CN104873457A - Delayed-release drug form - Google Patents
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- CN104873457A CN104873457A CN201510259573.0A CN201510259573A CN104873457A CN 104873457 A CN104873457 A CN 104873457A CN 201510259573 A CN201510259573 A CN 201510259573A CN 104873457 A CN104873457 A CN 104873457A
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Abstract
The invention relates to a delayed-release drug form, and particularly relates to a penetrant form. The penetrant form comprises (a) a core containing bioactive ingredients; (b) a semipermeable membrane covering the core; and (c) at least one channel passing through the semipermeable membrane, wherein the semipermeable membrane contains ethyl cellulose, an acrylic or methacrylic polymer and a water-soluble plasticizer, and the conditions are as follows: the semipermeable membrane does not contain water-soluble substances besides the water-soluble plasticizer or contains not more than 15wt% of water-soluble substances based on total dry weight of the semipermeable membrane.
Description
The present patent application is the divisional application based on the applying date is on June 2nd, 2009, application number is 200980160530.X (international application no is PCT/CN2009/072099), name is called the application for a patent for invention of " slow release formulation ".
Technical field
The present invention relates to the core comprised containing bioactive ingredients, the semipermeable membrane covering described core and at least one osmotic dosage form by the passage of described semipermeable membrane.
Background technology
Osmotic dosage form from United States Patent (USP) 3,845,770; 3,916,899; 4,034,758; 4,077,407; 4,327,725; With 4,783,337 learn.The exploitation of osmotic dosage form is by Alza ORO S
tMthe exploitation of (a kind of preliminary oral osmotic system) opened up.Osmotic dosage form is according to penetration theory work with nearly zero level distribution (near zero order profile) delivering drugs.Osmotic dosage form comprises the core containing bioactive ingredients and covers the semipermeable membrane of described core.Semipermeable membrane (being also often called semi-transparent wall) as gastric juice or intestinal juice is permeable passes through for moisture external fluid, and allows described external fluid through film and optionally dissolves described bioactive ingredients.Described film for the active component in the solution of external fluid or suspension by being impermeable substantially.There is provided the infiltration lane that runs through described wall with by the active delivery in the solution of external fluid or suspension to environment, instead of to send through the diffusion of described film.Osmotic dosage form allows active component to extend release.If osmotic dosage form is included in active component insoluble in external fluid, so osmotic dosage form often comprises polymers swell agent, described polymers swell agent with external fluid contact after expand and promote active component and pass through passage.WO 2006/046114 discloses osmotic dosage form, its in essence by comprise medicine layer and push layer core, form around the semipermeable membrane of described core and at least one passage in described semipermeable membrane.
Above-mentioned patent openly discloses, and in formation semipermeable membrane, available material is cellulose esters, cellulose two esters, cellulose iii esters, cellulose ethers, cellulose esters-ethers, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose-acetate propionate and cellulose acetate-butyrate.The open CN1923184-A of Chinese patent discloses the permeability release tablet dosage form of VENLAFAXINE HCL (a kind of water soluble drug).The additional osmotic tablet in controlled release bunch hole comprises lamellar core and coating.Described coating comprise in the film forming polymer being selected from cellulose acetate, ethyl cellulose, hydroxypropyl emthylcellulose and/or polyacrylics one or more and also comprise the pore former of 20-45wt.%, such as sugar, sodium chloride, sorbitol, Polyethylene Glycol or hydroxypropyl cellulose, based on the weight of coating.Described coating also can comprise plasticizer, such as triethyl citrate, dibutyl sebacate, phthalic acid ester and/or Macrogol 4000.Unfortunately, this coating does not have enough film-strengths and can be generally comprised within the polymers swell agent destruction in infiltration release tablet.
Most preferably and the semipermeable membrane material known be ethyl cellulose.Many commercial osmotic dosage form are as ALZA exploitation
push-Pull
tMsystem comprises cellulose acetate as filmogen for semipermeable membrane.In the process manufacturing osmotic dosage form, usually with the coated core comprising the shaping of bioactive ingredients of semipermeable membrane raw material dissolved in organic solvent.When osmotic dosage form comprises cellulose acetate as semipermeable membrane filmogen, individuality as this osmotic dosage form of human consumption and as described in bioactive ingredients start release between there is obvious lag time.And, for preparing semipermeable membrane, cellulose acetate have to dissolve in acetone because security reason this be undesirable.
Those skilled in the art have carried out several and have attempted to overcome this lag time.The most frequently used method namely releases the coated osmotic dosage form of coating with the outside comprising described bioactive ingredients.Unfortunately, complexity and the cost that coating increases osmotic dosage form is released in this outside in addition namely.And due to product safety reason, the layers exterior comprising described bioactive ingredients is often undesirable.
Therefore, it is desirable to provide and do not comprise the new osmotic dosage form of cellulose acetate as semipermeable membrane filmogen.More preferably, be provided in picked-up osmotic dosage form and comprise cellulose acetate starts not have between delivery of biologically active composition obvious lag time new osmotic dosage form as the osmotic dosage form of semipermeable membrane filmogen.
Particularly desirably, provide so new osmotic dosage form, this new osmotic dosage form is providing zero level substantially to distribute with liquid, aqueous beginning in the 2-12 after contacting hour.Also particularly desirably, provide so new osmotic dosage form, this new osmotic dosage form has enough film-strengths, and the polymers swell agent that it is not generally comprised within osmotic dosage form destroys.
Summary of the invention
One aspect of the invention is osmotic dosage form (101,201,301), it comprises:
A () comprises the core (102,202,302) of bioactive ingredients (204);
B () covers the semipermeable membrane (105,205,305) of described core; With
(c) at least one passage (106 by semipermeable membrane, 206,306), wherein said semipermeable membrane comprises ethyl cellulose, acrylic compounds or methacrylic polymer and water dissolvable plasticizer, condition is: except water dissolvable plasticizer, described semipermeable membrane is not containing water soluble substance or comprise the water soluble substance being no more than 15 % by weight, based on the gross dry weight of described semipermeable membrane.
Another aspect of the invention is the method preparing above-mentioned osmotic dosage form, it comprises the following steps:
I) core is formed by described bioactive ingredients and optional member;
II) with the coated described core of film composition comprising ethyl cellulose, acrylic compounds or methacrylic polymer, water dissolvable plasticizer and optional member, thus semipermeable membrane is provided;
III) in described semipermeable membrane, at least one passage is created; And optionally
IV) decorative layer (finishing layer) is applied to described osmotic dosage form.
