestic and single muscarine antagonist.At one In embodiment, the single analgestic is aspirin.In another embodiment, the single analgestic is Bu Luo It is fragrant.In another embodiment, the single analgestic is naproxen or naproxen sodium.In another embodiment, institute It is Indomethacin to state single analgestic.In another embodiment, the single analgestic is Nabumetone.In another reality Apply in mode, the single analgestic is paracetamol.The analgestic and muscarine antagonist can be with above-mentioned scopes Dosage administration.
In some embodiments, described pharmaceutical composition is 50- comprising one or more consumptions alone or in combination 2000mg,50-1500mg,50-1200mg,50-1000mg,50-800mg,50-600mg,50-500mg,50-400mg,50- 300mg,50-250mg,50-200mg,50-150mg,50-100mg,100-2000mg,100-1500mg,100-1200mg, 100-1000mg,100-800mg,100-600mg,100-400mg,100-250mg,250-2000mg,250-1500mg,250- 1200mg,250-1000mg,250-800mg,250-600mg,250-400mg,400-2000mg,400-1500mg,400- 1200mg,400-1000mg,400-800mg,400-600mg,600-2000mg,600-1500mg,600-1200mg,600- 1000mg,600-800mg,800-2000mg,800-1500mg,800-1200mg,800-1000mg,1000-2000mg, 1000-1500mg, 1000-1200mg, 1200-2000mg, 1200-1500mg or 1500-2000mg analgestic, wherein, institute State composition and be formulated into the extension release with a kind of release profiles, in the release profiles, one or more analgesias Agent is continuously released by within the period of 5-24 hours, 5-8,8-16 hours or 16-24 hours.
In some embodiments, the composition is formulated into the extension release with a kind of release profiles, is released at this Put in curve, one or more analgestics at least 90% 5-24 hours, 5-8,8-16 hours or 16-24 hours when It is continuously released by section.
In some embodiments, the composition is formulated into the extension release with a kind of release profiles, is released at this Put in curve, one or more analgestics are 5, quilt in the period of 6,7,8,10,12,14,16,18,20,22 or 24 hours Continuous release.In some embodiments, described pharmaceutical composition further includes muscarine antagonist, antidiuretic or spasmolysis Agent.
In other embodiment, the composition is formulated into the extension release with a kind of release profiles, In the release profiles, the analgestic is within the period of 5-24 hours, 5-8,8-16 hours or 16-24 hours with stable speed Release.In other embodiment, the composition is formulated into the extension release with release profiles, bent in the release In line, the analgestic is 5, released in the period of 6,7,8,10,12,14,16,18,20,22 or 24 hours with stable speed Put." in a period with stable speed " used herein is defined as a kind of release profiles, in the release profiles, given The rate of release of the arbitrfary point of period is in the 30%-300% of the average rate of release of the given period.If for example, 80mg Aspirin was discharged within 8 hour period with stable speed, and the average rate of release in the period is 10mg/hr, then The actual rate of release of this stage random time be in the range of 3mg/hr to 30mg/hr (that is, within 8 hour period In the 30%-300% of 10mg/hr average rate of release).In some embodiments, described pharmaceutical composition is further wrapped Containing muscarine antagonist, antidiuretic or antispastic.
In some embodiments, the analgestic is selected from aspirin, brufen, naproxen sodium, naproxen, indoles U.S. Pungent, Nabumetone and paracetamol.Described pharmaceutical composition is formulated into a small amount of stable releases for providing analgestic, so that Maintain active drug concentration in blood so that compared to immediate release formulation, the medicine total amount in single dose medication is just reduced.
In some embodiments, described pharmaceutical composition includes 50-250mg, 250-400mg or 400-600mg quilt Be configured to a kind of analgestic of the extension release with release profiles, in the release profiles, analgestic at least 90% in 5- 24th, continuously or with stable speed discharged in the period of 5-8,8-16 or 16-24 hours.
In a specific embodiment, described pharmaceutical composition is released comprising being formulated into for 50-250mg with one kind The paracetamol of the extension release of curve is put, in the release profiles, at least 90% paracetamol is in 5-24,5- 8th, continuously or with stable speed discharged in the period of 8-16 or 16-24 hours.
In another specific embodiment, described pharmaceutical composition has comprising being formulated into for 250-400mg A kind of paracetamol of the extension release of release profiles, in the release profiles, 90% paracetamol 5-24, Continuously or with stable speed discharged in the period of 5-8,8-16 or 16-24 hours.
In another specific embodiment, described pharmaceutical composition has comprising being formulated into for 400-600mg A kind of paracetamol of the extension release of release profiles, in the release profiles, 90% paracetamol 5-24, Continuously or with stable speed discharged in the period of 5-8,8-16 or 16-24 hours.
In another specific embodiment, described pharmaceutical composition has comprising being formulated into for 600-800mg A kind of paracetamol of the extension release of release profiles, in the release profiles, 90% paracetamol 5-24, Continuously or with stable speed discharged in the period of 5-8,8-16 or 16-24 hours.
In another specific embodiment, described pharmaceutical composition has comprising being formulated into for 800-1000mg A kind of paracetamol of the extension release of release profiles, in the release profiles, at least 90% paracetamol exists Continuously or with stable speed discharged in the period of 5-24,5-8,8-16 or 16-24 hours.
