CN1543337A - Expandable gastric retention device - Google Patents

Abstract

The present application concerns gastric retention devices formed from compositions comprising polymeric materials, such as polysaccharides, and optional additional materials including excipients, therapeutics, and diagnostics, that reside in the stomach for a controlled and prolonged period of time.

Description

Expandable gastric retention device

Technical field

The application relates to gastric retention device, and this device forms by containing the compositions that polymeric material such as polysaccharide and selectivity contain other material, and other material comprises excipient, therapeutic agent and diagnostic agent, and described gastric retention device keeps the time period controlled and that prolong at gastric.

Background technology

Nearest oral drugs delivery system may command medicine discharged in more than 24 hours time period in a predefined manner in a few hours.Medication effect not only depends on the pattern that medicine discharges from preparation, and depends on the kinetics of medicine from gastrointestinal absorption.Some medicines only are absorbed in some zone of small intestinal, and described zone is called as " absorption window ".In case these medicines then seldom have drug absorption or drug absorption do not take place by this zone.Therefore, people have great interest in the exploitation of gastric retention device (GRD), and gastric retention device can make medicine keep prolongation and predictable time period at gastric.

All discussed fully in patent and scientific literature this need for equipment, described document comprises United States Patent (USP) 5,651,985 and list of references.In health care, it is very important carrying out the timing administration with respect to food intake.If use slow releasing preparation after the meal, mobile myoelectricity complex wave is ended by food, and this dosage form may keep 12 hours or the longer time at gastric, and this provides a chance for waiting to absorb the drug.Yet if products applied on an empty stomach, this product only can emptying in to 20 minutes enters intestinal and betransported by small intestinal in less than 3-5 hour few.For the medicine that need have absorption window, if or for not being dissolved in well before transfer enters small intestinal in the gastric juice with regard to nonabsorbable medicine, this can reduce the absorption of medicine significantly.Therefore, whether identical Drug therapy is according on the feed or carry out the diverse result of generation during fasting.

Attempted to adopt three kinds of main methods to produce gastric retention device already, all these methods all have significant disadvantage or failure, as substantially at United States Patent (USP) 5,651, described in 985, and people's such as Hwang summary (Gastric Retentive Drug-Delivery Systems, Critical Reviews in Therapeutic Drug Carrier Systems, 15 (3): 243-284 (1998)).Known prevailing method is hydrodynamic equilibrium (HBS) system (United States Patent (USP) 4,140,755 and 4,167,558), and this system design is used to float on the content of stomach and away from the pylorus zone of stomach, injects intestinal by this zone.Yet, these devices can only be when stomach contains food just floatability at gastric.For fasted subjects, HBS type pharmaceutical dosage form leaves stomach at short notice, they are eliminated from gastric by " house keeper's ripple (housekeeping wave) ", digestion myoelectricity complex wave (INC) or mobile (myoelectricity) complex wave (MMC) in described house keeper's ripple is also referred to as.House keeper's ripple has the effect of removing the gastric undigested material, and in case the food of any existence is digested and leaves away, house keeper's ripple then is responsible for nickel coin, fractional currency and other solid that child (and adult) swallows are gone out clearly from gastric.

The method of second kind of relevant gastric retention device comprises swollen tablet in the gastric juice, as United States Patent (USP) 3,574, and 820 and 4,434,153 is described.Be that these tablets take place broken when hydration lamentedly.The dimensional stability of production swelling tablet material therefor reduces greatly with swelling, and this causes the too early erosion or the dissolving of gel layer.In addition, swelling tablet and hydrodynamic equilibrium system all require drug products all to be made into preparation, that is, the tablet of preexist can not be introduced in the GRD.

Method of the third relevant gastric retention device comprises mechanically actuated, and as polymer coating, it is swallowing back expand by discharging gas (for example, referring to, United States Patent (USP) 4,207,890).Perhaps, this device can be by the opening (United States Patent (USP) 4,767 of " flower " shape structure, 627), wind up expansion (United States Patent (USP) 4,308,250 of sheet, for for animals) and play a role, or play a role by the automatic valve that has propellant and the bag that collapses that can be changed into balloon.Balloon expansion makes device be retained in gastric (United States Patent (USP) 3,797,492).Be that these methods can not be used in human body well lamentedly.Particularly, GRD need be kept at the fasting gastric during MMC, behind the gastric preset time, collapse or disintegrate, and stay original position and when having food to exist when this device, it needn't prevent food via pylorus from the gastric emptying.Still do not have any device at present and satisfy all these standards.

Except said method, GRD is by novel synthesis of acrylamide/sulfopropyl acrylate/acrylate copolymer manufacturing, this material contains the croscarmellose sodium salt, it has another name called " Superporous hydrogels composite " (people such as Chen, " Gastric retention properties ofsuperporous hydrogel composites ", Journal of Controlled Relese, 64,39-51 (2000); People such as Hwang).Need cost several hrs, the particularly size that can swallow with the people (from the tablet and the capsule of 1.36g raw material manufacturing) because expand, the performance of dried hydrogel is relatively poor usually, and may be from the gastric emptying before it reaches the complete swelling state.In addition, even after expanding, hydrogel can not pass through pylorus even as big as preventing expansion gear in the time expand section; People's such as Chen GRD only promptly arrived colon in three hours when being applied to the fasting dog.In addition, these new polymerss do not obtain the approval of FDA or any other government administration section.

Another problem of existing GRD is, when they when gastric keeps, disturb food via the transhipment of stomach to enteral.Obviously, present known not device can still allow the normal transhipment of food in the gastric reservation.

Summary of the invention

GRD disclosed herein has avoided many problems of the prior art, and this is because may have abundant dimensional stability and flexible simultaneously in the intumescent material that is formed by the mixture that contains polysaccharide.This mixture can be processed into a kind of swollen polymer gel, and whether it uses all and can keep at gastric with food.Surprisingly, said composition makes food pass through stomach incessantly; When normal filling of stomach quilt and emptying, this device keeps at gastric.This device may be tailored to degraded fully in gastric juice, thereby in preset time, is generally in 12-24 hour and leaves stomach, if desired, can keep the short or long retention time.In addition, gastric retention device is suitable for being administered to other intracavity except stomach, that is, and and mouth, rectum, vagina, nose or intestinal.In addition, this device can be incorporated diagnostic agent and/or therapeutic agent into, it includes but not limited to make the product of preparation and/or listing, as solution, suspension, Emulsion, powder, tablet, capsule or globule, and can provide product at gastric retention and the medicine sustained release at gastric.

GRD disclosed herein typically comprises the gel that is formed by polysaccharide or its mixture.For example, be suitable for the size that the experimenter who comprises humans and animals is used and form this device by removing any liquid part (for example dehydration), being collapsed into then to small part.Usually, yet and optionally, the coating that formed device has is vulnerable to the erosion of the gastric juice that contacts with its outer surface, perhaps formed device can be loaded into and can absorb in the capsule, described capsule is subject to the erosion of gastric juice.As selection, formed device can have enteric coating or be loaded in the enteric solubility capsule.In certain embodiments, polysaccharide comprises carbohydrate natural gum, and in certain embodiments, GRD is formed by the mixture that comprises sugar, polysaccharide or its combination.GRD can be processed to form the gel that needs, but described embodiment typically relates to heat-induced gelation.GRD dewaters basically, and in specific embodiments, GRD is cryodesiccated.Xanthan gum and locust bean gum are the examples that is used to form the material of preparation embodiment.The weight ratio of xanthan gum and locust bean gum typically is about 1: 4 to about 4: 1, and in specific embodiments, the weight ratio of xanthan gum and locust bean gum is about 1.5: 1 to about 1: 1 among the GRD.GRD can further comprise the material that is selected from plasticizer, pH regulator agent, GI wriggling regulator, viscous regulator, therapeutic agent, diagnostic agent, preparation, extender, surfactant and composition thereof.

Diagnostic agent or therapeutic agent can be used as solution, suspension, Emulsion, tablet, capsule, powder, globule, piller, granule, solid-state dispersant or its combination.Diagnostic agent or therapeutic agent are easier to be molten in gastric juice than in intestinal juice; In intestinal juice than easier to be molten in the gastric juice; Absorb better in the small intestinal internal ratio at big enteral; Better at gastric than absorbing at enteral; And in other embodiments, diagnostic agent or therapeutic agent are better than absorbing at gastric at enteral.

In some embodiments, GRD comprises compressor, this device the time fully expands in picked-up, and is enough firm when expanding, and still allows food to pass through by experimenter's pylorus (for example 2,6,9,12 or 24 hours or longer) to prevent this device in reaching 24 hours preset time.This device can be designed for and almost produce any geometry when expanding, as cube, cone (except the attention cone), cylinder, pyramid (except the attention cone), spheroid, cylinder or parallelepiped.Usually, the coefficient of expansion of GRD is at least 3.0, although unnecessary, preferred gel expand into 80% of its final size basically in 2 hours under aqueous environments, or, expand into 80% of its final size basically in 2 hours after experimenter's picked-up as selecting.Although be not limited to a kind of theory of operation, the expansion gel can have at least a size greater than the pylorus diameter.

GRD corrodes in the presence of gastric juice usually and pass through pylorus behind preset time.GRD can comprise enzyme, for example hydrolytic enzyme, protease, cellulase or glucanase (gluconase), and after device was ingested, auxiliary coating of these enzymes or capsule corroded.

The concrete preparation embodiment of GRD is the gel from a kind of mixture preparation, described mixture comprise about 0.1% to the carbopol of the xanthan gum of about 2.0% weight, about 0.1% locust bean gum, the Polyethylene Glycol of about 5% weight, the sodium lauryl sulphate of about 1% weight, about 1% weight to about 2.0% weight and biology effective dose therapeutic agent, diagnostic agent or its combination, remaining comprises liquid, for example water.This device is by dry and compression fully, forms to be suitable for embedding to be subject to the shape in the erosive capsule of gastric acid and to form the appropriate size that the experimenter is used.