Particularly, the present invention relates to every as follows:
1. osmotic dosage form, it comprises:
A () comprises the core of bioactive ingredients;
B () covers the semipermeable membrane of described core; With
(c) at least one passage by described semipermeable membrane,
Wherein said semipermeable membrane comprises the homopolymer of ethyl cellulose, acrylate or methacrylate or copolymer and water dissolvable plasticizer, and the gross weight of the homopolymer of wherein said ethyl cellulose, acrylate or methacrylate or copolymer and water dissolvable plasticizer is 85-100%, based on the gross dry weight of described semipermeable membrane.
2. the osmotic dosage form of 1, wherein said semipermeable membrane comprises homopolymer or the copolymer of 10-90 % by weight ethyl cellulose and 2-60 % by weight acrylate or methacrylate, based on the gross weight of described semipermeable membrane.
3. the osmotic dosage form of 1 or 2, wherein described in described semipermeable membrane, the homopolymer of ethyl cellulose and described acrylate or methacrylate or the weight ratio of copolymer are 0.1-15:1.
4. the osmotic dosage form of any one in a 1-3, wherein said semipermeable membrane comprises water dissolvable plasticizer described in 2-70 % by weight.
5. the osmotic dosage form of any one in a 1-4, the gross weight of the homopolymer of wherein said ethyl cellulose, described acrylate or methacrylate or copolymer and described water dissolvable plasticizer is 95-100%, based on the gross dry weight of described semipermeable membrane.
6. the osmotic dosage form of any one in a 1-5, wherein said core (a) comprises (i) and comprises the second layer that the ground floor of described bioactive ingredients and (ii) comprise polymers swell agent.
7. the osmotic dosage form of any one in a 1-6, wherein said core (a) comprises
(ai) medicine layer, it comprises bioactive ingredients, one or more ethylene oxide polymers, one or more optional binding agents, one or more optional penetrating agent, optional pigment and optional lubricant;
(aii) push layer, it comprises one or more ethylene oxide polymers, one or more optional binding agents, one or more optional penetrating agent, optional pigment and optional lubricant; And
Described semipermeable membrane (b) comprises the homopolymer of ethyl cellulose, acrylate or methacrylate or copolymer and is selected from the water dissolvable plasticizer of triethyl citrate, triacetin, Polyethylene Glycol and glycerol, condition is: except water dissolvable plasticizer, described semipermeable membrane is not containing water soluble substance or comprise the water soluble substance being no more than 10 % by weight, based on the gross dry weight of described semipermeable membrane.
8. the osmotic dosage form of 7, wherein said core (a) comprises
(ai) medicine layer, it comprises, based on the gross weight of described medicine layer, bioactive ingredients described in 4-50 % by weight, one or more ethylene oxide polymers of 15-90 % by weight, 0-10 % by weight one or more be selected from the binding agent of methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose and polyvinyl pyrrolidone, 0-10 % by weight penetrating agent, 0-2 % by weight pigment and 0-1 % by weight lubricant;
(aii) push layer, it comprises, based on the gross weight of described push layer, one or more ethylene oxide polymers of 15-60 % by weight, 1-10 % by weight one or more be selected from the binding agent of methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose and polyvinyl pyrrolidone, one or more penetrating agent of 15-50 % by weight, 0-2 % by weight pigment and 0-1 % by weight lubricant; And
Described semipermeable membrane (b) comprises, based on the gross weight of described semipermeable membrane (b), the homopolymer of 30-70 % by weight ethyl cellulose, 5-40 % by weight acrylate or methacrylate or copolymer and 10-40 % by weight are selected from the water dissolvable plasticizer of triethyl citrate, triacetin and glycerol, condition is: except water dissolvable plasticizer, and described semipermeable membrane is containing water soluble substance or comprise and be no more than 5 % by weight water soluble substances.
9. the osmotic dosage form of any one in a 1-8, wherein when t is that 2-12 is constantly little, met the formula of Zero order release between 2-12 hour with the accumulation drug release of percent basis:
After matching test, Y=100k (t-Tlag), wherein Tlag is the lag time of 2 hours, Y be described with the accumulation drug release of percent basis and k for constant, and
After linear fit, coefficient R
2for >0.9.
10. the osmotic dosage form of any one in a 1-9, is characterized in that in the described osmotic dosage form of picked-up and starts to discharge between described bioactive ingredients and do not have lag time.
The method of the osmotic dosage form of any one in 11. preparation 1-10, it comprises the following steps:
I) core is formed by described bioactive ingredients and optional member;
II) with the coated described core of film composition of the homopolymer or copolymer, water dissolvable plasticizer and optional member that comprise ethyl cellulose, acrylate or methacrylate, to provide semipermeable membrane, the gross weight of the homopolymer of described ethyl cellulose, acrylate or methacrylate or copolymer and water dissolvable plasticizer is 85-100%, based on the gross dry weight of described film composition;
III) in described semipermeable membrane, at least one passage is created; And optionally
IV) decorative layer is applied to described osmotic dosage form.
The method of 12. 11, it comprises the following steps:
Ia) by described bioactive ingredients and polymeric suspending agent and one or more optional members blended, and be optionally granulated described blend;
Ib) by polymers swell agent and one or more other compositions blended, and be optionally granulated described blend;
Ic) by step Ia) blend or groups of grains synthesis ground floor and by step Ib) blend or groups of grains synthesis the second layer, and two layers described in combination are to manufacture core (a), described core (a) comprises the ground floor that (i) comprises described bioactive ingredients, described hydrophilic suspending agent and optional member, and (ii) comprises the second layer of described polymers swell agent and other composition;
II) with the coated described core (a) of film composition of the homopolymer or copolymer, water dissolvable plasticizer and optional member that comprise ethyl cellulose, acrylate or methacrylate to provide semipermeable membrane;
III) in described semipermeable membrane, at least one passage is created; And optionally
IV) decorative layer is applied to described osmotic dosage form.
Accompanying drawing explanation
Fig. 1-3 illustrates three different embodiments of osmotic dosage form of the present invention.
Detailed description of the invention
A primary aspect of the invention relates to the semipermeable membrane (b) of osmotic dosage form.Semipermeable membrane (b) for external aqueous fluid as gastric juice or intestinal juice permeable, and for the product selected in the described core (a) as described in bioactive ingredients substantially impermeable.Semipermeable membrane (b) maintains physics and chemistry integrity at described bioactive ingredients deenergized period usually.
Against expectation find, the semipermeable membrane comprising ethyl cellulose, acrylic compounds or methacrylic polymer and water dissolvable plasticizer is in osmotic dosage form, comprise the substitute that be applicable to of cellulose acetate as the semipermeable membrane of filmogen, condition is, except water dissolvable plasticizer, semipermeable membrane is not containing water soluble substance or comprise the water soluble substance being no more than 15 % by weight, based on the gross dry weight of described semipermeable membrane.Except water dissolvable plasticizer, semipermeable membrane of the present invention does not comprise the water soluble substance more than 15 % by weight.