In some other embodiments, described pharmaceutical composition is comprising one or more consumptions alone or in combination 50-2000mg,50-1500mg,50-1200mg,50-1000mg,50-800mg,50-600mg,50-500mg,50-400mg, 50-300mg,50-250mg,50-200mg,100-2000mg,100-1500mg,100-1200mg,100-1000mg,100- 800mg,100-600mg,100-500mg,100-400mg,100-300mg,100-200mg,200-2000mg,200- 1500mg,200-1200mg,200-1000mg,200-800mg,200-600mg,200-400mg,400-2000mg,400- 1500mg,400-1200mg,400-1000mg,400-800mg,400-600mg,600-2000mg,600-1500mg,600- 1200mg,600-1000mg,600-800mg,800-2000mg,800-1500mg,800-1200mg,800-1000mg,1000- 2000mg, 1000-1500mg, 1000-1200mg, 1200-2000mg, 1200-1500mg or 1500-2000mg analgestic, Wherein, the analgestic is formulated into the extension release with the characteristics of a kind of two sections of release profiles, in the release profiles, analgesia The 20-60% of agent apply 2 hours in discharge, and remainder within the period of 5-24 hour continuously or with stably speed Release.In an other embodiment, the analgestic is formulated into the extension release with a kind of two sections of release profiles, In the release profiles, 20%, 30%, 40%, 50% or the 60% of analgestic discharges using in 2 hours, and remainder Continuously or with stable speed discharged within the period of 5-8,8-16 or 16-24 hours.In one embodiment, the town Pain agent is selected from aspirin, brufen, naproxen sodium, naproxen, Indomethacin, Nabumetone and paracetamol.Another In an outer embodiment, the analgestic is paracetamol.In some embodiments, described pharmaceutical composition is entered One step includes muscarine antagonist, antidiuretic, antispastic or zolpidem.
In an other embodiment, described pharmaceutical composition being formulated into one kind two comprising 50-400mg Section release profiles extension release paracetamol, in the release profiles, paracetamol 20%, 30%, 40%th, 50% or 60% release in 2 hours is being applied, and remainder is within the period of 5-24,5-8,8-16 or 16-24 hours Continuously or with stable speed discharge.
In an other embodiment, described pharmaceutical composition being formulated into one kind comprising 100-300mg The paracetamol of the extension release of two sections of release profiles, in the release profiles, paracetamol 20%, 30%, 40%th, 50% or 60% release in 2 hours is being applied, and remainder is within the period of 5-24,5-8,8-16 or 16-24 hours Continuously or with stable speed discharge.
In an other embodiment, described pharmaceutical composition being formulated into one kind comprising 400-600mg The paracetamol of the extension release of two sections of release profiles, in the release profiles, paracetamol 20%, 30%, 40%th, 50% or 60% release in 2 hours is being applied, and remainder connected in the period of 5-24,5-8,8-16 or 16-24 hours Continuous ground is discharged with stable speed.
In an other embodiment, described pharmaceutical composition being formulated into one kind comprising 600-800mg The paracetamol of the extension release of two sections of release profiles, in the release profiles, paracetamol 20%, 30%, 40%th, 50% or 60% release in 2 hours is being applied, and remainder is within the period of 5-24,5-8,8-16 or 16-24 hours Continuously or with stable speed discharge.
In an other embodiment, described pharmaceutical composition being formulated into one kind comprising 800-1000mg The paracetamol of the extension release of two sections of release profiles, in the release profiles, paracetamol 20%, 30%, 40%th, 50% or 60% release in 2 hours is being applied, and remainder connected in the period of 5-24,5-8,8-16 or 16-24 hours Continuous ground is discharged with stable speed.
In an other embodiment, described pharmaceutical composition being formulated into one comprising 1000-1200mg The paracetamol of the extension release of kinds of two sections release profiles, in the release profiles, paracetamol 20%, 30%th, 40%, 50% or 60% release in 2 hours is being applied, and remainder was at 5-24,5-8,8-16 or 16-24 hours Continuously or with stable speed discharged in period.
Further aspect of the application is related to a kind of by applying the first medicine comprising diuretics to the people for having this needs Composition, then using the second pharmaceutical composition comprising one or more analgestics in the method for the treatment of bed-wetting.Described The dosage and formula of one pharmaceutical composition are set within applying 6 hours have diuretic effect, and at least 8 or 7 before sleeping Hour applies.Second pharmaceutical composition is formulated into the extension release of extension release or delay, and before sleeping in 2 hours Using.
The example of diuretics includes, but not limited to be acidified salt, such as CaCl2And NH4Cl；The antagonism of arginine vasopressin receptors 2 Agent, such as amphotericin B and Lithium Citrate；Aquaretic, such as chrysanthemum (Goldenrod) and needle juniper (Junipe)；Na-H is exchanged Agent antagonist, such as dopamine；Carbonic anhydrase inhibitor, such as acetazolamide and Dorzolamide；Loop diuretic, such as bumetanide, according to His Buddhist nun acid, frusemide and torsemide；Osmotic diuretic, such as glucose and mannitol；Potassium-sparing diuretic, such as amiloride, spiral shell Medial rotation ester sterol, triamterene, canrenoate potassium；Thiazide, such as bendroflumethiazide and Hydrochioro；And xanthine, such as coffee Cause, theophylline and theobromine.
