CN1805734A - Biphasic release of glipizide from monocompartment osmotic dosage form - Google Patents
Biphasic release of glipizide from monocompartment osmotic dosage form Download PDFInfo
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- CN1805734A CN1805734A CN200480016223.1A CN200480016223A CN1805734A CN 1805734 A CN1805734 A CN 1805734A CN 200480016223 A CN200480016223 A CN 200480016223A CN 1805734 A CN1805734 A CN 1805734A
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Abstract
The present invention relates to a monocompartment osmotic controlled delivery system of glipizide, providing a biphasic release of glipizide.
Description
Technical field
The present invention relates to a kind of monocompartment osmotic controlled delivery system, provide the two-phase of glipizide to discharge.
Background of invention
For the existing well narration of the advantage of the release delivery system of controlling.Many technology have been adopted for reaching required drug release type, to satisfy the needs of treatment needs and patient's compliance.A kind of controlled release system of extensive employing is based upon on the basis of drug delivery of osmotic pressure control, by F.Theewas at J.Pharm.Sci., Vol.64,12, propose first among the 1987-91 (1975).Initial (the ORS of oral osmotic system
, Alza Corp.) and adopt the form of conventional coated tablet.It is made of a homogenizing drug core and a hole that discharges the content of core by permeable membrane that is enclosed with semipermeable membrane/layer.When placing dissolution medium/gastrointestinal tract body fluid, water enters core and dissolved substance by semipermeable membrane.Therefore, produce osmotic pressure, drug solution is discharged by the hole on the film the pressure of permeable membrane.
The drug delivery system of infiltration control shows preferable inside and outside dependency, because its behavior and gastrointestinal pH and content are irrelevant.And it can also resist the mechanical pressure in the digestive tract.
Regrettably, the use of simple penetration system is confined to limited several soluble agents that can produce enough hyperosmosises.This system can not transmit the microsolubility medicine in a desired manner, therefore utilizes the advantage of infiltration transmission system to improve cleverly.
The United States Patent (USP) 4,111,202 that Alza Corp. is given in mandate discloses " recommending " (two chambers core) osmosis system, wherein, and OROS
The core of system is contained slightly, and the chamber of keeping of soluble drug compositions replaces with the promotion room that contains the agent of water solublity osmotically active.By elastomeric diaphragm two Room are separated.When working, the osmotic pressure that produces in the promotion room increases its volume.The increase of volume is expanded elastomeric diaphragm, thereby medicine is flowed out from keep the chamber by the hole.Make complexity and cost height on " pushing away-draw " systems technology, need between two Room, place elastomeric diaphragm suitably.And, omit soluble drug for high dose, the large scale that need be difficult to accept " pushes away-draw " system.
European patent application 52917 has been described the osmosis system that need not elastomeric diaphragm.In the disclosed osmosis system of this patent application, two Room of push-pull system are replaced by two kinds of different composition layers, the medicine layer that promptly contains medicine and penetrating agent, reach the inflatable promotion rete that forms by the water-swellable hydrogel, this inflatable promotion rete absorption fluids is expanded to swelling state from resting state in penetrating into and entering the room.The expansion that promotes film produces pressure on medicine layer, content is flowed out from the hole.Making said system needs repeatedly pressing step, requires grain diameter high level homogeneous in pressing process.The position boring suitable on the medicine layer surface is also difficult by semipermeable membrane.
Again United States Patent (USP) 4,857,336 and the United States Patent (USP) 4,992,278 published with RE 34990 all disclose homogenizing single chamber osmosis system.United States Patent (USP) 4,992,278 disclose a kind of single chamber therapy system, comprise (a) shell, its by water permeable but the impermeable material that contains the core component of active component constitute, (b) core, it contains the slightly water-soluble active component or the mixture of this active component, the hydrophilic polymer sweller that constitutes by the mixture of vinyl pyrrolidone/acetate ethylene copolymer and ethylene oxide homo, optional water-soluble substances enters the transhipment of core ingredient in the aqueous body fluid on every side to produce osmotic pressure with optional pharmaceutically acceptable additive and (c) by the path of shell (a).And, this patent disclosure, conventional sweller that uses in two chamber systems such as polyvinyl pyrrolidone, polyoxyethylene, polymethacrylates etc. are in one-chamber system not effect in one-chamber system.To such an extent as to this is that semipermeable membrane sharply expands because during the so big contact water of the imbibition pressure of these polymer, whole system is in the gastric disintegrate after the short time.
Therefore, need the suitable sweller of choose reasonable, being easy to make up one-chamber system, and the swelling of control is provided and does not cause semipermeable membrane to break.On the other hand, imbibition pressure should be enough to content is flowed out from system, reaches the release type of required control.