At least in the preferred implementation of osmotic dosage form of the present invention, the formula meeting Zero order release with the accumulation drug release of percent basis between 2 to 12 hours:
After matching test, Y=100k (t-Tlag).Tlag represents lag time, and it is 2 hours.Y is for constant with the accumulation drug release of percent basis and k.After linear fit, R
2for >0.9, preferred >0.95.
The term " gross dry weight " used about osmotic dosage form, core, semipermeable membrane, medicine layer and push layer represents except water or liguid organic solvent are as the gross weight of all the components except alcohol.
Term used in this application " water soluble " be applicable to plasticizer, polymer and other material and contain enumerate below the term " fairly soluble " that defines in American Pharmacopeia, " dissolving arbitrarily " and " solvable ".Dissolubility is 25 DEG C of measurements.
| Terminology | L part solute 1)The parts by volume of the solvent needed |
| Fairly soluble | Be less than 1 |
| Any dissolving | 1 to 10 |
| Solvable | 10 to 30 |
| Slightly molten | 30 to 100 |
| Sl. sol. | 100 to 1000 |
| Very slightly soluble | 1000 to 10,000 |
| Insoluble,practically or insoluble | 10,000 and Geng Duo |
1)for being the solute of liquid at 25 DEG C, 1 part of solute represents parts by volume; For being the solute of solid at 25 DEG C,
1 part of solute represents weight portion
Described semipermeable membrane comprises ethyl cellulose, preferably with such amount, that is, makes ethyl cellulose be the film forming polymer of semipermeable membrane.Ethyl cellulose is used to be very favorable, because it can dissolve to provide coating composition when there is not acetone.And, have been found that osmotic dosage form of the present invention can design by this way, that is, make it in picked-up osmotic dosage form and start there is no obvious lag time between delivery of biologically active composition.And, have been found that the preferred implementation of osmotic dosage form at least of the present invention is providing the basic Zero order release of bioactive ingredients to distribute with liquid, aqueous beginning in the 2-12 after contacting hour.
The ethoxyl content of described ethyl cellulose is preferably 40-55%, is more preferably 43-53%, most preferably is 45-52%.Percentage ratio ethoxy substituent in the weight of substitution product, and measures as described in ASTM D4794-94 (2003) according to Zeisel gas chromatographic technique.These ethoxyl content are equivalent to 1.9-3.0, preferred 2.1-2.9, more preferably the ethyl DS of 2.3-2.8.The molecular weight of ethyl cellulose is expressed as the viscosity measured at 25 DEG C of 5 % by weight solution of ethyl cellulose in 80 volume % toluene and 20 volume % alcohol mixtures.Ethyl cellulose concentration is based on the gross weight of toluene, ethanol and ethyl cellulose.Described viscosity as summarized and using the measurement of Ubbelohde pipe as further described in ASTM D446-04 (it is cited in ASTM D914-00) in ASTM D914-00.The viscosity of described ethyl cellulose preferably from 2mPa.s, more preferably from 5Pa.s, most preferably from 10mPa.s to 400mPa.s, preferably to 100mPa.s, more preferably to 50mPa.s.Preferably, the amount of ethyl cellulose is about 10 to about 90%, is more preferably about 20 to about 80%, and most preferably is about 30 to about 70%, based on the gross dry weight of described semipermeable membrane.
Described semipermeable membrane also comprises acrylic compounds or methacrylic polymer, such as comprise homopolymer or the copolymer of acrylic acid, methacrylic acid, acrylate, methacrylate or its polymerized unit combined, preferably comprise the C of acrylic acid, methacrylic acid, acrylic or methacrylic acid
1-4the amino C of-Arrcostab, acrylic or methacrylic acid
1-4the homopolymer of the polymerized unit of-Arrcostab or its combination or copolymer, such as comprise the polymerized unit of following material: methacrylic acid, ethyl acrylate (ethyl acrylate), methyl acrylate (acrylic acid methyl ester .), methyl methacrylate (methyl methacrylate), butyl methacrylate (butyl methacrylate), dimethylamine ethyl ester (dimethylaminoethyl methacrylate), dimethylaminoethyl acrylate ester (acrylate), methacrylic acid trimethyl ammonium ethyl ester (methacrylic acid trimethylammoniumethylester), acrylic acid trimethyl ammonium ethyl ester (acrylic acid trimethylammoniumethyl ester) or its combination, comprise the Eudragit polymeric families that can derive from Evonik Industries.Described acrylic compounds or methacrylic polymer are preferably homopolymer or the copolymer of above-mentioned monomer.Acrylic compounds or methacrylic polymer are generally insoluble polymer.The acrylic compounds of Eudragit family and methacrylic polymer are well known in the art, and comprise many different polymer, relate to EudragitL 100-55 (spray-dried forms of Eudragit L30D), Eudragit L30D, Eudragit L100, Eudragit S 100, Eudragit 4135F, Eudragit E100, Eudragit EPO (E100 powder type), Eudragit RL30D, Eudragit RL PO, Eudragit RL 100, Eudragit RS 30D, Eudragit RS PO, Eudragit RS 100, Eudragit NE 30D and Eudragit NE 40D.The amount of acrylic compounds or methacrylic polymer is preferably about 2 to about 60%, is more preferably about 5 to about 40%, and most preferably is about 10 to about 30%, based on the gross dry weight of described semipermeable membrane.
In described semipermeable membrane, the weight ratio of described ethyl cellulose and described acrylic compounds or methacrylic polymer is preferably about 0.1-15:1, is more preferably about 0.5-10:1, most preferably is about 1-5:1.
Described semipermeable membrane also comprises water dissolvable plasticizer.Typical water dissolvable plasticizer is monomeric compound or weight average molecular weight is at the most 10, the oligomeric compound of 000, be preferably triethyl citrate, triacetin, Polyethylene Glycol, being in particular weight average molecular weight is that the Polyethylene Glycol of 2000-6000 is as PEG 4000, Sorbitan polyoxyethylenated alcohol monoleate (can be purchased under trade name Tween, such as Tween 20 or Tween 80), and most preferably be glycerol.The amount of water dissolvable plasticizer is preferably about 2 to about 70%, is more preferably about 5 to about 50%, and most preferably is about 10 to about 40%, based on the gross dry weight of described semipermeable membrane.
In described semipermeable membrane, the weight ratio of ethyl cellulose and water dissolvable plasticizer is preferably about 0.1-20:1, is more preferably about 0.5-10:1, most preferably is about 0.9-3.4:1.