In some embodiments, second pharmaceutical composition is further comprising one or more muscarine antagonists. In some other embodiments, second pharmaceutical composition is further comprising one or more antidiuretics.In others In some embodiments, second pharmaceutical composition is further comprising one or more antispastics.In some other implementations In mode, second pharmaceutical composition further includes zolpidem.Second pharmaceutical composition can be formulated into be released immediately Put preparation or delayed release preparation.
Further aspect of the application is related to a kind of by selectively applying two kinds or more to subject in need A variety of analgestics are to prevent drug resistance to alleviate the method for frequent micturition.In one embodiment, this method includes applying pin To the first analgestic of the first period, the second analgestic for the second period is then applied.In another embodiment, should Method further comprises applying the 3rd analgestic for the 3rd period.First, second, and third analgestic is different from each other, And wherein at least one is formulated into the extension release of extension release or delay.In one embodiment, first analgesia Agent is paracetamol, and second analgestic is brufen and the 3rd analgestic is naproxen sodium.Each period Length can be different to the reaction of each analgestic according to subject.In some embodiments, during each period lasts Between from three days to three weeks.In another embodiment, first, second, and third analgestic is all formulated into extension release or prolonged Slow extension release.
Further aspect of the application is related to a kind of medicine comprising various active composition and pharmaceutically acceptable carrier Composition, wherein, at least one extension release for being formulated into extension release or delay of the various active composition.At some In embodiment, the various active composition includes one or more analgestics and one or more antidiuretics.At other In embodiment, the various active composition includes one or more analgestics and one or more muscarine antagonists.Another In a little embodiments, the various active composition includes one or more analgestics and zolpidem.In other embodiments, The various active composition includes one or more analgestics, one or more antidiuretics and one or more Antimuscarinics Agent.In other embodiments, the various active composition includes one or more analgestics, zolpidem and one or more Antidiuretic or one or more muscarine antagonists.The muscarine antagonist be selected from oxybutynin, solifenacin, darifenacin and Atropine.In other embodiments, described pharmaceutical composition comprising two kinds it is different selected from acetylsalicylic acid, brufen, Naproxen sodium, naproxen, Nabumetone, the analgestic of paracetamol and Indomethacin.In other embodiment, Described pharmaceutical composition comprising it is a kind of selected from acetylsalicylic acid, brufen, naproxen sodium, Nabumetone, paracetamol and The analgestic of Indomethacin；And the muscarine antagonist selected from oxybutynin, solifenacin, darifenacin and atropine.
In other embodiment, herein described pharmaceutical composition is further comprising one or more antispastics. The example of antispastic includes, but not limited to carisoprodol, benzene (simultaneously) diazepine, Baclofen, cyclobenzaprine, metaxalone, U.S. Suo Bamo, clonidine, clonidine analog and dantrolene.In some embodiments, antispastic with daily 1mg extremely 1000mg, 1mg are to 100mg, 10mg to 1000mg, 10mg to 100mg, 20mg to 1000mg, 20mg to 800mg, and 20mg is extremely 500mg, 20mg are to 200mg, 50mg to 1000mg, 50mg to 800mg, 50mg to 200mg, 100mg to 800mg, and 100mg is extremely The dosage of 500mg, 200mg to 800mg and 200mg to 500mg is used.Antispastic can individually or with other in pharmaceutical composition Active component is formulated into together to be discharged, extends release, delay-extension release or its combination immediately.
In some embodiments, described pharmaceutical composition is selected from aspirin, brufen, Nabumetone comprising one or more Life, naproxen sodium, Indomethacin, Nabumetone and paracetamol consumption for every dose of 50-400mg analgestic, and The muscarine antagonist that total amount of the one or more selected from oxybutynin, solifenacin, darifenacin and atropine is 1-25mg, its In, described pharmaceutical composition is formulated into the extension release with a kind of two benches release profiles, in the release profiles, activity The 20-60% of composition is released in 2 hours applying, and the remainder of active component was in 5-24 hours, 5-8 hours, 8-16 Continuously or with keeping steady rate discharged in the period of hour or 16-24 hours.
In some embodiments, described pharmaceutical composition is selected from aspirin, brufen, Nabumetone comprising one or more Life, naproxen sodium, Indomethacin, Nabumetone and paracetamol consumption for every dose of 50-400mg analgestic, and One or more antidiuretics, the antidiuretic is selected from antidiuretic hormone (ADH), angiotensinⅡ, aldosterone, blood vessel and added Pressure element, the similar thing of vasopressing are (for example, minirin Argipressin, lypressin, felypressin, bird ammonia add Pressure element, terlipressin)；Vasopressin receptor activator, atrial natriuretic peptide (ANP) and c-type natriuretic peptide (CNP) acceptor are (i.e., NPR1, NPR2, NPR3) antagonist (for example, HS-142-1, isatin, [Asu7,23 '] b-ANP- (7-28)], An Nanting (anantin) cyclic peptide, from streptomyces coelicolor (Streptomyces coerulescens), and 3G12 monoclonals are anti- Body)；The receptor antagonist of somatostatin 2 (e.g., somatostatin), and its pharmaceutically acceptable derivates, Analog, salt, hydrate and solvate, wherein, described pharmaceutical composition is formulated into a kind of two benches release profiles Extension release, in the release profiles, the 20-60% of active component is released in 2 hours applying, and remainder is in 5- Continuously or with keeping steady rate discharged in the period of 24 hours, 5-8 hours, 8-16 hours or 16-24 hours.