Summary of the invention
In the drug delivery system of single chamber infiltration-control, use at least a alginic acid derivant as sweller can overcome conventional infiltration-control system's relevant issues, help microsolubility medicine reaches the drug release type of required control.The two-phase of using alkali metal or alkaline earth metal derivative to help to reach medicine such as glipizide in monocompartment osmotic controlled delivery system discharges.
Therefore, on the one hand, the transmission system that the single chamber infiltration that provides the glipizide two-phase to discharge is controlled, described transmission system comprises glipizide, at least a alginic acid derivant and at least a alkali metal or alkaline earth metal derivative.
On the other hand, the transmission system that the single chamber infiltration that provides the glipizide two-phase to discharge is controlled, described transmission system comprises:
(a) comprise the core of following composition
(i) glipizide,
(ii) at least a alginic acid derivant,
(iii) at least a alkali metal or alkaline earth metal derivative and
(iv) at least a pharmaceutically acceptable inert excipient;
(b) semipermeable membrane of parcel core; With
(c) at least one path in the semipermeable membrane enters surrounding medium with the content transmission with core.
On the other hand, the transmission system that the single chamber infiltration that provides the glipizide two-phase to discharge is controlled, described transmission system comprises:
(a) comprise the core of following composition
(i) glipizide,
(ii) at least a alginic acid derivant,
(iii) at least a alkali metal or alkaline earth metal derivative,
(iv) penetrating agent and
(v) at least a pharmaceutically acceptable inert excipient;
(b) parcel core semipermeable membrane and
(c) at least one path in the semipermeable membrane enters surrounding medium with the content transmission with core.
On the other hand, the method for the transmission system that the single chamber infiltration that provides preparation glipizide two-phase to discharge is controlled said method comprising the steps of:
(a) glipizide, at least a alginic acid derivant, at least a alkali metal or alkaline earth metal derivative and at least a pharmaceutically acceptable inert excipient are mixed; With binding agent compound is randomly granulated; With compound/granule is pressed into densified core;
(b) with the coated composition solution/dispersion parcel core that contains semipermeable membrane shaped polymer and other coating additive; With
(c) in semipermeable membrane, produce at least one path.
On the other hand, provide and the method for transmission system of the single chamber infiltration control that discharges of preparation glipizide two-phase, said method comprising the steps of:
(a) glipizide, at least a alginic acid derivant, at least a alkali metal or alkaline earth metal derivative, penetrating agent and at least a pharmaceutically acceptable inert excipient are mixed; With binding agent compound is randomly granulated; With compound/granule is pressed into densified core;
(b) with the coated composition solution/dispersion parcel core that contains semipermeable membrane shaped polymer and other coating additive; With
(c) in semipermeable membrane, produce at least one path.
On the other hand, provide the method that makes glipizide two-phase release in vitro from the drug delivery system that the single chamber infiltration that contains glipizide, at least a alginic acid derivant and at least a alkali metal or alkaline earth metal derivative is controlled.
On the other hand, provide the method that glipizide is discharged in the two-phase body from the drug delivery system that the single chamber infiltration that contains glipizide, at least a alginic acid derivant and at least a alkali metal or alkaline earth metal derivative is controlled.
On the other hand, provide the method that makes glipizide two-phase release in vitro from the drug delivery system that the single chamber infiltration that contains glipizide, at least a alginic acid derivant and at least a alkali metal or alkaline earth metal derivative is controlled; Wherein, second of glipizide release about beginning in 3-12 hour.
On the other hand, provide the method that glipizide is discharged in the two-phase body from the drug delivery system that the single chamber infiltration that contains glipizide, at least a alginic acid derivant and at least a alkali metal or alkaline earth metal derivative is controlled; Wherein, second of glipizide release about beginning in 3-12 hour.
Brief Description Of Drawings
Fig. 1 has compared the release in vitro of glipizide from Glucotrol XL (10mg) the single chamber osmosis system of embodiment 1-4 and Pfizer sale.
Fig. 2 has compared in the glipizide body that Glucotrol XL (10mg) that oral single chamber osmosis system of the present invention and Pfizer sell obtains mean plasma concentration distribute (12 experimenters).
Detailed Description Of The Invention
The alginic acid derivative that is used as sweller in the drug delivery system of single chamber infiltration-control has required swelling property, forms the dispersion of microsolubility medicine, and its denseness is easy to flow through path and does not destroy pellicle. The conventional sweller that uses has above-mentioned advantage seldom simultaneously in the osmosis system. And the amount of the alginic acid derivative that uses in the core can change in broad range. Having proved that most of alginic acid derivatives are oral does not have toxicity to people and other mammal, and approved is used for human body. And by using magnesium derivative, the system that can design single chamber infiltration control provides the two-phase of medicine to discharge. By thickness and the character of control pellicle, namely suitably select other dressing additive, also the speed of controlled pharmacy release.