Usually, the total amount of ethyl cellulose, acrylic compounds or methacrylic polymer and water dissolvable plasticizer is about 85-100%, is preferably about 90-100%, is more preferably about 95-100%, most preferably be about 98-100%, based on the gross dry weight of described semipermeable membrane.
Except water dissolvable plasticizer, described semipermeable membrane comprises and is no more than about 15%, preferably more than about 10%, more preferably no more than about 5%, is most preferably not exceeding the water soluble substance of about 2%, based on the gross dry weight of described semipermeable membrane.Particularly, except water dissolvable plasticizer, described semipermeable membrane does not comprise or comprises and is no more than about 15%, preferably more than about 10%, more preferably no more than about 5%, is most preferably not exceeding the water soluble substance being called as pore former of about 2%.The known embodiment of pore former is sodium chloride, potassium chloride, sucrose, sorbitol, mannitol or hydroxy propyl cellulose.If described semipermeable membrane comprises the pore former more than 15% except water dissolvable plasticizer, too high bioactive ingredients amount will be released by film, and this is undesirable for osmotic dosage form of the present invention.
Described semipermeable membrane can comprise other optional additives, such as water-insoluble plasticizer.The example of water-insoluble plasticizer comprises adipate ester, azelate, enzoates, citrate, stearate, isoebucates, sebacate, such as tri-n-butyl citrate, the positive butyl ester of citric acid acetyl three and citrate.Preferred water-insoluble plasticizer is acetylated monoglyceride, Oleum Vitis viniferae, olive oil, Oleum sesami, acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, ethyl oxalate, ethyl maleate., DEF, dibutyl succinate, diethyl malonate, diethyl phthalate, dibutyl phthalate, dioctyl phthalate, dibutyl sebacate and three (butanoic acid) glyceride.Most preferred water-insoluble plasticizer is acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, diethyl phthalate, dibutyl phthalate and dibutyl sebacate.
If described semipermeable membrane comprises one or more optional additives, their total amount is generally at the most about 15%, is preferably at the most about 10%, is more preferably at the most about 5%, based on the gross dry weight of semipermeable membrane.
Preferably, the semipermeable membrane (b) around described core (a) is about 10 to about 45%, is preferably about 15-35%, most preferably from about 20-30%, based on the weight of described core (a).
The core (a) of osmotic dosage form of the present invention can comprise the bioactive ingredients of wide region, such as vitamin, medical herbs (herbals) and mineral supplement and medicine.Described bioactive ingredients comprises hydrophobicity, hydrophilic and amphiphilic compound.Medicine can be the form of officinal salt, solvate, enantiomer, ester and composition thereof.The example be applicable to comprises the medicine of following classification: central nervous system stimulants, opiate drug thing, antidiabetic drug, antineoplastic agent, antihypertensive, sleeping pill, group of barbiturates medicine, psychostimulant, cannabinoids drug, Catecholamine drugs, cardiovascular drugs, anticoagulant, analgesic, antimicrobial, diuretic and spasmolytic, but, the medicine of other classification can also be used on demand.Instantiation comprises methylphenidate (methylphenidate), amphetamine (amphetamines), glipizide (glipizide), doxazosin (doxazosin), isradipine (isradipine), nifedipine (nifedipine), nisoldipine (nisoldipine), bendroflumethiazide (bendroflumethazide), chlorpropamide (chlorpropamide), hydrocortisone (hydrocortisone), ibuprofen (ibuprofen), diclofenac (diclofenac), oxycodone (oxycodone), isosorbide mononitrate (isosorbide mononitrate), YM-617 (tamsulosinhydrochloride), methylphenidate hydrochloride (methylphenidate hydrochloride), verapamil hydrochloride (verapamil hydrochloride), Itopride Hydrochloride (itopride hydrochloride), albuterol aerosol (salbutamol aerosol), diltiazem hydrochloride (diltiazem hydrochloride), pseudoephedrine hydrochloride (pseudoephedrine hydrochloride), ditropan XL (oxybutyninhydrochloride), phenylpropanolamine HC1 (phenylpropanolamine hydrochloride), felodipine (felodipine), haloperidol (haloperidol), desvenlafaxin, carbamazepine (carbamazepine), isradipine (isradipine), Carclura (doxazosin mesylate), metformin (metformin) and carvedilol (carvedilol).Other useful medicine fairly soluble or not easily molten in water is disclosed in United States Patent (USP) 5,021,053, and the 10th hurdle 26-68 is capable, and the 11st hurdle 1-50 is capable.Preferably, described medicine forms about 1 to about 80% of the gross dry weight of described core (a) (not containing coat weight), is more preferably about 4 to about 50%.
The layer that described core can comprise bioactive materials by one forms, such as in FIG shown in.Further describe the core be made up of a layer below.
Selectively, described core can be made up of two layers, such as in figs 2 and 3 shown in, or to be even made up of more multi-layered, to be generally three layer (not shown).In this embodiment of the present invention, described core (a) comprises the ground floor that (i) comprises described bioactive ingredients, is commonly referred to " medicine layer ", and (ii) comprises the second layer of polymers swell agent.The second layer is commonly called " push layer ", due to described polymers swell agent with external fluid contact after expand and promote active component and pass through passage.Preferably, medicine layer forms about 5 to about 95% of the gross dry weight of core (a), and more preferably from about 50 to about 80%.Preferably, push layer forms about 5 to about 95% of the gross dry weight of core (a), and more preferably from about 20 to about 50%.
Described medicine layer preferably comprises about 1 to about 80 % by weight, more preferably from about one or more bioactive materials as above of 4 to about 50 % by weight, based on the dry weight of medicine layer.