In some embodiments, described pharmaceutical composition is selected from aspirin, brufen, Nabumetone comprising one or more Life, naproxen sodium, Indomethacin, Nabumetone and paracetamol consumption for every dose of 50-400mg analgestic, and one Kind or it is a variety of selected from carisoprodol, benzene (simultaneously) diazepine, Baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine, The total amount of clonidine analog and dantrolene is 50-500mg antispastic, wherein, described pharmaceutical composition is formulated into tool The extension for having a kind of two benches release profiles is discharged, in the release profiles, and the 20-60% of active component is being applied 2 hours in Be released, and remainder within the period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours by continuously or protect Discharge with holding steady rate.
The present invention will be further illustrated by the following non-limiting examples.That quotes in this application is all with reference to text The content of part, patent and disclosed patent application is all incorporated herein by reference.
Embodiment 1：The suppression of urination impulsion
20 trial volunteers that men and women participates in are recruited, they each be experienced, and too early urination is got excited or urination is needed Ask, this disturbs the ability that they are enough to feel the sleep for a period of time fully rested.Each 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 frequently urination impulsion Wake up, they can preferably rest.
There are several subjects reporteds to say, used at night after brufen several weeks, can no longer realize urination impulsion not Frequently benifit.However, all these subjects further report, after abandoning taking medicament several days, obtain again 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.) mediation inflammation and non-inflammation stimulate 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, culture cell is exposed to analgestic and/or muscarine antagonist.
The effector includes：Lipopolysaccharides (LPS), inflammatory agent and Cox2 inducers, are used as inflammatory stimulus；Kappa courage Alkali or acetylcholine, smooth muscle contraction stimulant, are used as non-inflammation stimulus；Botulic neurotoxin A, it is a kind of known The inhibitor of acetylcholine release, is used 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 Produced successively after oxidation AA, DGLA or EPA 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.'s ketone or Relafen；APAP (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 material or long-term (24-48 hours)：
(1) every kind of single analgestic of various dose.
(2) in the presence of LPS various dose every kind of analgestic.
(3) in the presence of carbachol or acetylcholine various dose every kind of analgestic.
(4) in the presence of AA, DGLA or EPA various dose every kind of analgestic.
(5) the single 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) single every kind of muscarine antagonist of various dose.
(10) in the presence of LPS various dose every kind of muscarine antagonist.
(11) in the presence of carbachol or acetylcholine various dose every kind of muscarine antagonist.
(12) in the presence of AA, DGLA or EPA various dose every kind of muscarine antagonist.
Then the PGH of cell is analyzed2、PGE、PGE2, prostacyclin, thromboxane, IL-1 β, IL-6, the release of TNF-α, COX2 activity, cAMP and cGMP generation, IL-1 β, IL-6, TNF-α and COX2mRNA generation, and CD80, CD86 and MHC The surface expression of II quasi-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 RPMI 1640 culture medium, and it is supplemented with 10% hyclone (FBS), 15mM HEPES, 2mM l-glutamine, 100U/ The streptomysin of ml penicillin and 100 μ g/ml.By cell in 37 DEG C, 5% CO2Cultivated 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 individual cells/well (in 100 μ l culture mediums) is seeded in In 96 orifice plates.Cell is handled with following material：(1) analgestic (paracetamol, aspirin, the Bu Luo of various concentrations Fragrant or naproxen), the lipopolysaccharides (LPS) of (2) various concentrations, it is the effector to the inflammation sexual stimulus of macrophage, (3) no With the carbachol or acetylcholine of concentration, they are the effector that non-inflammation is stimulated, (4) analgestic and LPS or (5) analgesia Agent and carbachol or acetylcholine.(that is, 15mM is supplemented with short, analgestic is dissolved in no FBS culture medium The RPMI 1640 of the streptomysin of HEPES, 2mM l-glutamine, 100U/ml penicillin and 100 μ g/ml), and by using identical The serial dilution of medium is diluted to required concentration.For the cell handled in the presence of without LPS with analgestic, to every 50 μ l analgestic solution and the 50 μ l culture medium without FBS are added in individual hole.For easing pain in the presence of having LPS The cell of agent processing, 50 μ l analgestic solution is added into each hole and the 50 μ l LPS in the culture medium without FBS (comes From salmonella typhimurium (Salmonella typhimurium)).All condition retests are twice.
Culture 24 or 48 hours after, collect 150 μ l culture supernatant, at 4 DEG C, under 8,000rpm rotate 2 minutes with Cell and fragment are removed, and stores to pass through the reaction of elisa assay cell factor at -70 DEG C.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 is dyed with fluorescent monoclonal antibody and passes through fluidic cell Meter analysis.