The embodiment of disclosed manufacturing gastric retention device method comprises: form the mixture that contains polymeric material; Mixture is processed to form desiccant gel and optional be positioned over to the desiccant gel coating or with gel and be subject in the erosive capsule of gastric juice with being subject to the erosive material of gastric juice.This method can comprise that heating blends forms heat-induced gelation and lyophilization gel effectively.Be suitable for size and shape that the experimenter is used desiccant gel can being compressed into to the gel coating or before being placed in the capsule.

This paper also discloses the method for using gastric retention device.The embodiment of described method comprises to be provided a kind of gastric retention device and the experimenter is used the gastric retention device that this paper describes generally.This paper also discloses the embodiment of appetite-suppressing, and it comprises provides a kind of gastric retention device, and this device fully expands to suppress experimenter's appetite at least in part at experimenter's gastric.The experimenter is used gastric retention device periodically.In certain embodiments, this device further comprise effective dose fatty acid, appetite suppressant, agent or its combination lose weight.This paper also discloses the method that does not change accumulated dose and produce improved pharmacological reaction, and the diuretic of for example using given oral dose is to increase the urine amount.

Aforesaid feature and advantage and other feature and advantage will and be consulted accompanying drawing and become more apparent from several embodiments of following detailed description.

The accompanying drawing summary

Fig. 1 is the xanthan gum/hydration percentage of locust bean gum glued membrane in water of various solids ratios.

Fig. 2 is the xanthan gum/hydration percentage of locust bean gum glued membrane in simulated gastric fluid of various solids ratios.

Fig. 3 is the initial hydration percentage of xanthan gum/locust bean gum glued membrane in water of various solids ratios.

Fig. 4 is xanthan gum/locust bean gum glued membrane hydration percentage during 0-3 hour in simulated gastric fluid of various solids ratios.

Fig. 5 represents the shape and size of the GRD of four kinds of tests.

Fig. 6 is GRD hydration during 3-24 hour in simulated gastric fluid.

Fig. 7 is GRD hydration during 0-3 hour in simulated gastric fluid.

Fig. 8 is during 20 hours, the comparison of the amoxicillin mg that discharges amoxicillin mg that discharges from amoxicillin scrotiform tablet (caplet) and the amoxicillin scrotiform tablet in GRD.

Fig. 9 is during 20 hours, contains the comparison that the amoxicillin mg of release the core scrotiform tablet (core caplet) and the amoxicillin in GRD contain the amoxicillin mg that discharges the core scrotiform tablet from the amoxicillin.

Figure 10 is during 20 hours, from ranitidine ^Ranitidine hydrochloride mg that discharges in the tablet and ranitidine in the GRD ^The comparison of the ranitidine hydrochloride mg that discharges in the tablet.

Figure 11 is the percent of the utilized riboflavin of release comparison in time from riboflavin globule and the riboflavin globule in GRD.

Figure 12 is the percent of the utilized riboflavin that discharges in time the riboflavin globule in improved GRD.

Figure 13 is the percent of the utilized riboflavin that discharges in time the riboflavin solid dispersion in improved GRD.

Figure 14 is the digital image of the X ray picture of the stomach of fasting dog, at once the GRD of gastric behind its expression prescribe medicine.

Figure 15 is the digital image of the X ray picture of dog stomach, the GRD of its expression prescribe medicine gastric after 2 hours.

Figure 16 is the digital image of the X ray picture of dog stomach, the GRD of its expression prescribe medicine gastric after 9 hours.

Figure 17 is the digital image of the X ray picture of dog stomach, the GRD of its expression prescribe medicine interior disintegrate of postcolon in 24 hours.

Figure 18 is the digital image of the X ray picture of dog stomach, the GRD of its expression prescribe medicine gastric after 2 hours.Use the food that gives behind the GRD from the gastric emptying and not emptying of GRD.

Figure 19 is the digital image of the X ray of dog stomach, and its expression contains radiopaque GRD.At once the empty stomach of (0 hour), prescribe medicine back 1 hour and 2 hours dogs before X ray is represented prescribe medicine, behind the prescribe medicine.

Figure 20 is the digital image of the X ray of dog stomach, and its expression contains radiopaque GRD.X ray is represented to put in poison and was had GRD at the dog gastric in back 3 hours, 7 hours, 9 hours, and does not have GRD back 24 hours of prescribe medicine at the dog gastric.

Figure 21 is illustrated in the comparison of the excretion rate of amoxicillin behind the excretion rate of using amoxicillin behind the scrotiform tablet of amoxicillin under the fasted conditions and the amoxicillin scrotiform tablet of using in the GRD.

Figure 22 is the excretion rate of amoxicillin use the amoxicillin separately under fasted conditions after and the comparison of using the amoxicillin excretion rate of the amoxicillin in the GRD.

Figure 23 is when sending as immediate release formulation or with small-sized, medium-sized or large-scale GRD, in time the cumulant of excretory riboflavin.

Figure 24 is when sending as immediate release formulation or with small-sized, medium-sized or large-scale GRD, the homaluria rate of riboflavin.

Figure 25 removes the flatung input function for what the biological study data from the immediate release formulation of riboflavin and GRD preparation obtained.

Figure 26 represents to use the comparison after Hydrochlorothiazide behind the immediate release formulation of Hydrochlorothiazide is drained in time cumulant and the Hydrochlorothiazide of using in the GRD.

Figure 27 is the Hydrochlorothiazide excretion rate in time that discharges (IR) capsule and new formulation (GRD) immediately.

Figure 28 has compared the urine generation, the water that derive from the Hydrochlorothiazide in IR and the GRD and has taken in and the accumulation voided volume.

Describe in detail

I. foreword

Unless otherwise indicated, the meaning of all technology used herein and scientific terminology with the present invention relates to the common same meaning of understanding of technical staff in the field.Unless context points out clearly that in addition singular references " ", " a kind of ", " this kind " comprise plural implication.Though method and the material similar or of equal value with material to method as herein described can be used in practice of the present invention or the test, suitable method and material are described below.Described material, method and embodiment only are illustrative but not are intended to limit.

II. term

The definition that term is provided is for the reader considers fully, and any specific embodiment that is provided should be provided the definition term, or is restricted to than the narrower definition of the acceptable definition of those skilled in the art.

Active agents be meant at present known or hereinafter find can be by any therapeutic agent or the diagnostic agent that carries out preparation described herein.The embodiment of therapy without limits, it lists in United States Patent (USP) 4,649, in 043, this patent is incorporated herein as a reference.Additional embodiment lists in AmericanDruggist, in the 21-24 page or leaf (February nineteen ninety-five).

Can be by any known method to experimenter's administration, described method includes but not limited to oral administration, intravaginal administration, rectally, intranasal administration or oral administration.

Sustained release comprises regularly the term that discharges, continues release, pulse release, delay release and other release mode of all descriptions except discharging immediately.

Diagnostic method without limits, it is to be used to the material of checking a material or disease to have or do not have, and/or can improve the material of tissue or chamber imaging.

Effective dose is meant the amount of the diagnostic agent or the therapeutic agent that are used to produce Expected Results.

Erodiblely be meant that but absorbable, decomposable, soluble enzyme catalysis is cracked etc., and the combination of these erosion processes.Though do not limit, a kind of method of measuring the agent of erosion is meant when coating, capsule or GRD are exposed in suitable aqueous environments such as the simulated gastric fluid, adopt the oar formula of the American Pharmacopeia of 50rpm operation to stir the stripping instrument, judge coating, capsule or GRD in the preset time section, for example the extent of damage of the bonding force in 1,3,6,9,12 or 24 hour.Suitable aqueous environments can comprise or more than a kind of aqueous medium, be included in the change of medium during grinding that suitable aqueous environments will depend on specifically earmarking of GRD known in those skilled in the art usually a kind of.

The coefficient of expansion calculates by the volume of the GRD volume before expanding divided by the device of complete expansion.

Gastric retention device (GRD) is a kind of device that can use the experimenter, and this device can be used or use separately with other material.The GRD device can be customized to be fit to various body cavitys, comprises abdominal cavity (gastral cavity), enteric cavity, oral cavity, rectum, vagina or nasal cavity.The most usually, for the purpose that stomach is sent, this device form to be fit to the size to experimenter's administration, and after the administration, this device absorption liquid also expand into size greater than the administration size, and this is to be used to prevent that this device from passing through pylorus in preset time.For the purpose of other body cavity, this device forms the size that is suitable for described chamber, and for example, for the usefulness of enteric cavity, this installs the size that general oral administration administration arrives in the gastral cavity and is suitable for forming suitable intestinal, and the general dehydration polysaccharide gel that uses is made this device.For the purpose of other route of administration except that oral administration, GRD needn't necessarily absorb liquid, but GRD generally absorbs liquid.

Hydrophilic gel forms agent material or reagent, is also referred to as hydrogel, is the material that shows as the ability of the water that keeps signal portion in Shui Zhongshui is incorporated in its structure.Hydrogel can be a non-crosslinked, perhaps their available covalent bond or ionic crosslinkings.Hydrogel can derive from plant or animal, can be by modifying hydrogel and the synthetic polymeric hydrogel that naturally occurring structure prepares.

Monosaccharide is aldehyde or the ketone derivatives that contains the straight chain polyhydroxy-alcohol of at least three carbon atoms.

Polysaccharide is by forming by glycosidic bond monosaccharide connected to one another.

Tablet is term well known in the art and is used for this paper that it comprises all compactings, molded or by the material that alternate manner forms, does not limit size or shape and all preparation methoies of tablet.Therefore, as a common instance, comprise the compression shape or the molded shape that are known as the scrotiform tablet.