Described medicine layer preferably comprises non-crosslinked or slight crosslinked hydrophilic polymer, and it is used as the polymeric suspending agent of bioactive materials after external fluid is through film.It is 30,000-1 that preferred polymeric suspending agent comprises molecular weight, poly-(haloalkylacrylates) of 000,000; Molecular weight is 10,000-360, the PVP of 000; Anion and cationic water gel; Poly-(vinyl alcohol), it has low acetate ester residual (acetate residual), optional and Biformyl, formaldehyde or glutaraldehyde cross-linking, and has 200-30, the degree of polymerization of 000; Methylcellulose; Carboxymethyl cellulose; Or the water-swellable polymer of N-vinyl lactam.Preferred polymer is the polymer forming hydrogel, and such as molecular weight is 450,000-1, the Carbopol of 000,000
tMacid carboxyl polymer; Cyanamer
tMpolyacrylamide; Crosslinked water-swellable indenes-maleic anhydride polymer, molecular weight is 80,000-200, the Goodrite of 000
tMpolyacrylic acid; Polyox
tMpolyethylene oxide polymer, its molecular weight is about 100, and 000 to being less than 1,000,000, is more preferably about 100,000 to about 500,000, most preferably be about 100,000 to about 300,000; Hydroxypropyl emthylcellulose or starch graft copolymer.The representative polymer forming hydrogel is known in the art, such as, at United States Patent (USP) 3, and 865,108 (being issued to Hartop); 4,002,173 (being issued to Manning); In 4,207,893 (being issued to Michaels); And at ChemicalRubber Company, in the Handbook ofCommon Polymers of Scott and Roff that Cleveland, Ohio publish.Most preferred hydrophilic suspending agent is ethylene oxide polymer, is more preferably at trade name Polyox
tMthe hydrophilic suspending agent that can be purchased from The Dow Chemical company under WSR.It can obtain with various rank, depends on its molecular weight MW.The weight average molecular weight MW of poly(ethylene oxide) can be about 100 usually, and 000 to being less than 1,000,000, is more preferably about 100, and 000 to about 500,000, most preferably be about 100,000 to about 300,000.Other example of the priority of poly(ethylene oxide) comprises POLYOX
tMwSR N-10 (MW is about 100,000), WSR N-80 (MW is about 200,000) and WSR N-750 (MW is about 300,000).Preferably, described polymeric suspending agent forms 0 of the gross dry weight of the medicine layer in described core (a) to about 97%, is more preferably about 15 to about 90%, most preferably is about 50 to about 90%.
Described medicine layer also can comprise one or more pharmaceutically acceptable inert excipients.Term used in this application " pharmaceutically acceptable inert excipient " is included in and manufactures all excipient that are that use in bleed control agents V-neck V territory and that describe in the literature.Instantiation comprises binding agent, penetrating agent, lubricants/glidants, diluent, surfactant, pH adjusting agent, stabilizing agent and pigment/colorant.
Described medicine layer preferably comprises binding agent, and described binding agent is different from the hydrophilic polymer of the polymeric suspending agent as bioactive materials.The preferred embodiment of binding agent comprises methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose (being preferably the form of physiologically acceptable salt), polyvinyl pyrrolidone, gelatin, Radix Acaciae senegalis, polyvinyl alcohol, amylopectin (pullulan), pregelatinized Starch, agar, Tragacanth, sodium alginate or propylene glycol.Described binding agent be preferably water dissolvable with physiologically acceptable.Described binding agent preferably forms 0 of the gross dry weight of the medicine layer in described core (a) to about 30%, is more preferably 0 to about 10%.
And described medicine layer preferably comprises penetrating agent.Term used in this application " penetrating agent " is included in Pharmacoepias, or all pharmaceutically acceptable inertia water dissolvable compound being suitable for causing permeating mentioned in " Hager " and in Remington's Pharmaceuticalsciences.The example being suitable as the compound of penetrating agent comprises the water soluble salt of mineral acid as magnesium chloride or magnesium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, dibastic sodium phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate and potassium dihydrogen phosphate; Organic acid water soluble salt is as sodium acetate, potassium acetate, Magnesium succinate, sodium benzoate, sodium citrate and sodium ascorbate; Have the non-ionic organic compound of highly-water-soluble, such as, saccharide is as mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose and Raffinose; Water-soluble amino acid is as glycine, leucine, alanine or methionine; Urea and urea derivative.Described penetrating agent preferably forms 0 of the gross dry weight of the medicine layer in described core (a) to about 30%, and more preferably 0 to about 20%, most preferably 0 to about 10%.
Advantageously, described medicine layer comprises lubricant in addition, and lubricant is also referred to as " fluidizer ".The instantiation of lubricant comprises silica sol, stearic acid, magnesium stearate, calcium stearate, Talcum, castor oil hydrogenated, the sucrose ester of fatty acid, microwax, yellow beeswax or cera alba.Their amount is preferably 0 to about 2%, is more preferably 0 to about 1%, based on the gross weight of the medicine layer in described core (a).
Described medicine layer can comprise pH adjusting agent in addition.PH adjusting agent helps the pH of the local environment around medicine to maintain the material being conducive to the stripping of medicine or the value of suspension.The instantiation of pH adjusting agent comprises sodium hydrogen phosphate, sodium ascorbate, meglumine, sodium citrate, trimethanolamine, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium oxide, magnesium hydroxide, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine or 1B.
The instantiation of diluent comprises calcium carbonate, dicalcium phosphate, tricalcium phosphate, calcium sulfate, microcrystalline Cellulose, Powderd cellulose, dextrates, dextrin, dextrose excipient, fructose, Kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized Starch, Saccharum Sinensis Roxb. or sucrose.
Preferred pigments or coloring agent comprise that any FDA ratifies for those of oral use, such as ferrum oxide.Their amount is preferably 0 to about 3%, is more preferably 0 to about 2%, based on the gross weight of the medicine layer in described core (a).
Preferred stabilizer comprises antioxidant or buffer agent.
Described push layer comprises polymers swell agent usually.Described polymers swell agent preferably forms about 5 to about 70%, is more preferably about 15 to about 60%, most preferably is about 25 to about 60%, based on the gross dry weight of push layer.Described polymers swell agent is generally hydrophilic polymer, and it is swelling or expand after being designed to contact with water or aqueous biological fluids.Sweller presents and quite a few water sucked is retained in ability in polymer architecture.Usually, described polymers swell solvent swell or be expanded to very high degree, usually presenting 2-50 volume doubly increases.Above-mentioned hydrophilic polymer can be used as polymers swell agent, as long as their tools swelling property likely.Usually, be used as the hydrophilic polymer of suspending agent in described medicine layer compared with, described polymers swell agent has higher molecular weight.Most preferred polymers swell agent is ethylene oxide polymer, is more preferably Polyox
tMpoly(ethylene oxide) or hydroxypropyl emthylcellulose.The weight average molecular weight of poly(ethylene oxide) can be about 1,000 usually, and 000 to about 7,000,000, and be more particularly about 4,000,000 to about 7,000,000.Be particularly preferably POLYOX WSR-N750, POLYOX
tMwSR coagulant, POLYOX
tMwSR-301 and/or WSR-303.
Push layer can comprise one or more pharmaceutically acceptable inert excipients further, such as binding agent, penetrating agent, lubricant, pH adjusting agent, diluent, pigment or stabilizing agent.Preferred excipient on regard to described in medicine layer those.Push layer preferably comprises the pigment different from medicine layer.
Described binding agent preferably forms 0 of the gross dry weight of the push layer in described core (a) to about 20%, and more preferably from about 1 to about 10%.