The Flow Cytometry of costimulatory molecules expression
For Flow Cytometry, by macrophage 100 μ l FACS buffer solution (have 2% bovine serum albumin (BSA) and 0.01%NaN in vain3Phosphate buffer (PBS)) in dilute, and by add FITC- combination anti-CD40, PE- With reference to anti-CD80, PE- combine anti-CD86 antibody, anti-MHC II classes (I-Ad) PE (BD bioscience) and at 4 DEG C dye 30 minutes.Then by cell (at 4 DEG C, 1,500rpm lower 5 minutes) cleaning by being centrifuged in 300 μ l FACS buffer solution. After second is washed, cell is resuspended in 200 μ l FACS buffer solution, and (BD gives birth to by Accuri C6 flow cytometries Thing science) analytical table up to the cell of the combination (double positives) of given mark (single positive) or mark percentage.
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 and TNF-α reaction in the culture for the macrophage that LPS and analgestic combine processing.These measure be with Anti-mouse IL-6, the TNF-α mAbs (BD bioscience) of the 100 μ l in 0.1M sodium bicarbonate buffer liquid (pH 9.5) or Carried out on the Nunc MaxiSorp Immunoplates (Nunc) of IL-1 β mAb (R＆D systems) coatings overnight.With PBS After (per μ l of hole 200) cleaning twice, 200 μ l of the addition PBS 3%BSA in each hole (area), and plate 2 is incubated at room temperature Hour.200 μ l are added by every hole, clean plate twice, repeats 100 μ l of addition cytokine standards product and serial dilution again Culture supernatant, and the plate is incubated overnight at 4 DEG C.Finally, by plate cleaning twice, it is and biotinylated with 100 μ l Anti- mouse IL-6, TNF α mAbs (BD bioscience) or IL-1 β (R＆D systems) secondary antibody, then with the sheep of peroxidase labelling Antibiotin mAb (Vector laboratories) is incubated.By adding 2,2 '-azine-bis- (3- Ethylbenzyl thiazoline -6- sulfonic acid) (ABTS) substrate andH2O2 (Sigma) chrominance response is made to develop, and absorbance is usedV multiple labeling micropore board detectors (PerkinElmer) measured at 415nm.
COX2 determination of activity and cAMP and cGMP generation
The activity of COX2 in the macrophage of culture is determined by sequential competition ELISA (R＆D systems).CAMP and CGMP generation is determined by cAMP and cGMP determines to determine.These measure are generally carried out in the art.
As a result
Table 1 summarize the experiment that is carried out by the strain of Raw 264 macrophages and analgestic to costimulatory molecules CD40 and Main discovery in terms of the influence of CD80 cell surface expression.The expression of these molecules is pierced by COX2 and inflammatory signals Sharp, and the expression of these molecules is therefore assessed with the functional consequence for the suppression for determining COX2.
As shown in table 2, except maximum dose level (that is, 5x106NM) (it shows enhancing, rather than suppresses costimulatory molecules Expression) beyond, paracetamol, aspirin, brufen and naproxen are in all proof load (that is, 5x105nM、 5x104nM、5x103nM、5x102NM, 50nM and 5nM) under suppress macrophage costimulatory molecules CD40 and CD80 underlying table Reach.As shown in Figure 1A and 1B, observed when analgestic consumption is as little as 0.05nM (that is, 0.00005 μM) to CD40 and CD50 tables The such inhibition reached.This discovery supports such viewpoint：The control release of low dose of analgestic is than heavy dose of Acute delivering more preferably.Experiment is it is also shown that what paracetamol, aspirin, brufen and naproxen were induced LPS CD40 has similar inhibition with CD80 expression.
The experimental summary of table 1.
The summary that table 2. is mainly found
*ND：Do not carry out (toxicity)
Table 3 summarizes the result of several research, and 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 105In the range 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 the oral medication dosage of table 3. in human blood
Embodiment 3：Analgestic, botulic neurotoxin and muscarine antagonist are to mouse bladder smooth muscle cell to inflammation The influence of the reaction stimulated with non-inflammation
Experimental design
This research is intended to illustrate how the optimal dosage of the analgestic determined in example 2 is influenceed in cell culture or group Knit culture in bladder smooth muscle cells, and discuss inhomogeneous analgestic whether can cooperate with more effectively suppress 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 material 48 hours) stimulate：
(1) every kind of single analgestic of various dose.
(2) in the presence of LPS various dose every kind of analgestic.
(3) in the presence of carbachol or acetylcholine various dose every kind of analgestic.
(4) in the presence of AA, DGLA or EPA various dose every kind of analgestic.
(5) the single 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) single every kind of muscarine antagonist of various dose.
(10) in the presence of LPS various dose every kind of muscarine antagonist.
(11) in the presence of carbachol or acetylcholine various dose every kind of muscarine antagonist.
(12) in the presence of AA, DGLA or EPA various dose every kind of muscarine antagonist.