III. compositions

Usually, being used to form the material of expandable gel substrate by selecting material or selection, generally is that monomer material or polymeric material such as polysaccharide are made GRD; Then, select and use other excipient, diagnostic agent, therapeutic agent, preparation or its combination arbitrarily and form GRD; Selected polymeric material, excipient and/or diagnostic agent or therapeutic agent and/or preparation and liquid mixing obtain mixture; Process this mixture contains liquid with formation gel; Remove partially liq to make the desiccant gel film from gel then; And optional this desiccant gel film can be compacted into the size that is suitable for administration.The desiccant gel film can carry out coating or dress capsule with being subject to erosive coating of gastric acid and/or enteric coating.After the administration, desiccant gel absorbs liquid.Therefore, in each stage, this gel can contain liquid or exsiccant gel.To discuss each step in these steps below in more detail.

A. be used to form monomer material or the polymeric material of GRD

GRD disclosed herein is formed by the mixture that contains polymeric material usually.Yet, can form identical polymeric material with regard to monomer material, form these polymeric materials as original position, they also can be used.Polymeric material can be hydrophilic gel former.The example of hydrophilic gel former without limits, it comprises following material: as arabic gum, Tragacanth, guar gum, pectin, xanthan gum, locust bean gum, carbopol ^Acid carboxyl polymer, hydroxypropyl emthylcellulose, polycarbophil, poly(ethylene oxide), the polymethylacrylic acid hydroxy alkyl ester, compound polyelectrolyte, with the crosslinked polyvinyl acetate of hydrolyzable bond, the N-vinyl lactam polysaccharide of water-swellable, natural gum, agar, agarose, sodium alginate, carrageenin, sulfated fucan (fucoidan), Furcellaria polysaccharide (furcellaran), laminarin, husky Lepidium, Eucheuma, Radix Acaciae senegalis, Ficus elastica, karaya, arbinoglactan, amylopectin, gelatin, hydrophilic colloid, for example carboxymethyl cellulose gum or alginate gel, comprise non-crosslinked and crosslinked alginate gel, wherein crosslinked alginate gel can be with bivalence or trivalent ion, polyhydric alcohol such as propylene glycol, or other cross-linking agent, Cyanamer ^Polyacrylamide, Good-rite ^Polyacrylic acid, starch graft copolymer, Aqua-Keeps ^Poly-Portugal polysaccharide that acrylate polymer, ester are crosslinked etc. is crosslinked.Some hydrogels are at United States Patent (USP) 3,640, discuss in 741,3,865,108,3,992,562,4,002,173,4,014,335 and 4,207,893.Also referring to the Handbook Common Polymers, Scott and Roff write in the discussion of hydrogel, are published Cleveland, Ohio by ChemicalRubber Company.

Polysaccharide can be used for forming the preparation embodiment of GRD.As selection, GRD can comprise carbohydrate natural gum or can be formed by the mixture that comprises one or more sugar, one or more polysaccharide or its combination.The preparation embodiment uses xanthan gum and locust bean gum to form GRD, and the weight ratio of xanthan gum and locust bean gum is about 1: 4 to about 4: 1.In the concrete preparation embodiment of GRD, the weight ratio of xanthan gum and locust bean gum is about 1.5: 1 to 1: 1.Usually, polysaccharide comprises about raw material of 0.1% to 5%, more typically comprises approximately 1% to 4%, more typically even about 1% to about 3%, typically is about 1% initial composition most.Percent is the percent that comprises total composition of liquid part.

B. excipient

As selection, GRD also can comprise excipient, for example plasticizer, pH regulator agent, GI wriggling regulator, viscous regulator, extender, surfactant or its mixture.

Plasticizer can be added in the compositions with the plasticity that increases mixture to the degree that is suitable for experimenter's administration.Plasticizer can be hydroxylated chemical compound, particularly polyhydroxylated organic compound.For example, Polyethylene Glycol (PEG) is the hydroxylated organic compound of polyester family that is used for preparing embodiment.The person skilled in the art can use other plasticizer succedaneum, for example glycerol or surfactant.Usually, the preparation embodiment comprises about plasticizer of 1% to 8%.

Can add the pH regulator agent and arrive the pH level of needs with the pH that regulates GRD.For example, believe that at present the pH that increases in the GRD zone can increase it and expand in the sour environment of stomach.The PH regulator also can be used for improving the viscosity of some polymeric excipient such as carbopol.Suitable pH regulator agent comprises buffer, mineral acid or inorganic base or organic acid or organic base.The pH regulator agent optionally is a buffer, in the preparation embodiment, has used sodium hydrogen phosphate and sodium phosphate.Other pH regulator agent is known for those skilled in the art, and it can include but not limited to hydrochloric acid, sodium hydroxide, potassium hydroxide, organic acid, and as acetic acid and organic amine, particularly rudimentary (10 carbon atom or still less) alkylamine is as triethylamine.

Can add viscous regulator and regulate viscosity to making GRD keep the levels of adhesion of preset time at gastric.Viscous regulator can include but not limited to carbopol, polyvinylpyrrolidone, alginate, cellulose, natural gum and hydrogel.Viscous regulator carbopol and polyvinylpyrrolidone have been comprised in the preparation embodiment.Other viscous regulator can be selected by those skilled in the art.Usually, the preparation embodiment comprises about 0.25% to 1% carbopol and/or polyvinylpyrrolidone.

C. diagnostic agent and therapeutic agent

GRD also can introduce diagnostic agent or therapeutic agent, and it is selected from nucleic acid, protein, naturally occurring organic compound, synthetic and semisynthetic chemical compound and combination thereof.More specifically, diagnostic agent or therapeutic agent can be the AIDS adjuvant; the alcohol abuse preparation; the Alzheimer inorganic agent; the amyotrophic lateral sclerosis therapeutic agent; analgesic; anesthetis; antacid; anti-arrhythmia agent; antibiotic; anticonvulsant; antidepressant; the anti-diabetic medicament; antiemetic; antidote; the fibrosis therapeutic agent; antifungal; hydryllin; hypotensive agent; anti-infective; antibacterial; antineoplastic agent; tranquilizer; the anti-Parkinson medicament; antirheumatic; appetite stimulator; appetite suppressant; biological respinse modifier; biological preparation; Hemoregulatory; the bone modulators of metabolism; heart protective agent; cardiovascular agents; central nervous system stimulant; cholinesterase inhibitor; contraceptive; the cystic fibrosis inorganic agent; deodorizer; diagnostic agent; nutritional supplement; diuretic; dopamine-receptor antagonist; the endometriosis inorganic agent; enzyme; therapeutic agent for erection failure; fatty acid; gastrointestinal agent; ceramide glucoside enzyme deficiency disease inorganic agent; the gout preparation; homeopathic drug; hormone; the hypercalcemia inorganic agent; somnifacient; hypocalcemia disease inorganic agent; immunomodulator; immunosuppressant; ion exchange resin; levocarnitine lacks inorganic agent; mast cell stabilizers; the migraine preparation; the motion sickness goods; the multiple sclerosis inorganic agent; muscle relaxant; the anesthetics antidote; anesthetis; nucleoside analog; NSAID (non-steroidal anti-inflammatory drug); fat inorganic agent; the osteoporosis preparation; odinagogue; parasympathomimetic agent; parasympatholytic; phosphate binder; the hematoporphyria medicament; psychotherapy's agent; the radiopaque medicament; treatment psychosis medicament; sclerosing agent; tranquilizer; the sickle cell disease inorganic agent; the aiding smoking cessation medicament; steroid; analeptic; sympatholytic; sympathomimetic; Tourette syndrome medicine; preparation trembles; the urinary tract medicament; vagina preparation; vasodilation; dizzy medicine; anoretic; wilson disease inorganic agent and composition thereof.The instantiation of these therapeutic agents or diagnostic agent includes but not limited to abacavir sulfate, abacavir sulfate/lamivudine/zidovudine, acetazolamide, acycloguanosine, albendazole, salbutamol, spironolactone, allopurinol BP, the amoxicillin, amoxicillin/clavulanate potassium, amprenavir, atropic cuts down ketone, atropic cuts down ketone and proguanil hydrochlorate, the atracurium benzene sulfonate, beclomethasone dipropionate, the berlactone Betamethasone 17 valerate, the BUP hydrochlorate, BUP hydrochlorate SR, carvedilol, caspofungin acetate, cefazolin sodium, ceftazidime, cefuroxime (non-sulfuric acid salt), chlorambucil, chlorpromazine, cimetidine, the cimetidine hydrochlorate, the cisatracurium benzene sulfonate, CBP, bactrim, the colfosceril palmitate, dextroamphetamie sulfate, digoxin, English sodium Puli maleate, epoprostenol, esomeprazole magnesium, fluticasone propionate, furosemide, Hydrochlorothiazide/triamterene, lamivudine, lamotrigine, lithium carbonate, LOSARTAN POTASSIUM, melphalan, purinethol, mesalazine, the mupirocin calcium cream, Na Biemin, naratriptan, omeprazole, ondansetron hydrochloride, ovine, oxiconazole nitrate, paroxetine hydrochloride, prochlorperazine mesylate, the kemadrin hydrochlorate, pyrimethamine, the ranitidine bismuth citrate, ranitidine hydrochloride, Luo Fukaoxi, the ropinirole hydrochlorate, the rosiglitazone maleate, salmeterol xinafoate, salmaterol, FLUTICASONE PROPIONATE, aseptic ticarcillin disodium/clavulanate potassium, suffering is cut down its spit of fland, spironolactone, succinylcholine chloride, sumatriptan, 2-am-inopurine-6-thiol, tirofiban HCI, the topotecan hydrochlorate, tranylcypromine sulfate, trifluoperazine hydrochloride, the valaciclovir hydrochlorate, nvelbine, Zha Namiwei, azidothymidine AZT, azidothymidine AZT, rummy husband fourth or its mixture.