When the drug delivery system with single chamber of the present invention infiltration control placed dissolution medium/intestines and stomach body fluid, water entered core by semipermeable membrane. Absorption water makes the alginic acid derivative swelling in the core, thereby produces the pressure to pellicle, forces the microsolubility pharmaceutical dispersions to enter medium on every side by path. When medicine flowed out from system, the medicine dissolving in the dispersion was in medium on every side.
Term used herein " two-phase release " refers to two different phases that Glipizide discharges from formulation, be with or without the preceding time lag. The unexpected increase of rate of release determines to discharge the appearance of second-phase in the time of can beginning by the detection second-phase. Variation by accumulation medicine release profile slope can be observed this phenomenon.
The increase of volume when term used herein " swelling " is abutment water. In some cases, swelling even can form gel sample thick substances, the microsolubility medicine is embedded in wherein with the form of dispersion. Therefore, term " swelling " and " gelatification " Alternate in this article.
Term used herein " core " comprise have given shape such as sheet, any compact composition of mould, capsule etc.
Term used herein " microsolubility medicine " comprises that solubility is about 1 part of medicine that is dissolved in 25 parts or more parts of water. Comprise that also 1 part of medicine is dissolved in the water less than 25 parts, but under acidity or alkali condition, or under the impact of other excipient, solubility is reduced to 1 part of medicine that is dissolved in 25 parts of water. The example that medicine of the present invention is suitable comprises: antidiabetic, antineoplastic, antihypertensive, psychotropic agent, cardiovascular drugs, platelet aggregation inhibitor, antalgesic, antiseptic, diuretics, antispastic etc. The object lesson of microsolubility medicine comprises: Glipizide, Doxazosin, Verapamil, prazosin, isradipine, Cilostazol, nifedipine, Nisoldipine, bendroflumethiazide, chlorpropamide, hydrocortisone, brufen, Diclofenac, and their combination. Term used herein " medicine " comprises free drug and any pharmaceutically acceptable salt thereof. Microsolubility medicine used herein is above-mentioned commercial form; Or use the technology such as pulverizing, microemulsified, congruent melting, spray-drying, process altogether the form processing of pharmaceutically acceptable inert excipient, pastille Inclusion Complexes etc.
Term used herein " alginic acid derivative " comprises alginic acid and any pharmaceutically acceptable salt, ester etc. and their mixture. The object lesson of alginate comprises alginic acid sodium salt, sylvite, magnesium salts, calcium salt or ammonium salt. Concrete alginic acid ester comprises propylene glycol alginate.
Alginic acid is the hydrophilic colloid polysaccharide of natural origin, mainly is comprised of the D-MANNOSE aldehydic acid of β-Isosorbide-5-Nitrae-connection and the L-glucuronic acid residue of α-Isosorbide-5-Nitrae-connection. According to the type of the marine alga of using in generating, the ratio of mannuronic acid and glucuronic acid content is generally 0.4-0.9. The alginic acid mean molecule quantity is about 10,000-6, and 00,000, be widely used as stabilizing agent, intensifier, gelling agent and emulsifying agent at pharmaceutical field. Alginic acid is water insoluble, but its salt and water form heat irreversible gel, reduced viscosity under higher pH value. The alginic acid derivative is sold by ISP alginates company to fawn-coloured filament, particle, granule or powder type with white, trade name-KELACID、ALGINIC ACID HF/D、ALGINIC
ACID DC、KETONE
LVCR、KELTONE
HVCR、MANUCOL
LKX、
MANUCOL LB、MANUCOL DMF、KELCOSOL
、MANUEL
DMB、
KELCOLOID
LVF, MANUCOL ESTER ERK, improved KELMAR、
KELTOSE
And other. According to used rank and required medicine release type, the amount of alginic acid derivative is about the 5%-98% of core gross weight.
Reaching the key factor that effective aquation makes alginic acid derivative control swelling is that each particle disperses in core suitably. Relatively poor dispersion can cause forming not hydration alginic acid derivative of bulk, and obviously prolongs hydration and swelling time, produces unsettled medicine release type.
A kind of method that obtains the suitable dispersion of alginic acid derivative particles is to mix with bleeding agent, is lowered into piece trend. And, can use the viscosity of the microsolubility pharmaceutical dispersions that forms in the bleeding agent control core, and control the medicine release profile.