Then the PGH of cell is analyzed2、PGE、PGE2, prostacyclin, thromboxane, IL-1 β, IL-6, the release of TNF-α, COX2 activity, cAMP and cGMP generation, IL-1 β, IL-6, TNF-α and COX2mRNA generation, and CD80, CD86 and MHC The surface expression of II quasi-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, being 10ml's by the bladder scissors chopping obtained from 10 mouse Digest the refined slurries in buffer solution (RPMI 1640,2% hyclone, 0.5mg/ml clostridiopetidase As, 30 μ g/ml DNA enzymatic). By bladder slurries at 37 DEG C enzymic digestion 30 minutes.Indigested fragment is entered one by cell training aids (cell-trainer) Step is scattered.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% hyclone, 15mM HEPES, In the RPMI 1640 of the streptomysin of 2mM l-glutamines, 100U/ml penicillin and 100 μ g/ml, and with 3x104Individual cells/well The cell density of (100 μ l) is inoculated into the micro- culture plate of hole cell culture of black 96 of clarification bottom.By cell at 37 DEG C, 5% CO2Cultivated under atmosphere.
Cell is with the external treatment of analgestic
By bladder cells with analgestic solution (50 μ l/ holes) individually or with carbachol (10 moles, 50 μ l/ holes) (make 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 L/ holes) (being used as the example of non-inflammation stimulus) be jointly processed by.When no other effectors are added in cell, Xiang Kongzhong The 50 μ l RPMI 1640 without hyclone is added to adjust final volume as 200 μ l.
After 24 hours of incubation, 150 μ l culture supernatant is collected, 2 minutes are rotated at 4 DEG C, under 8,000rpm to remove Cell and fragment, and store to pass through elisa assay prostaglandin E2 (PGE at -70 DEG C2) reaction.Cell is fixed, Permeabilization is simultaneously closed with using fluorogenic substrate detection cyclooxygenase-2 (COX-2).In selected experiment, cell stimulates 12 in vitro The analysis that hour reacts for COX2.
COX2 response analysises
COX2 reactions are divided by the ELISA based on cell of the total COX2 immunoassays of user/mouse (R＆D systems) Analysis, the analysis is carried out according to the specification of manufacturer.In short, after cell fixation and permeabilization, to the black of clarification bottom Mouse is added in the hole of the micro- culture plate of hole cell culture of color 96 and resists total COX2 and the total GAPDH of rabbit-anti.After cultivation and cleaning, Xiang Kongzhong adds the anti-rabbit IgG for anti-mouse IgG and the AP combination that HRP is combined.After another cultivation and cleaning, HRP- is added glimmering Light substrate and AP- fluorogenic substrates.Finally, useV multiple labeling micropore board detectors (PerkinElmer) are read The fluorescence that 600nm (COX2 fluorescence) and 450nm (GAPDH fluorescence) place are sent.As a result total COX2 relative level is expressed as, it leads to Relative fluorescence units (RFUs) determination is crossed, and is standardized as house keeping protein GAPDH.
PGE2 response analysises
The reaction of prostaglandin E2 is analyzed by sequential competition ELISA (R＆D systems).Specifically, it is small to being resisted by goat Culture supernatant or PGE2 standard samples are added in the hole of the coated 96 hole polystyrene microwell 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 clean Plate, and the addition HRP substrate solutions into each hole.Allow colour developing 30 minutes, and by (correcting ripple at 570nm in 450nm It is long) place adds sulfuric acid to stop reaction before reading plate.As a result the average pg/ml of PGE2 are expressed as.
Other experiments
PGH2, PGE, prostacyclin (Prostacydin), thromboxane, the release of IL-1 β, IL-6 and TNF-α, cAMP With cGMP generation, the table of IL-1 β, IL-6, TNF-α and COX2mRNA generation, and CD80, CD86 and MHC II quasi-molecules Face expression is determined using method as described in example 2 above.
As a result
Analgestic suppresses mouse bladder cell and the COX2 of inflammation sexual stimulus is reacted
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.The analysis shows of culture in 24 hours, institute The analgestic of test does not induce the COX2 in mouse bladder cell in vitro to react.
It is also tested for the COX2 reactions that these analgestics are stimulated carbachol or LPS mouse bladder cell in vitro Influence.As shown in table 1, the dosage of the carbachol of test has no significant effect for the COX-2 levels in mouse bladder cell. On the other hand, LPS dramatically increases total COX2 levels.It is worth noting that, paracetamol, aspirin, brufen and naphthalene General life can suppress influences of the LPS to COX2 levels.When these medicines are being tested for 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 suppresses mouse bladder cell and the PGE2 of inflammation sexual stimulus is reacted
The secretion of the PGE2 in mouse bladder cell culture supernatant is measured, 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, trained in the bladder cells not stimulated or in the presence of carbachol PGE2 is not detected by the culture supernatant of foster bladder cells.It is consistent with above-mentioned COX2 reactions, stimulate mouse with LPS Bladder cells induce PGE2 high-level secretory.Analgestic paracetamol, aspirin, the addition of brufen and naproxen The influence for inhibiting LPS to secrete PGE2, and do not observed between the cell effect handled with the analgestic of 5 or 50 μM of dosage To difference.
Table 5. stimulates the PGE2 secretions with mouse bladder cell after analgestic processing in vitro
In a word, the COX2 that these as shown by data only will not be in inducing mouse bladder cells under 5 μM or 50 μM with analgestic With PGE2 reactions.However, under 5 μM or 50 μM, it is thin that analgestic significantly inhibits the external mouse bladder by LPS (1 μ g/ml) stimulations COX2 and the PGE2 reaction of born of the same parents.Not it was observed that analgestic to the COX2 of mouse bladder cell that is stimulated by carbachol (1mM) and What PGE2 reacted significantly affects.