The diagnostic agent of effective dose or therapeutic agent can be introduced among the GRD with the form of solution, suspension, Emulsion, tablet, capsule, powder, globule, piller, granule, solid dispersion or its combination.As selection, diagnostic agent or therapeutic agent are easier to be molten in gastric juice than in intestinal juice, and be easier to be molten in intestinal juice than in gastric juice, better in big enteral absorption in the small intestinal internal ratio, better than absorbing at enteral at gastric, or absorb better at gastric at the enteral ratio.

D. liquid

Polymeric material, excipient and/or diagnostic agent or therapeutic agent dissolve in and/or are suspended in any liquid, and they are solvable to small part in these liquid.Preferred liquid is water.Other liquid comprises polar organic compound, as alcohols.Usually, after adding polymeric material, diagnostic agent and/or therapeutic agent and excipient, liquid is added into as the surplus of mixture.

IV. form GRD

Usually, the formation of GRD is as follows: selected composition is merged mix; Induced gelatination; The gel of dry gained; With as selecting the exsiccant molding gel dress of gained capsule in being subject to the erosive coating of gastric acid.Each step in these steps will be described below in more detail.

A. mix

The method of formation gel mixture comprises with the selected polymeric material of the liquid of requirement and appropriate amount or material merging and mixes.Excipient or excipient and/or diagnostic agent or therapeutic agent or medicament can be directly and polymeric material merge, perhaps as selecting, they can mix respectively and merge with the mixture of polymeric material subsequently.Only before gelatine, prior dosage form such as capsule or tablet are joined in the polymeric material, or after forming gel, will have dosage form now and be embedded in the gel.

B. gelation

The gelling of gel can be by any method known to those skilled in the art, and for example, chemical gelization or Thermogelling are induced and finished.It mainly is for fear of using chemical gel to form agent that preparation embodiment uses heat-induced gelationization.For example, in concrete preparation embodiment, gelation comprises that heating blends is enough to make the solid constituent dissolving to small part, for example, be heated to about 50 ℃ and arrive about 100 ℃ temperature, typically about 80 ℃, and mixture is remained under this temperature up to abundant dissolving, thus carry out gelation subsequently.Be about 10 minutes to about 30 minutes typical heat time heating time during small lot, but can change according to batch size heat time heating time; After the heating, cooling mixture forms gel thus with induced gelatination usually.Preparation embodiment is cooled to about room temperature with mixture.

C. dry

Can remove liquid to form desciccator diaphragm from the gel that forms, method therefor is known in those skilled in the art, and it comprises aeration drying, lyophilization, vacuum drying or any other drying well known by persons skilled in the art or dewatering.Some preparation embodiment is at room temperature dewatered by vacuum drying.Other preparation embodiment is dewatered by oven drying under about 35 ℃ to about 75 ℃.In other embodiments, gel dewaters by lyophilization.

Dry or dehydration is meant total liquid flux of removing more than 50%, normally removes 90% or the liquid of higher any existence.The liquid that uses in the preparation can be retained in the device as required, and gel film keeps certain pliability and intensity because described liquid can help " drying ", or promotes swelling, or because there is no need fully to remove these liquid.

D. compression

As selection, can be suitable for size and shape that the experimenter is used desciccator diaphragm being compressed into the GRD coating or before being placed in the capsule.Can use and well known to a person skilled in the art any compression method, although in the preparation embodiment, it is to compress in 2,1,0,00 or No. 000 capsules by rolling or by pushing or exsiccant film being folded into suitable size that desciccator diaphragm uses extrusion die.The capsule of reduced size can be fit to make device to be delivered to enteral through stomach.In other preparation embodiment, desciccator diaphragm can compress with the pressure of about 500-3000 pound/square inch at punch press and Mo Nei.

E. adorn capsule

The GRD of dehydration is by well known to a person skilled in the art any method, for example spraying or dip-coating or have coating in the capsule by being embedded into, and described coating is subject to the erosion of the gastric juice that contacts with its outer surface.In addition or as selecting, GRD can have enteric coating, as is administered to the Eudragit of outer surface ^Or Opadry ^, maybe can be embedded in the capsule.In the preparation embodiment of GRD, GRD is embedded into size and is in 2,1,0,00 or No. 000 the capsule.Those skilled in the art can select any known method to make GRD coating or dress capsule.

V. administration

Usually, GRD is an oral administration.Yet in certain embodiments, GRD can be administered to other intracavity except that stomach, as the oral cavity, and rectum, vagina, nasal cavity or intestinal.This device is full of described chamber and is used as the imaging auxiliary agent by containing dyestuff or other image forming material and swelling.Perhaps be part or systemic effect, this device can be used for therapeutic agent or diagnostic agent are delivered to the chamber wall to intracavity by swelling and releasable material.For example, this device can be placed in the capsule, this capsule is carried out enteric coating, make this device not discharge, and expand to contact with intestinal wall at enteral at gastric.The swelling of GRD also can be used for making GRD to be kept in the position of required intracavity.In certain embodiments, the preferred size of swelling device can be different from and is designed for the size that this device is kept at gastric, and described size will be littler usually.For example, the device of enteral existence can be used for reducing hunger sensation and appetite-suppressing; In this embodiment, when particularly using multiple dose in time, the size of the GRD of hope is generally less than the size of the used GRD of gastric.Even preferred less size is for the usefulness of nasal cavity.

By following non-limiting example explanation the present invention.

Embodiment

Embodiment 1

This embodiment relates to the method for making GRD.The acquisition of listed material and process as described below.

I. with xanthan gum (XG, Spectrum Chemical Mfg.Corp., Gardena, CA) and locust bean gum (LBG, Sigma Chemicals, St.Louis, dried powder MO) closely mixes, and is compressed into circular tablet.

II. at 80 ℃, that XG and LBG is water-soluble, gelation, dry and pulverizing forms viscous gel, and is poured in the Petri dish, and is dry in baking oven.Then exsiccant chunk is squeezed into powder, and this powders compression is become tablet.

When III. stirring, it is in 70-75 ℃ the water that the LBG (0g-1g) that accurately weighs is joined the 100ml temperature.The solution that generates is heated to 80-85 ℃ temperature to be used to add XG, under constant agitation, slowly adds XG.The high viscous solution of preparation thus is poured in the suitable shaping dies, after the cooling, the gelling that generates is cut into the size that needs.Make these gellings dryings and carry out hydration studies.

When IV. stirring, it is in 70-75 ℃ the water that the LBG (0g-1g) that accurately weighs is joined the 100ml temperature.At 80-85 ℃, when stirring, in gained solution, add XG.The Polyethylene Glycol (PEG) 400 that adds 10ml in the mixture that obtains, cooling (gelation) then cuts into the size and the drying that need.

V. before the gel drying film forming, with multiple different reagent (0.5g-4g) in each experiment, comprise sodium bicarbonate (Mallinckrodt, Paris KY), tartaric acid, Water-Loc respectively ^(Grain Processing Corp., Muscatine IA), hydroxypropyl emthylcellulose, poly(ethylene oxide) N-80 (Union Carbide Corp., Danbury CT) is incorporated in the gel, to estimate the influence of described each composition to the hydration rate in the simulated gastric fluid (SGF).

The direct tablet made of the LBG that obtains from supplier of compression and the blended powder of the XG fusible hydrated gel of generation water or gastric juice of failing.In fact, when putting into water or gastric juice, tablet disintegrates.

Two kinds of natural gum dissolve the interaction that produces and cause taking place gelation in water.At 80 ℃ XG and LBG be dissolved in and obtain solution in the water, described solution is produced gel under cooling, and it is by the dry film that produces.Gel strength depends on two kinds of natural gum interactional temperature takes place, and, makes agglomerative temperature that is.The gelling that the interaction that takes place more than the Tm of XG obtains has better gel strength.At 70-75 ℃ of dissolved gum, at first dissolve LBG, dissolve XG then, the gelling that obtains has better gel strength.

The gel that so makes is dry in baking oven, produces gel film, efflorescence then, and be compressed into tablet.Such tablet disintegrates when contacting with water or simulated gastric fluid; Yet, hydration widely takes place when individual particle contacts with medium.

B. in other embodiments, make GRD according to following method:

Material

Following chemicals from shown in standard source obtain.All chemicals former states are used.

Xanthan gum (XG; Spectrum Chemical Mfg.Corp., Gardena, CA), locust bean gum (derives from the galactomannan of carob seed, Sigma catalog number (Cat.No.) G-0753, SigmaChemicals, St.Louis, MO), polyvinyl pyrrolidone (PVP) and riboflavin (SigmaChemicals, St.Louis, MO), SDS (SLS, Matheson Coleman﹠amp; Bell, Cincinnati, OH), PEG400 (PEG400) and poly(ethylene oxide), molecular weight 200,000 (Union Carbide Corp.Danburg, CT), microcrystalline Cellulose [Avicel, PH101] (FMC Corp.Newark, DE), the barium of dipping polyethylene ball, diameter is 1.5mm (BIPS) (Chemstock Animal Health LTD, New Zealand), radiopaque line (the veterinary's medical college by Oregon university provides).

Prepared two types GRD: a kind of conventional GRD and a kind of modified model GRD.The preparation method of conventional GRD is that LBG (0.5gm) and XG (0.75gm) are dissolved in the 100mL water.The preparation method of improving GRD is in order PVP (0.5gm), LBG (0.5gm), SLS (0.15gm) and XG (0.75gm) to be dissolved in the 100mL water under constant agitation.Two kinds of solution are heated to 85 ℃ temperature.In each hot viscous solution, add 6mL PEG400 then.Then join in the hot viscous solution and produce homogeneous quality at the riboflavin of constant agitation following the powder of accurately weighing, globule or solid dispersion form.

The mould of highly viscous solution impouring suitable shape, the gel that obtains is at room temperature placed cooling 4 hours, and is cut into desired size then.The gel of cutting in vacuum drying oven about 16 hours of 50 ℃ of dryings.Dry run produces flexible film, and it is offhand and be put into capsule easily.The GRD that is made up of the capsule that comprises desiccant gel (film) and medicine is fit to use.