Term used herein " bleeding agent " comprises the pharmaceutically acceptable inertia water soluble compound that all can cause infiltration, with reference to pharmacopeia, or " Hager " and RemingtonShi pharmaceutical science. The suitable example that is used as the compound of bleeding agent comprises: the water soluble salt of inorganic acid such 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, potassium dihydrogen phosphate; Organic acid water soluble salt such as sodium acetate, potassium acetate, Magnesium succinate, Sodium Benzoate, natrium citricum, sodium ascorbate; The nonionic organic compound of high water soluble is carbohydrate such as sweet mellow wine, D-sorbite, arabinose, ribose, wood sugar, glucose, fructose, mannose, galactolipin, sucrose, maltose, lactose, gossypose; Water-soluble amino acids such as glycine, leucine, alanine or methionine; Urea and urea derivative etc. and their mixture. The amount of used bleeding agent can be up to about 60% of core gross weight in the core.
Term used herein " pellicle " is film or dressing, hydrone can by but the content of core can not pass through. Pellicle is made of film shaped polymer and other pharmaceutically acceptable dressing additive. The not metabolism in intestines and stomach of film shaped polymer is namely discharged with prototype in ight soil. The film shaped polymer comprises polymer and the United States Patent (USP) 3,916,899 and 3,977 of structure pellicle known in the art, the polymer described in 404. The example of pellicle shaped polymer comprises: cellulose derivative such as cellulose acetate, Triafol T, acetic acid agar, acetic acid amylose, acetic acid urethanes cellulose, CAP, acetic acid methyl carbamate cellulose, acetic acid succinate cellulose, acetic acid dimethylamino acetic ester fiber element, acetic acid ethyl carbonate cellulose, acetic acid chloracetate cellulose, acetic acid grass acetoacetic ester cellulose, acetic acid methylmesylate cellulose, acetic acid sulfonic acid cellulose butyrate, cellulose acetate propionate, acetic acid diethylamino cellulose acetate, the sad cellulose of acetic acid, acetic acid laurate cellulose, acetic acid p-methyl benzenesulfonic acid cellulose, acetylbutyrylcellulose; The poly epoxides; The copolymer of alkylene oxide and alkyl glycidyl ether; Polyethylene glycol or polylactic acid derivative; The copolymer of ethyl acrylate and methyl methacrylate etc. and their mixture. Can select in various degree acetylizad cellulose acetate combination as the film shaped polymer. Along with the increase of cellulose acetate degree of acetylation, permeability of the membrane reduces. Specifically, can use acetyl content to be about the combination of the cellulose acetate of 8%-50%. And, also can with other dressing additive and the combination of film shaped polymer, regulate required permeability. Controlling diaphragm thickness also helps to control permeability of the membrane, and it is about the 3%-40% of core weight.
Any suitable device that the content of core is discharged into surrounding medium contained in term used herein " path ". This term comprises passage, hole, hole, hole, opening etc., by pellicle, and connection-core and medium on every side. Can produce path by machine drilling or laser boring, or owing to the osmotic pressure that acts on drug delivery system forms. Based on the character of required medicine release profile, can regulate number and the diameter of path. Yet the diameter of path should be greatly to making body fluid enter drug delivery system by convection process.
Term used herein " pharmaceutically acceptable inert excipient " comprises use and described all excipient of document in the formulation field that produces infiltration control. Example comprises adhesive, diluent, surfactant, pH adjusting agent, lubricants/glidants, stabilizing agent, plasticizer, colouring agent etc. and their mixture.
The object lesson of adhesive comprises methylcellulose, hydroxy propyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, PVP, gelatin, Arabic gum, ethyl cellulose, polyvinyl alcohol, amylopectin, pregelatinized starch, agar, tragacanth, sodium alginate, propane diols etc., and their mixture.
The object lesson of diluent comprises calcium carbonate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, glucan, dextrin, dextrose excipient, fructose, white bole, Lactitol, lactose, sweet mellow wine, D-sorbite, starch, pregelatinized starch, sucrose, compression sugars, candy etc. and their mixture.