Embodiment 4：Analgestic, botulic neurotoxin and muscarine antagonist are to mouse bladder smooth muscle cell contraction Influence
Experimental design
Make culture mouse or rat bladder smooth muscle cell and mouse or rat bladder smooth muscle tissue Bu Tong dense Inflammatory stimulus and non-inflammation stimulus are exposed in the presence of the analgestic and/or muscarine antagonist of degree.Measurement is stimulated 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 material 48 hours) stimulate：
(1) every kind of single analgestic of various dose.
(2) in the presence of LPS various dose every kind of analgestic.
(3) in the presence of carbachol or acetylcholine various dose every kind of analgestic.
(4) in the presence of AA, DGLA or EPA various dose every kind of analgestic.
(5) the single 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) single every kind of muscarine antagonist of various dose.
(10) in the presence of LPS various dose every kind of muscarine antagonist.
(11) in the presence of carbachol or acetylcholine various dose every kind of muscarine antagonist.
(12) in the presence of AA, DGLA or EPA various dose every kind of muscarine antagonist.
Material and method
Primary mouse bladder cells are separated as described in Example 3.In selected experiment, the culture of bladder body is used Thing.Shunk using Grass polygraphs (U.S. Quincy Mass) record bladder smooth muscle cells.
Embodiment 5：What oral analgestic and muscarine antagonist were reacted the COX2 and PGE2 of mouse bladder smooth muscle cell Influence.
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 mouse with overactive bladder syndrome. After final dose 30 (30) minute, collect bladder and stimulated in vitro with carbachol or acetylcholine.In selected experiment, Bladder uses botulic neurotoxin A processing before being stimulated with carbachol.Animal is retained in metabolic cage, and the row of assessment Frequent micturition rate (and volume).Bladder discharge rate is determined by monitoring water intake and cage litter weight (cage litter weight).Pass through ELISA determines serum PG H2、PGE、PGE2, prostacyclin, thromboxane, IL-1 β, IL-6, TNF-α, cAMP and cGMP levels. The expression of CD80, CD86, MHC II classes in whole blood cells is detected by flow cytometry.
After experiment terminates, 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 for the reaction that non-inflammation is stimulated
Experimental design
Design how the optimal dosage for the analgestic that this research is determined to be characterized 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 material or long-term (24-48 hours)：
(1) every kind of single analgestic of various dose.
(2) in the presence of LPS various dose every kind of analgestic.
(3) in the presence of carbachol or acetylcholine various dose every kind of analgestic.
(4) in the presence of AA, DGLA or EPA various dose every kind of analgestic.
(5) the single 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) single every kind of muscarine antagonist of various dose.
(10) in the presence of LPS various dose every kind of muscarine antagonist.
(11) in the presence of carbachol or acetylcholine various dose every kind of muscarine antagonist.
(12) in the presence of AA, DGLA or EPA various dose every kind of muscarine antagonist.
Then the PGH of cell is analyzed2、PGE、PGE2, prostacyclin, thromboxane, IL-1 β, IL-6, the release of TNF-α, COX2 activity, cAMP and cGMP generation, IL-1 β, IL-6, TNF-α and COX2mRNA generation, and CD80, CD86 and MHC The surface expression of II quasi-molecules.
Embodiment 7：The shadow of analgestic, botulic neurotoxin and muscarine antagonist to human bladder smooth muscle cell contraction Ring
Experimental design
Make human bladder smooth muscle cell exposure in the presence of the analgestic and/or muscarine antagonist of various concentrations of culture In inflammatory stimulus and non-inflammation stimulus.Measurement stimulates the contraction of muscle of induction 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 material or long-term (24-48 hours)：
(1) every kind of single analgestic of various dose.
(2) in the presence of LPS various dose every kind of analgestic.
(3) in the presence of carbachol or acetylcholine various dose every kind of analgestic.
(4) in the presence of AA, DGLA or EPA various dose every kind of analgestic.
(5) the single 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) single every kind of muscarine antagonist of various dose.
(10) in the presence of LPS various dose every kind of muscarine antagonist.
(11) in the presence of carbachol or acetylcholine various dose every kind of muscarine antagonist.
(12) in the presence of AA, DGLA or EPA various dose every kind of muscarine antagonist.
Shunk using Grass polygraphs (U.S. Quincy Mass) record bladder smooth muscle cells.
Embodiment 8：Influence of the analgestic to normal person's bladder smooth muscle cells 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 separated by enzymic digestion from macroscopical normal segments of human bladder.Cell is existed It is external by 37 DEG C in 5%CO2Atmosphere in be supplemented with 10% hyclone, the left-handed paddy acyl of 15mM HEPES, 2mM In the RPMI 1640 of the streptomysin of amine, 100U/ml penicillin and 100mg/ml cultivate and expand, and by using trypsase at Reason is per week to separate subsequent inoculated in new blake bottle of cell to pass on once.First week of culture, culture medium is mended Filled with 0.5ng/ml EGFs, 2ng/ml fibroblast growth factors and 5 μ g/ml insulin.