Fill the capsule (' 0 ', ' 00 ' and ' 000 ' size) of three kinds of different sizes with the GRD of the different size that comprises riboflavin.

Two kinds of main components of described GRD are XG and LBG.Use XG and LBG with 1.5: 1 ratio respectively.The ratio that increases XG surpasses 1.5 and produces very heavy-gravity gel and produce harder film after drying.Because XG and LBG are the high viscosity colloids, therefore be difficult to prepare the solution that comprises more than 3% natural gum.The ratio that XG uses is than LBG height, because can obtain better p H stability when the colloid ratio tends to XG.XG is stable in whole pH scope, and LBG has relatively poor absolute acid stability.Surpass 9 hours because some GRD will keep under the sour environment of stomach, higher XG ratio can produce stronger gel after the hydration in gastric juice, and the gel that obtains can not degraded rapidly.The solution that comprises less than 1% natural gum has less viscosity, and desciccator diaphragm is thinner, and when its in simulated gastric fluid during hydration, can forfeiture its common rigidity and integrity in less than 6 hours.When adding PVP and SLS attempt when increasing speed that riboflavin discharges from GRID and amount, surprisingly, when gel is dried, produce and have more elastic film.Further improve the amount that adds PVP and SLS in gum-solution, dry back produces very softish film.When these softish films immerse SGF, the weak glue of generation, their integrity of forfeiture in about 4 hours in SGF.

Gum-solution is heated to 85 ℃.The viscosity of solution descends rapidly under this temperature, and this makes that viscous solution can be by the impouring mould.When solution from 85 ℃ of whens cooling, at approximately 40-50 ℃, viscosity increases sharply once more.Before gel is shaped fully by cooling, can be to the therapeutic agent that wherein adds solution, suspension, powder, tablet, capsule, globule, piller, granule, Emulsion, solid dispersion or its combining form, diagnostic agent or preparation.

Embodiment 2

This section relates to the film forming method of the dry shape of gelling that makes.

A. use embodiment 1A, the method for describing in the IV part for preparing gel makes the film forming distinct methods of gel drying shape be used to produce the film with different hydration cycles.The method of using is included in 45 ℃ of oven dryings, at 35-60 ℃ of following vacuum drying with-20 ℃ of following lyophilizations.

Gel is dry in being higher than 40 ℃ the baking oven of temperature to form the loss (positive according to expectation because the boiling point of liquid PEG is about 45 ℃) that film causes PEG.Gel need just can form film greater than 24 hours in lower temperature such as 30-35 ℃ of drying.

When the baking oven vacuum drying of gel at 30 ℃, the loss of PEG is inappreciable.Be about 12-18 hour drying time.

When gel refrigeration drying formed film, PEG is loss not.These films can easily be compressed to be fit to capsule.Lyophilization comprises at first-20 ℃ of freezing gels 2 hours, carries out lyophilization at-46 ℃ then.

B. the GRD that makes according to the dry embodiment 1B of following method:

In 50-55 ℃ of baking oven, obtained pliable and tough and soft film in the about 16-17 of vacuum drying gel hour.Pliable and tough and soft film be beneficial to roll and with the capsule fit, and be easy to rapid swelling in immersing SGF the time.When attempting in the dry short period of higher temperature (60-70 ℃) (12-15 hour), obtain harder film, easier fragmentation when it is involved in capsule, and equally can swelling when immersing SGF.When attempting, needed about 48 hours just can obtain desciccator diaphragm, and desciccator diaphragm is not as fast in the film swelling of 50-55 ℃ of production in lower temperature (30-40 ℃) drying.

Embodiment 3

This section relates to makes the desciccator diaphragm compression form the size that is suitable for administration.

Dry embodiment 1A, the gel of IV part, the desciccator diaphragm of formation embodiment 2A, described desciccator diaphragm must help special punch press and punch die compresses.The punch die that uses a series of internal diameters decrescence to narrow down.Punch press pushes next punch die to film from a punch die, then film is pushed next punch die by another punch press.This process recurs up to film little of the capsule size that enough can enter expectation, for example ' 000 ' capsule.Other numbers capsule can use the film or the scrotiform tablet of other size.

Embodiment 4

This section relates to the hydration studies that GORD is carried out.

A. in certain embodiments, hydration studies is carried out as follows:

According to embodiment 1A, IV partly prepares gel, as described in embodiment 2A, make gel drying form desciccator diaphragm, and shown in embodiment 3 the compression drying film, carry out the hydration studies of film in water and simulated gastric fluid, described film is difformity and never comes with the xanthan gum of ratio and locust bean gum preparation.In simulated gastric fluid, carry out hydration studies at 37 ℃.Being calculated as of hydration percentage:

The initial weight of hydration percentage=100 * (initial weight of the final weight-film of film)/film.

Be cut into film hydration in water or gastric juice of different size and shape.Also (1 part of SGF and 3 parts of water) carry out hydration studies and are used for comparison in the gastric juice of dilution.The shape of research is as annular, star, cube shaped, rectangle, triangle etc.

In all shapes of research, finds that cube shaped gel swelling is the fastest and volume is maximum, described cube shaped gel has been dried to the orthogonal film of being substantially of slightly flat, for irregular, and is uneven highly, in width and depth.Yet, based on to its research of suitable capsular size, preferred shape be dry before the cuboid gel of the about 4cm * 4cm of size * 1cm.

As shown in table 1, xanthan gum prepares gel with locust bean gum with different solids ratios, and drying and forming-film.Fig. 1 and 2 represents the fully hydration 24 hours in water or simulated gastric fluid of described film respectively.Film is in the initial hydration expression in Fig. 3 and 4 respectively of water or simulated gastric fluid.When capsule or tablet were taken on an empty stomach, it can depend on the time of advent of MMC (travel motion complex wave) from a few minutes to two hour by the interval that stomach enters intestinal.The GRD capsule dissolves in the capsule is incorporated in to reach in 15-20 minute and is enough to big size in case just should begin water ideally to avoid passing through sphincter of pylorus.The structural intergrity of hydrated gel is enough stood MMC.Therefore, initial hydration rate and structural intergrity are very important.

The composition of table 1:XG/LBG film

Film #	??XG(％ ??w/w)	??LBG(％ ??w/w)	Film #	??XG(％ ??w/w)	??LBG(％ ??w/w)
						??1	??100	??0	??7	??40	??60
??2	??90	??10	??8	??30	??70
						??3	??80	??20	??9	??20	??80
??4	??70	??30	??10	??10	??90
						??5	??60	??40	??11	??0	??100
??6	??50	??50

According to hydration studies figure and gel strength, consider the gel of 50: 50 ratios is further modified.Visual observations and the gel by physical examination film hydration after form of gel strength during based on film hydration.

Shown in Fig. 1 to 4, the hydration of film in SGF is widely, but than poor in water.Hydration in water is approximately than big 10 times in SGF.Therefore, in order to be manufactured on the faster and larger sized film of formation of energy swelling among the SGF, attempted the interpolation buffer agent, sodium hydrogen phosphate or sodium phosphate.The film about 12 hours thorough swellings in SGF that contain sodium hydrogen phosphate or sodium phosphate (doubling gummy amount of solid).After 12 hours, the pH that discovery is used for the SGF (about 500ml volume) of hydration studies is 6.8.In vivo, gastric acid will be secreted with the one-level process continuously with the liquid of removing from gastric, so the pH of gastric can not reach 6.8 as external, and external, the volume of acid is fixed.Yet the pH of micro environment may remain alkalescence or neutral in the film when film hydration, and promotes film swelling and significantly do not change the pH of stomach rapidly in gastric juice.Adding of basifier is limited in the amount of basifier and mould is shortened into and be fit between the capsular ability dependency is arranged.The hydration of film and improvement more significantly in gastric juice separately in the medium that contains 25% simulated gastric fluid and 75% water.The medicine water is taken in, and therefore, the hydration studies of carrying out in water: SGF is 3: 1 medium has been simulated the anticipation condition during with the absorption of 8-10 ounce water as GRD.

During gel formation to wherein adding other additive, as poly(ethylene oxide), carboxymethyl cellulose (CM) and/or Water-Loc ^, can be used for improving the initial hydration of film in SGF.Table 2 has been described the various preparations that contain different additive.All above researchs are checked the hydration of film by periodical visual inspection and are estimated.

Gel can become too crisp and can not fold or be compressed in the capsule.In gel, add Polyethylene Glycol (PEG) and behind gel drying, produce submissiveer film.

B. in other embodiments, carry out hydration studies according to following method:

According to the method for embodiment 1B,, it is carried out hydration studies at 37 ℃ in simulated gastric fluid from XG, LBG, PVP, SLS and PEG400 preparation four kinds of difform desiccant gels (film).By preparation desiccant gel that composition is dissolved in the water.Then at 85 ℃ of heating blends, the viscous solution of 10mL heat is poured in the difform mould, to produce the shape that needs.Described four kinds of shapes are cube shaped, cuboid, short cylinder and elongated cylinder.Make gel drying then and carry out hydration studies.