Described penetrating agent preferably forms 0 of the gross dry weight of the push layer in described core (a) to about 60%, and more preferably from about 15 to about 50%.
Selectively, the layer that described core can comprise bioactive materials by forms, such as in FIG shown in.Advantageously, this layer comprises the bioactive materials for the type described in described medicine layer and content and the polymers swell agent for the type described in push layer above and content.Push layer can comprise one or more pharmaceutically acceptable inert excipients further, such as, for the binding agent of the type described in medicine layer and content, penetrating agent, lubricant, pH adjusting agent, diluent or stabilizing agent.Usually, in the core of one deck, suspending agent is not contained.
Term passage used in this application comprises opening (aperture), aperture (orifice), boring (bore), hole (hole), atenuator region or easily loses element, such as, corrode to form infiltration lane for the plug from dosage form delivery of biologically active composition.The specific descriptions of passage can see United States Patent (USP) 3, and 845,770; 3,916,899; 4,034,758; 4,077,407; 4,783,337 and 5,071,607.Preferably, boring, such as machine drilling or, more preferably, laser drill runs through semipermeable membrane for the formation of passage.
Be more preferably such osmotic dosage form, wherein
Described core (a) comprises
(ai) medicine layer, it comprises bioactive ingredients, one or more ethylene oxide polymers, one or more optional binding agents, one or more optional penetrating agent, optional pigment and optional lubricant;
(aii) push layer, it comprises one or more ethylene oxide polymers, one or more optional binding agents, one or more optional penetrating agent, optional pigment and optional lubricant; And
Semipermeable membrane (b) comprises ethyl cellulose, acrylic compounds or methacrylic polymer and is selected from the water dissolvable plasticizer of triethyl citrate, triacetin, Polyethylene Glycol and glycerol, condition is: except water dissolvable plasticizer, described semipermeable membrane is containing water soluble substance or comprise and be no more than 10 % by weight water soluble substances, based on the gross dry weight of described semipermeable membrane.
Most preferably such osmotic dosage form, wherein
Described core (a) comprises
(ai) medicine layer, it comprises, based on the gross weight of described medicine layer, about 1 to about 80 % by weight, more preferably from about bioactive ingredients described in 4 to about 50 % by weight, about 15 to about 90 % by weight, most preferably from about 50 to about 90 % by weight one or more ethylene oxide polymers, 0 to about 10 % by weight one or more be selected from methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, the binding agent of carboxymethyl cellulose and polyvinyl pyrrolidone, 0 to about 30 % by weight, more preferably 0 to about 20 % by weight, the most preferably penetrating agent of 0 to about 10 % by weight, 0 to about 3%, more preferably 0 to about 2 % by weight pigment and 0 to about 2 % by weight, more preferably 0 to about 1 % by weight lubricant,
(aii) push layer, it comprises, based on the gross weight of described push layer, about 5 to about 70%, more preferably from about 15 to about 60%, most preferably from about 25 to about 60% one or more ethylene oxide polymers, 0 to about 20%, more preferably from about 1 to about 10 % by weight one or more be selected from methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, the binding agent of carboxymethyl cellulose and polyvinyl pyrrolidone, 0 to about 60 % by weight, more preferably from about 15 to about 50 % by weight one or more penetrating agent, 0 to about 2 % by weight pigment and 0 to about 2 % by weight, more preferably 0 to about 1 % by weight lubricant, and
Semipermeable membrane (b) comprises, based on the gross dry weight of semipermeable membrane (b), about 10 to about 90%, more preferably from about 20 to about 80%, and most preferably from about 30 to about 70% ethyl celluloses, about 2 to about 60%, more preferably from about 5 to about 40%, and most preferably from about 10 to about 30% acrylic compounds or methacrylic polymer and about 2 to about 70%, more preferably from about 5 to about 50%, and most preferably from about 10 be selected from triethyl citrate to about 40%, the water dissolvable plasticizer of triacetin and glycerol, condition is: except water dissolvable plasticizer, described semipermeable membrane is containing water soluble substance or comprise and be no more than about 10 % by weight, more preferably no more than about 5 % by weight, be most preferably not exceeding the water soluble substance of about 2 % by weight.
Osmotic dosage form of the present invention can comprise decorative layer in addition on semipermeable membrane.Decorative layer is preferably water miscible and can be painted or transparent, such as known under trade name Opadry and Opadry Clear coating.
At least in the preferred implementation of osmotic dosage form of the present invention, when time t is that 2-12 is constantly little, accumulation drug release meets the formula of Zero order release with percent basis:
After matching test, Y=100k (t-Tlag).Tlag represents lag time, and it is 2 hours.Y is for constant with the accumulation drug release of percent basis and k.After linear fit, coefficient R
2for >0.9, be preferably >0.95.
Osmotic dosage form of the present invention is by standard technique manufacture.Manufacture method comprises the following steps:
I) core is formed by described bioactive ingredients and optional member,
II) with the coated described core of film composition comprising ethyl cellulose, acrylic compounds or methacrylic polymer, water dissolvable plasticizer and optional member, thus semipermeable membrane is provided;
III) in described semipermeable membrane, at least one passage is created; And optionally
IV) decorative layer is applied to osmotic dosage form.
In preferred at one, described manufacture method comprises the following steps
Ia) by described bioactive ingredients and polymeric suspending agent and one or more optional members blended, and the described blend of optional granulation;
Ib) by polymers swell agent and one or more other compositions blended, and optional this blend of granulation;
Ic) by step Ia) blend or groups of grains synthesis ground floor, and by step Ib) blend or groups of grains synthesis the second layer, and two layers described in combination are to manufacture core (a), described core (a) comprises (i) and comprises the second layer that the ground floor of described bioactive ingredients, described hydrophilic suspending agent and optional member and (ii) comprise described polymers swell agent and other composition;
II) with the coated described core (a) of film composition comprising ethyl cellulose, acrylic compounds or methacrylic polymer, water dissolvable plasticizer and optional member, thus semipermeable membrane is provided;
III) in described semipermeable membrane, at least one passage is created; And optionally
IV) decorative layer is applied to osmotic dosage form.
In step I), Ia) and Ib) in, described bioactive ingredients and other composition can be in a known manner blended.Optionally blend being granulated, preferably by known wet granulation technique, such as, by using water or alcohol to carry out wet granulation as ethanol, then carrying out the drying of granule and optional screening step in appropriate circumstances.The blend be optionally granulated can be pressed into the shape of preliminary election by tabletting method.If prepared at least one independently medicine layer and at least one independently push layer, described layer can be combined in the mode shown in Fig. 2 and 3.