Can use surfactant with the wetability that improves the microsolubility medicine and the aquation that promotes the alginic acid derivative, comprise the nonionic and ion (cation, anion, the amphion) surfactant that are applicable to pharmaceutical composition. Comprise: polyoxyethylene aliphatic acid and derivative thereof, for example PEG400 distearate, polyethylene glycol-20 dioleate, the single dilaurate of polyethylene glycol 4-150, polyethylene glycol-20 tristerin; Alcohol-grease exchange product, for example polyethylene glycol-6 corn oil; Bound to polyglycerol aliphatic acid, for example polyglyceryl-6 five oleate; Methyl glycol fatty acid ester, for example Sefsol 218; List and two glyceride such as castor oil acid glyceride; Sterol and steroid derivatives; Sorbitan fatty acid ester and derivative thereof, for example polyethylene glycol-20 dehydrating sorbitol monooleate, sorbitan mono-laurate; Polyethylene glycol alkyl ether or phenol, for example polyethylene glycol-20 cetyl ether, polyethylene glycol-10-100 nonyl phenol; Sugar ester, for example sucrose palmitic acid ester; Pluronic F68 is called " poloxamer "; Ionic surface active agent, such as sodium n-caproate, NaGC, soybean lecithin, fumaric acid sodium stearyl ester, propylene glycol alginate, sulfo-succinic acid monooctyl ester disodium, palmityl carnitine etc. and their mixture.
PH adjusting agent is to help to keep around the material of the local environment pH value of medicine, and suitable pH is the solubility behavior of regulating drug and/or the gel behavior of alginic acid derivative suitably. The object lesson of pH adjusting agent comprises: meglumine, trimethanolamine, ammonia, diethanol amine, ethylenediamine, 1B; Alkali metal derivant such as sodium dihydrogen phosphate, sodium ascorbate, natrium citricum, sodium phosphate, NaOH and potassium hydroxide; Alkaline earth metal derivative such as light magnesium oxide, heavy-burned magnesia, magnesium hydroxide, calcium hydroxide etc. and their mixture.
Using alkali metal or alkaline earth metal derivative to help to reach two-phase in the transmission system that the single chamber infiltration of Glipizide is controlled discharges. The object lesson of alkali metal derivant comprises sodium dihydrogen phosphate, sodium ascorbate, natrium citricum, sodium phosphate, NaOH and potassium hydroxide; Alkaline earth metal derivative comprises light magnesium oxide, heavy-burned magnesia, magnesium hydroxide, calcium hydroxide etc. and their mixture.
Especially can use magnesia or magnesium hydroxide. The concentration of alkali metal or alkaline earth metal derivative is the 0.1%w/w-30%w/w of drug core weight.
The object lesson of lubricants/glidants comprises cataloid, stearic acid, dolomol, calcium stearate, talcum powder, rilanit special, fatty acid cane sugar ester, microwax, cera flava, cera alba etc. and their mixture.
The object lesson of plasticizer comprises acetylation triacetyl glycerine, triethyl citrate, ATBC, tributyrin, monoglyceride, rapeseed oil, olive oil, sesame oil, citroflex A-4, CitroflexA-2, glycerine D-sorbite, diethy-aceto oxalate, diethyl phthalate, diethyl maleate, DEF, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate etc. and their mixture.
Stabilizing agent comprises antioxidant, buffer, acid etc. and their mixture.
Colouring agent comprises the oral pigment of any FDA approval and their mixture.
Term used herein " dressing additive " comprises the use of packaging technique field and described all the conventional dressing additives of document. Example comprises flow improver additive and the material described in the pharmaceutically acceptable inert excipient above.
Flow improver additive is water-soluble substances, and help absorbs water from surrounding medium and helps to control semi-transparent permeability of the membrane. Object lesson comprises CMC, hydroxypropyl methylcellulose, polyethylene glycol, hydroxypropyl cellulose, propane diols, PVP etc. and their mixture.
In one embodiment, can prepare by state of the art the transmission system of the single chamber infiltration control that the Glipizide two-phase discharges, such as by pulverizing, mixing, granulation, screening, filling, mold, spraying, dipping, dressing etc. The preparation process of core is as follows: with microsolubility medicine, at least a alginic acid derivative, at least a magnesium derivative, optional bleeding agent and other pharmaceutically acceptable inert excipient mix; Compound is randomly granulated; With compound/particle is pressed into densified core. The coated composition that contains the solution/dispersion form of pellicle shaped polymer and other dressing additive by coating is wrapped in core in the pellicle. At last, adopt suitable technology generation by the path of pellicle.
The example that is used as the solvent of granulation or preparation coated composition solution/dispersion comprises carrene, isopropyl alcohol, acetone, methyl alcohol, ethanol, water etc. and their mixture.
Alternatively, can be under pellicle or/and on core is applied the coatings of adding. Adding layer contains the dressing additive and smooth surface is provided; Adding even pellicle or the printed with identification indicia of applying on the layer. Improved in addition aesthstic attractive force.
If need immediately onset, on pellicle, can use by with core in the release layer of identical or different ingredients apply the transmission system of single chamber infiltration control.
And, in core and/or release layer, also can use the combination more than a kind of medicine.