Table 2: the various examples of formulations that are used for hydration studies at GRD between development period

(total percentage)

Dosage form	?XG	LBG	Sodium alginate	?Explotab	?PEG	?Water-Loc400	?HCO 3	?NaPO 3	?CM
										#
1	?0.	0.5	?0.5	?1	?PEG300-1	?-	?-	?-	?-
										#2	?0.	0.5	?-	?1	?PEG300-1	?-	?-	?-	?-
#3	?0.	0.5	?-	?2	?PEG300-1	?-	?-	?-	?-
										#4	?0.	0.5	?-	?1	?PEG400-1	?-	?-	?-	?-
#5	?0.	0.5	?-	?0.5	?PEG400-1	?-	?-	?-	?-
										#6	?-	-	?4	?0.5	?PEG300-2	?-	?-	?-	?-
#7	?-	-	?4	?1	?PEG300-2	?-	?-	?-	?-
										#8	?-	-	?4	?2	?PEG300-2	?-	?-	?-	?-
#9	?0.	0.5	?-	?-	?PEG400-5	?-	?1	?-	?-
										#10	?0.	0.5	?0.5	?-	?PEG400-5	?-	?1	?-	?-
#11	?0.	0.5	?-	?1	?PEG400-5	?1	?-	?-	?-
										#12	?0.	0.5	?-	?-	?PEG400-5	?1	?1	?-	?-
#13	?0.	0.5	?-	?-	?PEG400-5	?-	?-	?1	?-
										#14	?0.	0.5	?-	?1	?PEG540-5	?-	?-	?-	?1

Hydration becomes four kinds of difformities in simulated gastric fluid.Fig. 5 has represented the size and dimension of the GRD of detection.After 15,30,45,60,120 and 180 minutes, measure the increase of the percetage by weight of hydrated film, after 12 and 24 hours, measure once again.

Hydrated film keeps its integrity to reach 24 hours in simulated gastric fluid.In the middle of all shapes of research, find that the dry cuboid gel that becomes about flattened rectangular film has the fastest swelling and maximum volume.Select cuboid to be used for studying in further external and the body according to this research.

Fig. 6 represents the fully hydration 24 hours in simulated gastric fluid of described film.Fig. 7 represents the initial hydration of described film in SGF.Initial hydration is an important factors among the exploitation GRD.It is desirable to preferably make a kind of being small enough to and be fit to capsular device, but when contacting, expand into enough big size and can not pass through pylorus with gastric juice with easy-to-swallow.Use for some, swell to big like this size (for example from about 15 to about 30 minutes) gastric emptying of bringing with the strong contraction of avoiding by house keeper's ripple soon, lasting about 5 to 15 minutes of described house keeper's ripple.Therefore the quick swelling of the desiccant gel that is discharged and the integrity of swell gel are very important.

Embodiment 5

This section relates to the method among diagnostic agent or the therapeutic agent introducing GRD.

A. embodiment 1A is introduced in the amoxicillin of the tablet form of scrotiform tablet shape, among the GRD of IV part.Selecting the amoxicillin for use is because it has " absorption window " as drug model.

Will be according to embodiment 1A, in the gummy viscous solution impouring suitable mold of the heat of the described method preparation of IV part, make the tablet of introducing in the gel in gel, keep suspending.Then the gel that contains tablet is cut into desired size.Dry 12-18 hour, the desciccator diaphragm that then these is contained tablet compressed to be fit to ' 000 ' capsule with hydraulic pressure in punch press and punch die.

B. the riboflavin of powder, globule or solid dispersion form is introduced among the GRD of embodiment 1B.Before being about to be cooled to gel, by stirring riboflavin is introduced the cementitious mixtures that gel forms heat, described riboflavin still keeps suspending in gel.The desiccant gel (film) that comprises medicine globule, powder or solid dispersion can easily roll and with the capsule fit of suitable dimension.Then the GRD that contains medicine globule, powder or solid dispersion is carried out studying in external stripping research and/or the body.

Embodiment 6

This section relates to the preparation of the amoxicillin scrotiform tablet that uses with GRD and ' containing core ' scrotiform tablet.

By preparing amoxicillin scrotiform tablet the combination of table 3 ingredients listed and by direct compression forming.

Table 3: the prescription of amoxicillin scrotiform tablet

Composition	Quantity (mg)
		BRL-2333	????287
??Avicel?PH112	????50
		Magnesium stearate	????2.5

For forming the amoxicillin scrotiform tablet that ' contains core ', make amoxicillin scrotiform tablet and microcrystalline Cellulose concentrated in bigger punch die and punch press, and recompression so that amoxicillin scrotiform tablet be in the shell that forms by microcrystalline Cellulose.The novel scrotiform tablet of Xing Chenging contains amoxicillin scrotiform tablet as nuclear thus, and said preparation is commonly referred to " containing the chip agent " or " sheet in the sheet ".

Embodiment 7

This section relates to the preparation of the lactoflavin preparation that uses with GRD.

The riboflavin of powder, globule or solid dispersion form is introduced GRD.Form wet agglomerate and prepare the riboflavin globule with water by riboflavin, Avicel PH-101 and the poly(ethylene oxide) 200,000 of mixing known quantity.(120 types, Caleva Process LTD England) extrudes and makes ball to described agglomerate, produces medicine globule (diameter is 1.5-2.0mm) to use laboratory extruder (10/25 type) and marble forming machine then.Globule is placed 50 ℃ of baking oven dried overnight.Before being about to be cooled to gel, by stirring the viscous mixture of globule being introduced gel formation heat, described globule still is suspended in the gel.

Prescription prepares the riboflavin globule by extruding and make ball shown in the use table 4.When using the riboflavin of powder type, before being introduced into gel 120 ℃ of dryings 2 hours with dry-off moisture.

Table 4: the prescription of riboflavin globule

Composition	Quantity (mg)
		Riboflavin	????70
????Avicel?PH101	????25
		????Polyox(N-80)	????5

The PEG3500 that weighs by fusing in evaporating dish prepares the riboflavin solid dispersion, adds medicine that the medicine weigh obtains expecting and the ratio of PEG (1: 3) then.Heating systems thoroughly dissolves up to medicine.Then evaporating dish is transferred in the ice bath and also stirred up to material cooled.The solid mass that finally obtains is crushed, pulverizes and sieved, produce fine powder.Before introducing gel, solid dispersion is dried overnight in vacuum drying oven at room temperature.

Embodiment 8

This section relates to the stripping research that the GRD that contains diagnostic agent and/or therapeutic agent is carried out.

A. present embodiment shows that the therapeutic agent of tablet form can be introduced in the gastric retention device that is formed by polysaccharide, and this device can form the size that is fit to experimenter's administration, and packs into and be subject to that gastric juice is erosive to be absorbed in the capsule.Use embodiment 1A, the method for IV part prepares and contains the GRD of drug model amoxicillin or ranitidine hydrochloride, stirs with 75rpm by USP XXII oar formula and carries out stripping research in 20 hours 37 ℃ of stirrings.Dissolution medium is made up of the artificial gastric acid of 900mL (not containing enzyme).Collect sample at 0.5,1,2,3,4,6,8,12 and 20 hour and use the equal-volume medium to replace.Use the HP diode array spectrophotometer at 280nm to the sample analysis amoxicillin, and analyze ranitidine hydrochloride (Zantac at 219nm ^).

Being included in a) amoxicillin or b among the GRD) ranitidine hydrochloride compares with the independent dissolution studies of preparation.As preparation amoxicillin scrotiform tablet as described in the embodiment 6.Table 8 expression amoxicillin discharges the comparison of the stripping mode of same preparation among (IR) tablet and the GRD immediately.Amoxicillin IR discharged 80% medicine at 1 hour; Yet only there was 10% medicine to discharge at 1 hour, and do not reach 80% release yet up to 12 hours from GRD.This medicine is a zero level from the release mode of introducing the IR tablet of GRD.

Fig. 9 represents the stripping of the self-contained chip agent in amoxicillin (embedding the amoxicillin scrotiform tablet of microcrystalline Cellulose shell) and the comparison of the stripping of the GRD that contains the chip agent certainly.The chip agent that contains of amoxicillin discharged 80% medicine at 1 hour, and medicine is a zero level the release that contains in the chip agent in GRD in 24 hours, and discharged 80% medicine in about 20 hours.

From commercially available ranitidine hydrochloride (Zantac ^150) immediately release tablet with introduce GRD in identical tablet stripping more as shown in figure 10.Not in GRD, from Zantac ^1 hour consuming time of 150 complete stripping medicines, and in GRD, pro-was observed from tablet in 7 hours only 80% drug release.

B. to the GRD that contains drug model riboflavin, use USP XXII slurry formula stirring means to stir and carried out stripping research in 20 hours at 37 ℃ and 50rpm according to embodiment 1B method preparation.Dissolution medium is made up of the simulated gastric fluid that 900ml does not add enzyme.Collected sample at 1,2,4,6,8,10,12,16,20 and 24 hour.Use the HP diode array spectrophotometer at 446nm to sample analysis riboflavin.

The stripping research that will be included in riboflavin globule, powder and solid dispersion among the GRD (conventional or improved) compares with the stripping research of the immediate release capsule that contains the same amount vitamin.In all researchs, the amount of riboflavin equals 50mg and the GRD that uses is cuboid (3*1.5*1)." 0 " number capsule is used for being fit to immediate release formulation and GRD preparation.

Stripping from conventional GRD:

The stripping pattern that is contained in the riboflavin globule in the capsule and the stripping pattern that is included in the riboflavin globule among the conventional GRD of cuboid more as shown in figure 11.The riboflavin globule discharged 100% medicine at 9 hours, and conventional GRD only discharged 8% medicine at 5 hours, discharged about 30% at 24 hours.The release mode of medicine in conventional GRD almost is zero level.

Stripping among the conventional GRD of the stripping of the riboflavin powder in release capsule (50mg riboflavin+200mg lactose) immediately and the riboflavin powder of self-contained same amount compares.The riboflavin immediate release capsule discharged 100% medicine at about 1 hour, and GRD discharged about 50% medicine in the capsule at 24 hours.The release of riboflavin powder in conventional GRD also almost is zero level.

Stripping from modified model GRD:

The modified model GRD of preparation is used to change rate of drug release and amount.Modified model GRD contains PVP and SLS with the different modified model GRD that are of conventional GRD.The stripping of riboflavin powder in modified model GRD as shown in figure 12.Modified model GRD discharged about 65% medicine in 24 hours.The pattern that discharges seems also to be zero level.Increase from modified model GRD stripping may be because the existence of hydrophilic polymer PVP and surfactant SLS.PVP and SLS can help vitamin to spread in hydrogel.The existence of PVP and SLS has also produced more flexible desciccator diaphragm in the prescription, when comparing with the conventional film that the prescription of PVP and SLS never makes, described film easier with the capsule fit.Flexible increase helps to make bigger GRD and capsule fit.