Semipermeable membrane can be applied to by the following method pressed compact (pressed shape): molding, spraying or dipping pressed compact in semipermeable membrane raw material, or are used in United States Patent (USP) 2,779,241; J.Am.Pharm.Assoc, the 48th volume, 451-459 page, 1979; And ibid, the 49th volume, 82-84 page, the air suspension code described in 1960.Other standard manufactures code and is described in Modern Plastics Encyclopedia, the 46th volume, 62-70 page, 1969; With the Pharmaceutical Sciences of Remington, the 14th edition, 1626-1678 page, 1970, Mack Publishing Company, Easton, Penna publish.Except ethyl cellulose, acrylic compounds or methacrylic polymer and one or more optional additives, the raw material of semipermeable membrane comprises one or more solvents usually.Described solvent comprises widely and is selected from following member: aqueous solvent, alcohol, ketone, ester, ether, aliphatic hydrocarbon, halogenated solvent, alicyclic solvents, arsol, heterocyclic solvents and composition thereof.Typical solvent comprises methanol, ethanol, isopropyl alcohol, butanols, methyl acetate, ethyl acetate, isopropyl alcohol, butanols, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl iso-butyl ketone (MIBK), methyl propyl ketone, normal hexane, normal heptane, ethylene glycol monomethyl ether, ethylene glycol list ethylhexoate (ethyleneglycol monoethyl acetate), dichloromethane, dichloroethanes, dichloropropane, carbon tetrachloride, nitroethane, nitropropane, sym-tetrachloroethane, ether, diisopropyl ether, cyclohexane extraction, cyclooctane, benzene, toluene, Petroleum, 1, 4-diox, oxolane, diethylene glycol dimethyl ether, water and composition thereof.Most preferred solvent is alcohol, such as ethanol.For ethyl cellulose dissolved, acrylic compounds or methacrylic polymer and water dissolvable plasticizer, do not need to use acetone.
Describe the preferred embodiment of the present invention with reference to the accompanying drawings.
Fig. 1 illustrates osmotic dosage form 101, and it comprises core 102, semipermeable membrane 105 and one or more path 10 6.
Fig. 2 illustrates the preferred implementation of the osmotic dosage form 201 comprising core 202.Described core is made up of push layer 203 and the medicine layer 207 comprising bioactive ingredients 204.Described core is covered by semipermeable membrane 205.Passage 206 in described semipermeable membrane 205 not being connected described core with osmotic dosage form 201 outside by the composition of semipermeable membrane 205.
Fig. 3 illustrates another preferred implementation of the osmotic dosage form 301 comprising core 302.Described core is made up of push layer 303 and the medicine layer 307 comprising bioactive ingredients (not shown).Described core is covered by semipermeable membrane 305.Passage 306 in described semipermeable membrane 305 not being connected described core with osmotic dosage form 301 outside by the composition of semipermeable membrane 305.
When osmotic dosage form 101,202 or 301 is placed in external aqueous fluid as water, gastric juice or intestinal juice, aqueous fluid, mainly water, core 102,202,302 is entered into by path 10 6,206,306 and semipermeable membrane 105,205,305, and optionally under the impact of penetrating agent (not shown), medicine (204 in Fig. 2 represents with point) is partly or entirely dissolved or suspended in (not shown) in aqueous fluid.Core 102, preferred push layer 203,303, comprise polymers swell agent (not shown), described polymers swell agent absorption water after swelling and promote in core 102, medicine preferably in described medicine layer 207,307 by path 10 6,206,306, and provides sustained release or the controlled release of medicine thus.
Particularly preferred embodiments of the present invention illustrate in Table 1.
Table 1
Medicine layer is preferably the 5-95% of core, is more preferably the 50-80% of core
Push layer is preferably the 5-95% of core, is more preferably the 20-50% of core
Further illustrate the present invention by the following example, these embodiments should be considered as limiting the scope of the invention.Unless otherwise mentioned, all percent, number and ratio are all by weight.
Embodiment
embodiment 1-4 and comparative example B
Osmotic dosage form is prepared according to following general purpose discipline.The amount row of composition and composition in table 2.
medicine layer: by glipizide, Polyox
tMwSR N-80 and Fe
2o
3blended and by 60 mesh sieves screening.Blend is used the wet granulation of 95% ethanol.By 20 mesh sieve screening granules.By granule in an oven in 40 DEG C of dryings 12 hours, then grind.By granule by 18 mesh sieves screening and blended with magnesium stearate.
push layer: by Polyox
tMwSR coagulant, Polyox
tMwSR N-750, Methocel E5 cellulose ether, NaCl and Fe
3o
4blended and by 60 mesh sieves screening.Methocel E5 cellulose ether is the Hypromellose 2910 in American Pharmacopeia, and methoxyl substitution about 29%, and hydroxypropoxyl substitution about 10% and viscosity are 4-6mPas, uses Ubbelohde viscometer to measure as 2 % by weight aqueous solutions at 20 DEG C.Blend is used the wet granulation of 97.5% ethanol.By 20 mesh sieve screening granules.By granule in an oven in 40 DEG C of dryings 12 hours, then grind.By granule by 18 mesh sieves screening and blended with magnesium stearate.
the semipermeable membrane of embodiment 1-4: 30g ETHOCEL Standard 20 ethyl cellulose is dissolved in 400mL 95% ethanol.The solution viscosity of ETHOCEL Standard 20 ethyl cellulose is 18-22cP (mPa.s), in Ubbelohde viscometer as 5wt.% solution 25 DEG C of measurements.Solvent is 80% toluene and 20% ethanol.Ethoxyl content is 48.0-49.5%.ETHOCEL Standard 20 ethyl cellulose can be purchased from The Dow Chemical Company.By 7.5g EUDRAGIT
tMrL 100 is dissolved in 100mL 95% ethanol.EUDRAGIT
tMrL 100 is for having the copolymer of the low acrylic acid of quaternary ammonium group content and the methyl ester of methacrylic acid and ethyl ester.Glycerol is dissolved in 100mL 95% ethanol.By these solution blendings.
the semipermeable membrane of comparative example B: the semipermeable membrane of comparative example B is prepared in the mode identical with the semipermeable membrane of embodiment 1-4, unlike not using EUDRAGIT
tMrL 100.
prepared by tablet: the one-tenth of described medicine layer is divided into ground floor, then the compression of the composition of push layer is also pressed on medicine layer subsequently.170mL coated preparation solution is sprayed onto with 2.15mL/min on the rotation tablet in coating pan.Coating conditions is remained on 45-60% relative humidity.After coating process terminates, holed by semipermeable membrane with laser.The diameter in hole should be less than 2mm.
comparative example A:
Comparative example A is commercially available osmotic dosage form, and wherein said semipermeable membrane is made up of cellulose acetate and Polyethylene Glycol.