By appended description, these and others of the present invention will be apparent.
Following examples are further illustrated the present invention, and it is that example purpose and should not be construed as by any way limits the scope of the invention.
Embodiment
I. core is formed
| Composition | The weight of each core (mg) | |||
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | |
| Glipizide | 11 | 11 | 11 | 11 |
| Macrogol 4000 | 11 | 11 | - | 11 |
| Poloxamer (Lutrol F 127) | 11 | 11 | - | 11 |
| Light magnesium oxide | 15 | - | - | - |
| Magnesium hydroxide | - | 15 | - | - |
| Sodium alginate | 138 | 138 | 105 | 130 |
| Sorbitol | 137 | 137 | 170 | 145 |
| Silica sol | 2 | 2 | 2 | 2 |
| Polyvinyl pyrrolidone | 15 | 15 | 15 | 15 |
| Magnesium stearate | 4 | 4 | 6 | 4 |
II. pre-coated composition
| Composition | Amount/sheet (mg) | |
| Embodiment 1 | Embodiment 3 | |
| Hydroxypropyl emthylcellulose | 4.7 | 2.47 |
| Macrogol 4000 | 1.2 | 0.62 |
III. semipermeable membrane
| Composition | Amount/sheet (mg) | |||
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | |
| Cellulose acetate (32% acetyl content) | - | - | 45.46 | - |
| Cellulose acetate (39.8% acetyl content) | 44.3 | 35.2 | 6.83 | 41.6 |
| Hydroxypropyl emthylcellulose | - | - | 5.06 | - |
| Polyethylene Glycol | 11.1 | 8.8 | 5.06 | 10.4 |
Method (embodiment 1,2 and 4):
1. glipizide, light magnesium oxide/magnesium hydroxide, sodium alginate, Sorbitol and silica sol are sieved and mix formation uniform mixing material.
2. Polyethylene Glycol, a poloxamer polyvinyl pyrrolidone are scattered in isopropyl alcohol and water (75: in mixed liquor 25w/w), form the dispersion (except the dispersion concentration of embodiment 4 is 43%w/w) of 35%w/w.
3. the compound of step 1 and the dispersion of step 2 are granulated.
4. suitable sieve is passed through in wet granular dry also screening in fluidized bed dryer.
5. dried granule is mixed with magnesium stearate lubricant, and use proper tools that it is pressed into the core of round concave shape.
6. hydroxypropyl emthylcellulose and the pre-coated composition of Polyethylene Glycol are dissolved in isopropyl alcohol and dichloromethane (60: 40w/w) in the mixed liquor, prepare the solution of 5%w/w.
7. in coating pan, use the core (only embodiment 1) of the solution coating steps 5 of step 6, form the core of pre-coating.
8. cellulose acetate and Polyethylene Glycol are dissolved in acetone and water (90: in mixed liquor 10w/w), prepare the solution of 4%w/w.
9. the core (only embodiment 1) of the solution coating steps 7 pre-coatings of usefulness embodiment 8 or the core of step 5 form semi-permeable coating; The baking oven inner drying.
10. use the power auger of 0.6mm, boring obtains the transmission system of glipizide single chamber infiltration control by the semipermeable membrane of the Dragees of step 9.
Method (only embodiment 3)
1. glipizide, sodium alginate, Sorbitol and silica sol are sieved and mix formation uniform mixing material.
2. polyvinyl pyrrolidone is dissolved in the isopropyl alcohol.
3. the compound of step 1 and the solution of step 2 are granulated.
4. suitable sieve is passed through in wet granular dry also screening in fluidized bed dryer.
5. with dried granule and magnesium stearate lubricant mixed lubrication, and use proper tools that it is pressed into the core of round concave shape.
6. hydroxypropyl emthylcellulose and the pre-coated composition of Polyethylene Glycol are dissolved in isopropyl alcohol and dichloromethane (60: 40w/w) in the mixed liquor.
7. in coating pan, use the core of the solution coating steps 5 of step 6, form the core of pre-coating.
8. cellulose acetate, hydroxypropyl emthylcellulose and Polyethylene Glycol are dissolved in acetonitrile and water (80: in mixed liquor 20w/w), prepare the solution of 3.5%w/w.
9. use the core of the solution coating steps 7 pre-coatings of step 8, form semi-permeable coating; The baking oven inner drying.
10. use the power auger of 0.6mm, boring obtains the transmission system of glipizide single chamber infiltration control by the semipermeable membrane of the Dragees of step 9.
In 900ml phosphate buffer (pH 7.5), adopt USP II dissolving device, the oar rotating speed is 50rpm, the release in vitro of research glipizide from the transmission system of Glucotrol XL (10mg) the single chamber infiltration control of embodiment 1-4 and Pfizer sale.Result of the test as shown in Figure 1.