Riboflavin and PEG3500 ratio be 1: 3 the stripping of solid dispersion in modified model GRD as shown in figure 13.Observe in 24 hours and from said preparation, to discharge 100% medicine, yet GRD loses its integrity in about 6 hours.

When riboflavin and PEG3500 solid dispersion join in the thickness gum-solution of heat, produce softish film behind the gel drying.After some times of hydration, gel disintegrates and forms fragment in GF.

Embodiment 9

This section relates to the dog of being tried that is used for detecting in the body GRD.

A. be used for detecting in the body embodiment 1A, the GAD that IV partly makes is tried dog

Two hybrid dogs at use 2.5 years old age and 5 years old are studied the gastric transit time of the GRD of different size and shape.Animal is in the zooscopy laboratory of the institute of veterinary of Oregon university, and keeps canned protein diet (d/d Hills) two weeks.They are fed allowing it to carry out in the independent fence of reasonable freely-movable and normal activity, thereby expectation obtains normal gastrointestinal peristalsis.

B. the dog of being tried that is used for research embodiment 1B makes in the body GRD

The age be 8 and 9 years old between two adult German shepherds on study.They are fed with commercially available food and are in the zooscopy laboratory of Oregon institute of veterinary of university.They are fed in contiguous independent fence, and it has gummed metal gauze, is below to have the soil floor with fixed attention on slope so that sweep health.Thereby the space of animal fence allows dog to carry out rational freely-movable and normal activity and obtains normal gastrointestinal peristalsis.The residential area of dog keeps illumination in the daytime, keep dark at night.

Embodiment 10

This section relates to dosage form and the prescribe medicine that is used for detecting GRD in being tried the dog body.

A. be used for detecting in the body embodiment 1A, the dosage form of the GRD that IV partly makes

The described experimenter of embodiment 9A is used GRD, use and introduce " 0 " number capsular four kinds of difform GRD.In these researchs, also detected the cuboid GRD of introducing ' 000 ' capsular 7 * 1.5 * 1cm.All dosage forms comprise radiopaque line to carry out the X ray developing.

In the dog body, detect and introduce ' 0 ' number capsular four kinds of difform GRD to measure gastric transit time.The size column of described four kinds of shapes is in Fig. 8.All GRD comprise the roentgenopaque line that is no less than 10 fritters, and these lines help GDR developing under X ray in the gastrointestinal tract, also help to observe the hydration and the disintegrate of gel.

The dog overnight fasting.Use the dosage form that is loaded with radiopaque line with 4 ounces of mouth of a river clothes in the morning.

Food mixes with BIPS and gives after 2 hours at prescribe medicine, to study GRD to the effect of food from gastric emptying.Detect the GRD of two kinds of different sizes, a kind of is to introduce ' 0 ' number capsule, ' 000 ' number capsule of another kind of introducing.These two kinds of sizes are equivalent to 3 * 1.5 * 1cm and 7 * 1.5 * 1cm respectively.

B. the dosage form that is used for the GRD that detection embodiment 1B makes in the body

The described experimenter of embodiment 9B is used GRD.Use is included in the gastric retention device in ' 000 ' capsule, and this capsule contains the polyethylene ball (BIPS) of barium sulfate scrotiform tablet, roentgenopaque line or bismuth dipping.Then system is used X ray.

The dog overnight fasting is also used this dosage form with 10 ounces of mouth of a river clothes in the morning.Put in poison and provide food after 3 hours.Just taking the ray photograph before prescribe medicine, is empty to guarantee stomach.Use carry out X ray behind the gastric retention device and behind prescribe medicine to dog feed 3 hours.Food can easily be identified as the dark areas of gastric under X ray.

In the body of identical dog, comprise dissimilar saturating X ray reagent in different number of days research, as barium sulfate tablet, roentgenopaque line and the preparation of saturating X ray BIPS not.Under fasted conditions, contain the saturating X ray marker of capsule mensuration of roentgenopaque line at the intravital normal gastric emptying of dog by feed.

BaSO ₄The manufacturing of tablet is to be compressed into the scrotiform figure of tablet in the Carver press.Attempt diverse ways and introduce tablet.Basically, described method comprises layer of gel impouring mould, tablet distance is on demand put into mould and added another gel layer immediately.These gels are dry under vacuum.The compression drying film enters ' 000 ' capsule.These films are carried out hydration studies, find that the hydration caudacoria is divided into two layers, and release tablet prematurely.

Make the online help low suspension of scrotiform tablet so that it is parked in the central authorities of mould inboard.When by impouring, hot gel is captured the scrotiform tablet.Find BaSO ₄During gel expands research, from gel or tablet, leak, so that be difficult to determine the position of GRD.Consider these shortcomings, dog is carried out in vivo test.As expected, because BaSO ₄Tablet dissolved also is dispersed throughout GIT, is difficult to follow the trail of system at the dog gastric.

Embodiment 11

This section relates to the actinogram that is used to detect GRD in the dog body.

A. be used for detecting in the body embodiment 1A, the actinogram of the GRD that IV partly makes

As described in embodiment 10, use GRD.Use Transworld 360 V-type X ray generating units to carry out the actinogram inspection.The x-ray cassette that uses is 3M Trimax 12, and is supporting with 3Multradetail (1416) film.Carry out radiography along the passage of GRD in gastrointestinal tract.0 minute (just before prescribe medicine to guarantee on an empty stomach), 5 minutes (just behind prescribe medicine with assurance device at gastric), dog is carried out radiography 2 hours (whether observe GRD is removed by house keeper's ripple) with at 9 hours.After radiography in 2 hours, take food to dog.Sometimes food mixes with the research dosage form the effect of food from gastric emptying with BIPS (the polyethylene ball of barium dipping).The density of BIPS is similar to food but has competent radiodensity, can show by the radiography of abdominal part is clear.The passage of little BIPS (1.5mm) the simulation food that uses, it provides the gastric emptying speed and the accurate estimation of intestinal transhipment time of food via the gastrointestinal tract transhipment.Known Hills d/d diet can make BIPS suspend, and it is unique diet that concerns between BIPS emptying and the food emptying of having checked and verify therein and proved.BIPS and roentgenopaque line are differentiated.For every animal, carry out radiographic inspection from two angles, the one, side view, the one, back of the body abdomen view.

Find that cuboid stopped 9 hours at the gastric of a dog at least.Three kinds of shapes in addition in less than 2 hours from gastric emptying.X-ray in the time of 24 hours shows at gastric does not have the roentgenopaque line of cuboid GRD to exist, and shows four kinds of difform GRD disintegrates in the distribution of colon center line.Use cuboid GRD to carry out four kinds of researchs altogether.In four kinds of all researchs, GRD stops at the gastric of same dog rather than another dog.These results of study are shown in Figure 14-17.

X ray after food mixes 2 hours with BIPS shows food from the gastric emptying, and GRD does not have.This result of study as shown in figure 18.This shows that GRD does not influence food and enters intestinal from gastric emptying.Use the result of the GRD of large-size to show that also sphincter of pylorus is not blocked by GRD.According to the result who studies in these bodies, select the GRD that introduces ' 000 ' the capsular large volume to detect at human body.

B. be used for the radiography of the GRD that detection embodiment 1B makes in the body

As described in embodiment 10B, use GRD, use X ray to follow gastric retention device passing through in the gastrointestinal tract of dog.Just carrying out radiography on an empty stomach before the prescribe medicine, and behind prescribe medicine, carrying out radiography immediately with assurance.Carried out X ray then at 0.5,1,2,3,6,9 and 24 hour.All X ray are side view, and (the abdomen back of the body, VD) X ray is to confirm the position of dosage form at the dog gastric to carry out some front and back (anterioposterior).

Radiographic inspection uses Transworld 360V X ray generating unit (360 milliamperes and 125 kilovoltages) to carry out.The x-ray cassette that uses is 3M Trimax 12, and is supporting with 3MUltradetail (1416) film.Exposure is provided with as shown in table 5.

Table 5: be used for the exposure setting of the X-ray production apparatus of two dogs

Dog	????mA	????KVP	????MAs
				The Hans-side view	????150	????70	????8.3
The Gretel-side view	????150	????68
				The Hans-VD view	????150	????82	????10.1
The Gretel-VD view	????150	????80

The polyethylene ball (BIPS) of bismuth dipping is as the term suggests be the bismuthiferous polyethylene ball of bag, and this makes their not saturating X ray.These balls are introduced into GRD to study in the body that is used for dog.The system that contains two big BIPS is subsequently used X ray at different time points, and described time point is 0,0.5,1,2,3,6,8,9 and 24 hour.The gastric that still is present in a dog in the 9th hour system of test.In the time of 24 hours, just carry out next X ray.Among 2 BIPS, one still at gastric, and finds another in intestinal, shows that system has corroded to have discharged a BIPS.For second dog, in the time of 9 hours, find two BIPS at small intestinal.

Roentgenopaque line has been used to veterinary and surgery, and these lines are introduced GRD.These lines not only help to follow the trail of film but also help to observe the gel hydration.

Two dogs are all carried out placebo research.Under fasted conditions, dog is used the capsule that comprises roentgenopaque line and lactose, to study when described line is not in GRD the situation of its gastric emptying.Regularly use X ray.These lines were discharged from the gastric of dog between 2 and 3 hours enters small intestinal.

After being used the gastric retention device that contains roentgenopaque line, dog uses X ray.System stopped 10 hours at the gastric of dog at least.The X ray that used in the time of 24 hours is presented at and does not have roentgenopaque line in stomach or the small intestinal.The result who uses the GRD that comprises roentgenopaque line in the dog body is shown in Figure 19 and 20.Use contains not, and the GRD of saturating X ray material has carried out 5 research altogether.The discovery system stopped 9 hours at the gastric of dog at least in our 3 researchs.