Table 2
By 6 osmotic dosage form samples being placed in the release of buffer solution testing drug, described buffer solution is prepared by the following method: by 54.4g KH
2pO
4be dissolved in 8L water with 7.168g NaOH to manufacture the solution that pH is 6.8.By means of water-bath, the temperature of buffer solution is remained on 37 DEG C.At 0 hour, 2 hours, 4 hours, 8 hours, 12 hours and 16 hours, measure drug release by UV-spectrophotography with the journey of 276nm and 1cm long (absorption cell thickness).By being that UV absorption is compared in the UV absorption of the series of standards solution of 1,2,4,8,10,12 and 20 mcg/ml by the concentration of glipizide in methanol, measure the concentration of medicine in simulated intestinal fluid.
By drug release test in triplicate with test reproducibility.The results are shown in table 3.
Table 3
The result of table 3 illustrates, osmotic dosage form of the present invention can be made to be suitable for realizing the drug release substantially identical with comparative example A and distribute, comparative example A comprises cellulose acetate as film forming polymer in semipermeable membrane.The drug release of embodiment 1 distributes the requirement met at 2-12 hour Zero order release.After linear fit, embodiment 1, the R of test 1
2be 0.999; Embodiment 1, the R of test 2
2be 0.9986 and embodiment 1, the R of test 3
2be 0.9924, the R of comparative example A
2be 0.9878.
Table 4
The osmotic dosage form of embodiment 4 realized the drug release suitable with comparative example A at 4-16 hour and distributes, and even as the osmotic dosage form of comparative example A, did not have obvious lag time between picked-up osmotic dosage form and beginning delivery of biologically active composition.
The drug release distribution of embodiment 2-4 met the requirement of Zero order release from 2-12 hour.After linear fit, the R of embodiment 2
2be 0.9736; The R of embodiment 3
2be 0.9988, the R of embodiment 4
2be the R of 0.9999 and comparative example A
2be 0.9878.After linear fit, the R of comparative example B
2be 0.98.
In comparative example B, find that all tablets are cracked when osmotic dosage form and buffer solution contact.This is unaccommodated for osmotic dosage form.
Enumerating of reference marks
101 osmotic dosage form
102 cores
105 semipermeable membranes
106 passages
201 osmotic dosage form
202 cores
203 push layer
204 bioactive ingredients
205 semipermeable membranes
206 passages
207 medicine layers
301 osmotic dosage form
302 cores
303 push layer
305 semipermeable membranes
306 passages
307 medicine layers
Claims (6)
1. osmotic dosage form, it comprises:
A () core, described core comprises
(i) medicine layer, it comprises, based on the gross weight of described medicine layer, the bioactive ingredients of 4-50 % by weight, and
(ii) push layer, its gross weight based on described push layer comprises one or more ethylene oxide polymers of 15-60 % by weight, one or more of 1-10 % by weight are selected from the binding agent of lower group: methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose and polyvinyl pyrrolidone, and one or more penetrating agent of 15-50 % by weight;
B () covers the semipermeable membrane of described core, it comprises
The ethyl cellulose of (i) 30-70 % by weight,
(ii) acrylate of 5-40 % by weight or the homopolymer of methacrylate or copolymer, and
(iii) the water dissolvable plasticizer of 10-40 % by weight, it is selected from lower group: triethyl citrate, triacetin and glycerol, condition is: (1) is except any water dissolvable plasticizer, described semipermeable membrane containing water soluble substance or comprise be no more than 5 % by weight water soluble substance and (2) described semipermeable membrane containing cellulose acetate as filmogen and (3) component (i), (ii) and (iii) make the film of 85-100% film forming, based on the gross dry weight of semipermeable membrane, wherein said semipermeable membrane maintains its physics and chemistry integrity at described bioactive ingredients deenergized period, with
(c) at least one entered into the boring infiltration lane of core by described semipermeable membrane, wherein said dosage form provides the controlled release of described bioactivator.
2. the osmotic dosage form of claim 1, wherein in described semipermeable membrane, the homopolymer of ethyl cellulose and described acrylate or methacrylate or the weight ratio of copolymer are 0.1-15:1.
3. the osmotic dosage form of claim 1, the gross weight of the homopolymer of wherein said ethyl cellulose, described acrylate or methacrylate or copolymer and described water dissolvable plasticizer is 95-100%, based on the gross dry weight of described semipermeable membrane.
4. the osmotic dosage form of claim 1, the medicine layer in wherein said core (a) also comprises one or more ethylene oxide polymers of 15-90 % by weight.
5. the osmotic dosage form of claim 1, wherein when t is 2-12 hour, met the formula of Zero order release between 2-12 hour with the accumulation drug release of percent basis:
After matching test, Y=100k (t-Tlag), wherein Tlag is the lag time of 2 hours, Y be described with the accumulation drug release of percent basis and k for constant, and
After linear fit, coefficient R
2for >0.9.
6. the osmotic dosage form of claim 1, is characterized in that not having lag time between the picked-up and the beginning of delivery of biologically active composition of described osmotic dosage form.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106946431A (en) * | 2017-03-29 | 2017-07-14 | 柳州市惠鱼水产科技有限公司 | A kind of aquaculture pond changes priming agent and preparation method thereof |
| WO2018108152A1 (en) * | 2016-12-16 | 2018-06-21 | 中国科学院上海药物研究所 | Olaparib oral sustained and controlled release pharmaceutical composition and uses thereof |
| WO2018108151A1 (en) * | 2016-12-16 | 2018-06-21 | 苏州苏融生物医药有限公司 | Veliparib sustained controlled release pharmaceutical composition and use thereof |
| WO2018108157A1 (en) * | 2016-12-16 | 2018-06-21 | 苏州苏融生物医药有限公司 | Rucaparib oral sustained/controlled release pharmaceutical composition and use thereof |
-
2009
- 2009-06-02 CN CN201510259573.0A patent/CN104873457A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018108152A1 (en) * | 2016-12-16 | 2018-06-21 | 中国科学院上海药物研究所 | Olaparib oral sustained and controlled release pharmaceutical composition and uses thereof |
| WO2018108151A1 (en) * | 2016-12-16 | 2018-06-21 | 苏州苏融生物医药有限公司 | Veliparib sustained controlled release pharmaceutical composition and use thereof |
| WO2018108157A1 (en) * | 2016-12-16 | 2018-06-21 | 苏州苏融生物医药有限公司 | Rucaparib oral sustained/controlled release pharmaceutical composition and use thereof |
| CN106946431A (en) * | 2017-03-29 | 2017-07-14 | 柳州市惠鱼水产科技有限公司 | A kind of aquaculture pond changes priming agent and preparation method thereof |
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