Fig. 1 shows, beginning about about 6 hours greatly, and the rate of release of glipizide from the compositions of embodiment 1 and 2 sharply increases, and the prompting two-phase discharges.On the other hand, do not contain the embodiment 3 of alkali metal or alkaline earth metal derivative and 4 compositions and Glucotrol XL (embodiment 5) and show that the rate of release of glipizide roughly remains unchanged.
In healthy male volunteers, estimate the interior behavior of body that the present invention (T) monocompartment osmotic controlled delivery system is compared with Glucotrol XL (10mg) tablet (R).Glipizide content in adopting in the mark HPLC methods analyst blood sample.Mean plasma concentration to the time mapping as shown in Figure 2.
The above results clearly illustrates that the two-phase of using alkali metal or alkaline earth metal derivative can reach glipizide discharges.The increase that occurs in 6 hours rate of release approximately helps to increase the drug release at colon position, promotes that colon absorbs better.And if actual needs discharges by two-phase, the system of single chamber infiltration control helps to reach higher glipizide concentration during having meal next time.
Though for example and described the several concrete forms of the present invention, should understand and not deviate from spirit and scope of the invention, can describe various improvement and the combination of narrating in book and claims.For example, though this paper embodiment has narrated magnesium derivative, also can use other alkali metal or alkaline earth metal derivative to obtain similar result.And though use glipizide as the prototype medicine, the present invention can easily be used for other microsolubility medicine.And, consider that any single feature of variable of the present invention described herein or the combination of any optional feature can specifically be got rid of outside claims of the present invention, thereby be called potential invention.Therefore, the present invention is nonrestrictive, except that appended claims.
Claims (28)
1. the single chamber of a glipizide two-phase release permeates the transmission system of control, and described transmission system comprises:
(a) comprise the core of following composition
(i) glipizide,
(ii) at least a alginic acid derivant,
(iii) at least a alkali metal or alkaline earth metal derivative and
(iv) at least a pharmaceutically acceptable inert excipient;
(b) semipermeable membrane of parcel core; With
(c) at least one path in the semipermeable membrane enters surrounding medium with the content transmission with core.
2. the transmission system of single chamber infiltration control as claimed in claim 1 is characterized in that described alkali metal derivant is selected from: sodium hydrogen phosphate, sodium ascorbate, sodium citrate, sodium phosphate, sodium hydroxide and potassium hydroxide; Or described alkaline earth metal derivative is selected from light magnesium oxide, heavy-burned magnesia, magnesium hydroxide and calcium hydroxide.
3. the transmission system of single chamber infiltration control as claimed in claim 2 is characterized in that described alkaline earth metal derivative is a magnesium hydroxide.
4. the transmission system of single chamber infiltration control as claimed in claim 2 is characterized in that described alkaline earth metal derivative is light magnesium oxide or heavy-burned magnesia.
5. the transmission system of single chamber infiltration control as claimed in claim 4 is characterized in that described alkaline earth metal derivative is a light magnesium oxide.
6. the transmission system of single chamber infiltration control as claimed in claim 1 is characterized in that the concentration of described alkali metal or alkaline earth metal derivative is about the 0.1%-30%w/w of core.
7. the transmission system of single chamber infiltration control as claimed in claim 1 is characterized in that described core also comprises penetrating agent.
8. the transmission system of single chamber as claimed in claim 1 infiltration control is characterized in that, described core on semipermeable membrane and/or below be coated with and add layer.
9. the transmission system of single chamber as claimed in claim 8 infiltration control is characterized in that, the described layer that adds is the release layer that contains with the identical or different medicine of core Chinese medicine.
10. the transmission system of single chamber infiltration control as claimed in claim 1 is characterized in that described core is selected from any compact composition with given shape.
11. the transmission system of single chamber infiltration control as claimed in claim 1 is characterized in that described alginic acid derivant is selected from alginic acid and pharmaceutically acceptable derivates such as salt, ester etc.
12. the transmission system of single chamber infiltration control as claimed in claim 11 is characterized in that described alginate is selected from: the sodium salt of alginic acid, potassium salt, magnesium salt, calcium salt or ammonium salt etc.
13. the transmission system of single chamber infiltration control as claimed in claim 12 is characterized in that described alginate is a sodium alginate.
14. the transmission system of single chamber infiltration control as claimed in claim 11 is characterized in that described alginic acid ester is a propylene glycol alginate.