It is external that normal human bladder smooth muscle cell is handled with analgestic
By by Trypsin Induced, and with 3x104It is flat that the cell density of individual cells/well (100 μ l) is seeded in micro- culture Bladder smooth muscle cells in plate with analgestic solution (50 μ l/ holes) individually or with carbachol (10 moles, 50 μ l/ holes) (being used as the example of non-inflammation stimulus) is jointly processed by, or with the lipopolysaccharides (LPS) of salmonella typhimurium (1 μ g/ml, 50 μ l/ holes) (being used as the example of non-inflammation stimulus) be jointly processed by.When no other effectors are added in cell, to The 50 μ l RPMI 1640 without hyclone is added in hole to adjust final volume as 200 μ l.
After 24 hours of incubation, 150 μ l culture supernatant is collected, 2 minutes are rotated at 4 DEG C, under 8,000rpm to remove Cell and fragment, and store to pass through elisa assay prostaglandin E2 (PGE at -70 DEG C2) reaction.Cell is fixed, Permeabilization simultaneously is closed to detect COX2 using fluorogenic substrate.In selected experiment, cell stimulate in vitro 12 hours for COX2, PGE2 and the analysis of 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- Should.
As a result
Analgestic suppress normal human bladder smooth muscle cell inflammatory and non-inflammation stimulus COX2 is reacted- The analysis shows of 24 hours later cells and culture supernatant are cultivated, normal human bladder is induced 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 Induce low but significant COX2 reactions.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 suppress carbachol and LPS to COX2 The influence of level.When these medicines are being tested for 5 μM or 50 μM, it can be seen that suppression of the analgestic to the LPS reactions induced is imitated Really.
Table 6. after being stimulated and handled with analgestic with inflammatory and non-inflammation stimulus in vitro normal human bladder put down The COX2 expression of sliding myocyte
#Data are expressed with the average value being repeated twice
Analgestic suppress normal human bladder smooth muscle cell inflammatory and non-inflammation stimulus PGE2 react-and The above-mentioned induction reacted COX2 is consistent, the PGE2's of carbachol and the normal human bladder smooth muscle cell of LPS inductions Produce.It has also been found that paracetamol, aspirin, brufen and naproxen also suppress LPS inductions under 5 μM or 50 μM PGE2 reacts (table 7).
Table 7. stimulated and handled with analgestic with inflammatory and non-inflammation stimulus in vitro after normal human bladder The PGE2 secretions of smooth muscle cell
#Data are expressed with the average value being repeated twice
Analgestic suppress normal human bladder cell to the cell factor reaction of inflammatory stimulus-culture 24 hours with Cell afterwards and the analysis shows of culture supernatant, are induced in normal human bladder smooth muscle cell without the analgestic individually tested IL-6 or TNF α secretion.As shown in Tables 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 causes these proinflammatory cell factors A large amount of inductions.Paracetamol, aspirin, brufen and naproxen can suppress carbachol and LPS to TNF α and IL- The influence of 6 reactions.When these medicines are being tested for 5 μM or 50 μM, it can be seen that suppression of the analgestic to the LPS reactions induced is imitated Really.
Table 8. after being stimulated and handled with analgestic with inflammatory and non-inflammation stimulus in vitro normal human bladder put down The TNF α secretion of sliding myocyte
#Data are expressed with the average value being repeated twice
Table 9. after being stimulated and handled with analgestic with inflammatory and non-inflammation stimulus in vitro normal human bladder put down 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 foregoing phenomenon obtained by Muridae bladder cells.
With sustained release or alleviating prolongation delivery formulations or delay and the analgestic and/or muscarine antagonist of alleviating prolongation delivery formulations Repeat above-mentioned experiment.
Description above is to be used to instruct how one of ordinary skill in the art puts into practice the object of the invention, and it is not intended to Detailed description obviously those can be repaiied significantly after having read specification for the person of ordinary skill of the art Change and change.But, it is intended to all obvious 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 is intended to covering can effectively realize in any order The required component and step of its required purpose.

Claims (7)

1. the basic various active composition being made up of zolpidem and one or more analgestics is in manufacture alleviating experimenter's frequent micturition Purposes in medicine, wherein, one or more analgestics include paracetamol and brufen.
2. purposes according to claim 1, wherein, the medicine is formulated into release immediately, sustained release, extension release Or its combination.
3. purposes according to claim 1, wherein, one or more analgestics are formulated into extension release or postponed Release, and wherein described zolpidem is formulated into and discharged immediately.
4. a kind of pharmaceutical composition, it is included：
The basic various active composition being made up of zolpidem and one or more analgestics；And
Pharmaceutically acceptable carrier,
Wherein, one or more analgestics include paracetamol and brufen.
5. pharmaceutical composition according to claim 4, wherein, described pharmaceutical composition is formulated into be discharged, postpones immediately Release, extension release or its combination.
6. the pharmaceutical composition according to claim 4 or 5, wherein, one or more analgestics are formulated into extension Release, and wherein described zolpidem is formulated into and discharged immediately.
7. the pharmaceutical composition according to claim 4 or 5, wherein, one or more analgestics are formulated into delay Release, and wherein described zolpidem is formulated into and discharged immediately.
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