15. the transmission system of single chamber infiltration control as claimed in claim 1 is characterized in that described pharmaceutically acceptable inert excipient is selected from: binding agent, diluent, surfactant, lubricants, stabilizing agent, plasticizer and coloring agent.
16. the transmission system of single chamber infiltration control as claimed in claim 1 is characterized in that described semipermeable membrane comprises semipermeable membrane shaped polymer and coating additive.
17. the transmission system of single chamber infiltration control as claimed in claim 16, it is characterized in that described semipermeable membrane shaped polymer is selected from: cellulose derivative such as cellulose acetate, Triafol T, acetic acid agar, the acetic acid amylose, acetic acid urethanes cellulose, cellulose acetate phthalate, acetic acid methyl carbamate cellulose, acetic acid succinate cellulose, acetic acid dimethylamino acetic ester fiber element, acetic acid ethyl carbonate cellulose, acetic acid chloracetate cellulose, acetic acid grass acetoacetic ester cellulose, acetic acid methylmesylate cellulose, acetic acid sulfonic acid cellulose butyrate, cellulose acetate propionate, acetic acid diethylamino cellulose acetate, the sad cellulose of acetic acid, acetic acid lauric acid cellulose, acetic acid p-methyl benzenesulfonic acid cellulose, acetylbutyrylcellulose; The poly epoxide; The copolymer of alkylene oxide and alkyl glycidyl ether; Polyethylene Glycol or polylactic acid derivative; The copolymer of ethyl acrylate and methyl methacrylate etc.
18. the transmission system of single chamber infiltration control as claimed in claim 17 is characterized in that described cellulose derivative is a cellulose acetate.
19. the transmission system of single chamber infiltration control as claimed in claim 16 is characterized in that described coating additive is selected from flow improver additive and pharmaceutically acceptable inert excipient.
20. the transmission system of single chamber infiltration control as claimed in claim 19 is characterized in that described flow improver additive is selected from: hydroxy methocel, hydroxypropyl emthylcellulose, Polyethylene Glycol, hydroxypropyl cellulose, propylene glycol, polyvinyl pyrrolidone etc.
21. the transmission system of single chamber infiltration control as claimed in claim 20 is characterized in that described flow improver additive is a Polyethylene Glycol.
22. the drug delivery system of single chamber infiltration control as claimed in claim 7, it is characterized in that described penetrating agent is selected from: the water soluble salt of mineral acid such as magnesium chloride, magnesium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, dibastic sodium phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate; Organic acid water soluble salt such as sodium acetate, potassium acetate, Magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate; The nonionic organic compound of high water soluble such as carbohydrate such as mannitol, Sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, Raffinose; Water-soluble amino acid such as glycine, leucine, alanine or methionine; Urea and urea derivative.
23. the drug delivery system of single chamber infiltration control as claimed in claim 22 is characterized in that described penetrating agent is a Sorbitol.
24. a method for preparing the drug delivery system of single chamber infiltration control said method comprising the steps of:
(a) with microsolubility medicine, at least a alginic acid derivant, at least a alkali metal or alkaline earth metal derivative and at least a pharmaceutically acceptable inert excipient mixing formation compound as the pH regulator agent;
(b) with binding agent compound is randomly granulated;
(c) compound/granule is pressed into densified core;
(d) with the coated composition solution/dispersion parcel core that contains semipermeable membrane shaped polymer and other coating additive; With
(e) in semipermeable membrane, produce at least one path.
25. method as claimed in claim 24 is characterized in that, the compound of step (a) also contains penetrating agent.
26. method as claimed in claim 24 is characterized in that, the solution/dispersion of described pelletize or coated composition is selected from the following solvent at one or more and forms: dichloromethane, isopropyl alcohol, acetone, methanol, second alcohol and water.
27. one kind makes the glipizide method that two-phase discharges in external/body from the drug delivery system that the single chamber infiltration that contains glipizide, at least a alginic acid derivant and at least a alkali metal or alkaline earth metal derivative is controlled.
28. method as claimed in claim 27 is characterized in that, what glipizide discharged second began about 3-12 hour.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IBPCT/IB03/01771 | 2003-05-06 | ||
| PCT/IB2003/001771 WO2003092660A1 (en) | 2002-05-06 | 2003-05-06 | Monocompartment osmotic controlled drug delivery system |
| IN818/DEL/2004 | 2004-04-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1805734A true CN1805734A (en) | 2006-07-19 |
Family
ID=36867447
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200480016223.1A Pending CN1805734A (en) | 2003-05-06 | 2004-05-06 | Biphasic release of glipizide from monocompartment osmotic dosage form |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1805734A (en) |
-
2004
- 2004-05-06 CN CN200480016223.1A patent/CN1805734A/en active Pending
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