Prescribe medicine 7 hours the time or the X ray that uses afterwards show that food is not under one's belt and in intestinal.Yet find that GRD is at gastric.This shows that GRD does not influence passage and the GRD that food enters intestinal and do not block sphincter of pylorus.

Embodiment 12

This section relates to the splanchnoscopy that is used to detect GRD in the dog body

Use endoscope with visual inspection embodiment 1A, the GRD that IV partly makes is in the swelling of gastric.A dog is used to this research.Animal before prescribe medicine fasting 14-16 hour.Prescribe medicine when dog wakes.Intravenous administration of ketamine to (252mg) and stable (7.5mg) induced animal.Animal is with the endotracheal tube intubate that puts tube head and keep general anesthesia with the isoflurane G﹠O.After reaching appropriate anaesthetization agent level, the endoscope optical of flexible fibre (135cm length; The 9mm external diameter) is introduced in mouth and the esophagus, and arrives stomach.By being attached to the photographing unit monitoring GRD of endoscope, at 45 fens clock time video recording swelling processes.

Animal regularly carries out splanchnoscopy, and endoscopic procedure is had good toleration.Be induced to total process time of extracting intubate from anesthetis and be about 1 hour.Endoscope is placed on the gastric of animal, and splanchnoscopy figure shows the position of GRD at gastric.In 45 minutes time, pass through the camera continuous monitoring GRD of endoscope then.Capsule shells was dissolved in a few minutes, and discharged GRD.GRD swelling gradually in 30 fens clock times, swollen gel reclaims to study its size and to compare with the in vitro tests result from gastric after 45 minutes.The swell gel (2.8 * 1.3 * 0.8) that reclaims from the dog gastric is compared with the similar GRD (3 * 1.5 * 1) 37 ℃ of immersion simulated gastric fluids has approximate same size.The GRD that makes swells to suitable size and therefore more may avoid being discharged from the gastric of fasting by house keeper's ripple in less than 30 minutes in gastric juice.

Embodiment 13

This section relates to uses GRD to the people

A. use embodiment 1A, the GRD that the method for IV part makes uses GRD to people experimenter

Under fasting and feed condition, in a subject to the gastric retention device that contains the 200mg amoxicillin or do not have this device only to contain 200mg amoxicillin tablet to intersect biological study.Require described experimenter overnight fasting in two researchs.During studying, under fasted conditions, provide breakfast after two hours at prescribe medicine.In the research of state, the experimenter accepts dosage form with breakfast on the feed.Breakfast of standard is original flavor bagel, one ounce of cream cheese and 125ml fruit juice.After 48 hours eccysis phases (washout period), use alternately dosage.Collected urine at 0,1,2,3,4,5,6,8,12 and 24 hour.Urine sample is analyzed by HPLC immediately.

B. the GRD that uses the method for embodiment 1B to make uses GRD to people experimenter

The I phase: six health volunteers (four male and two women) take in (IR) capsule (A treatment) or (LGRD) capsule (B treatment) carry out the trial design at random that the eccysis phase is at least one week.Capsule is taken in 200ml water.Require all experimenters fasting 10 hours and put in poison and do not give food in back three hours at least before research.

The II phase: this research bag is made up of a kind of treatment under fasted conditions, and wherein each all takes in (IGRD) capsule (C treatment) among six experimenters.

The III phase: this research also is made up of a kind of treatment under fasted conditions, and wherein each name is taken in (SGRD) capsule (D treatment) among six experimenters.

The preparation composition

Select for use riboflavin as therapeutic agent (Sigma Chemicals, St.Louis, MO).No matter all detection preparations are GRD form or releasing pattern immediately, all contain the riboflavin of 100mg powder type, and these preparations are produced in the pharmaceutical college of Corvallis Oregon university.The GRD preparation prepares as mentioned above.

The capsule that uses in the biological study

1. discharge (IR) capsule immediately: for containing ' 1 ' number capsule of lactose as main excipient (200mg) and the pre-dried riboflavin of 100mg.

2. large size GRD capsule (LGRD): be ' 000 ' number capsule of filling with the dry GRD that contains 100mg riboflavin.The GRD that introduces was of a size of 7 * 1.5 * 1cm before drying.

3. medium size GRD capsule (IGRD): be ' 00 ' number capsule of filling with the dry GRD that contains 100mg riboflavin.The GRD that introduces was of a size of 5 * 1.5 * 1cm before drying.

Small size GRD capsule (SGRD): be ' 0 ' number capsule of filling with the dry GRD that contains 100mg riboflavin.The GRD that introduces was of a size of 3 * 1.5 * 1cm before drying.

Embodiment 14

This section relates to uses to people experimenter that HPLC analyzes excretion of drug behind the GRD

A.HPLC analyzes the experimenter's who derives from embodiment 13A urine sample

Internal standard substance: acetaminophen USP (1mcg/ml).

This solution is in cooling preservation and be metastable under the point-blank situation of lucifuge preferably.

Buffer solution: prepare buffer by in the 350ml deionized water, adding 100ml 0.5M sodium hydrogen phosphate.With 1M Fructus Citri Limoniae acid for adjusting pH to 6.The solution that obtains is supplied the 500ml volume with deionized water.

The preparation of mobile phase: in the 3800ml deionized water, add the 0.26g potassium dihydrogen phosphate.Add 200ml HPLC level methanol.Filtering solution is removed any granule, and stirs about 20 minutes to remove bubble under vacuum.

HPLC instrument: Waters Intelligent Sample Processor (WISP ^TM) 712, the auto injection syringe is used for reaching the interior sample feeding of 48 sample flaskets to post.

Post: anti-phase C18,25cm, 5 microns, 100A Rainin Microsorb-MV ^

Detector: UV absorption detector, model 440, fixed wave length.

Buffer sample: the 2ml sample that derives from each urine joins in the 2ml pH6 buffer, and the solution eddy current mixes to guarantee suitable mixing.

The buffered urine of HPLC sample: 1ml is diluted with the 5ml deionized water.This dilute sample to 50 microlitres in the small plastic centrifuge tube adds 50 microlitre inner mark solutions.The solution eddy current that obtains mixes to guarantee mixing.Assembling HPLC sample flasket is added a cover, and is put into WISP ^TMBeing used for HPLC in the automatic sampler analyzes.The sample of sample introduction 20 microlitres.Other parameter of HPLC is as follows.

Flow rate of mobile phase: 1.3ml/ minute

Detect wavelength: 229nm

Flowing time: about 23 minutes

The generation of standard curve

Produce the amoxicillin calibration curve by the following method: the 0.03g BRL-2333 places the 100mL volumetric flask, and be 1: 10, do not contain the urine of medicine (blank) with ratio: 100mL is also supplied in the mixture dissolving of deionized water.Stir about 40 minutes under the room temperature to guarantee thorough dissolving.Make a series of 1: 1 dilution to obtain 6 samples with deionized water.Produce a series of samples with finite concentration scope by the serial dilution process, described concentration is used to produce calibration curve.Be used for sample preparation methods that HPLC analyzes as previously mentioned.Every kind of sample sample injection is 20 microlitres altogether.

B.HPLC analyzes the urine sample that derives from 13B experimenter

1) reagent of HPLC analysis:

Methanol (the HPLC level, Fisher Chemicals, NJ), potassium dihydrogen phosphate (FisherChemicals, NJ), sodium hydroxide (Mallinckrodt).The water that this process is used uses Milli-Q Reagent Water System (Millipore, Bedford MA, USA) deionization.

2) drug abuse test method:

Post is anti-phase microgranule C ₁₈(Bondapak C ₁₈, particle size 10 μ m, 30cm * 4mm, Waters Assoc., Milford, MA USA), uses C ₁₈Anti-guard post (ODS, 4 * 3mm, Phenomenax, CA, USA) the pre-filling.

Follow the described analysis programme of Smith.Eluent is 0.01m KH ₂PO ₄(pH5): methanol (65: 35), flow velocity are 1.2mL/min.Methanol and 0.01 potassium dihydrogen phosphate by mixing precise volumes also is adjusted to pH5 with the 1N sodium hydroxide and prepares mobile phase, filters via 0.2 μ m filter under vacuum then.The degassing before mobile phase is used.Detector be fixed wave length spectrofluorophotometer (Gilson Spectra/Glo Fluorometer, Middleton, WI).Excitation wavelength is 450nm.The wave-length coverage of emission light filter is 520-650nm.(Kuoto Japan) measures peak area for C-R3A Chromatopac, Schimadzu Corp. with the Schimadzu integrator.

Other Instruments in the HPLC system comprises infusion pump (Waters 550 Solvent DeliverySystem, Waters Associates, Milford, MA), automatic sampler (Waters WISPModel 712B, Waters Associates, Milford, MA).

3) collection of urine sample:

Experimenter's overnight fasting, urine when the prescribe medicine prerequisite supplies zero is taken in preparation then.Behind prescribe medicine, collected urine sample with the 16oz container in 1,2,3,4,6,8,10,12 and 24 hour.Owing to the vitamin of each urine sample of record is taken in and is to measure a vitamine concentration deposit part to cause volume and time lapse.

4) standard solution:

The riboflavin standard inventory formulations prepared from solutions that contains 100 μ g/mL reference standards is as follows: in 1 liter of flask, add 100mg riboflavin (105 ℃ dry 2 hours in advance), 750ml water and 1.2ml glacial acetic acid, heating for dissolving, and be diluted with water to described volume.This stock solution dilutes to contain the riboflavin of 1,2,4,6,8,10 and 15 μ g/ml with blank urine.All solution keep in Dark Place.These standard sample sample introductions are to post, and the record chromatograph is measured peak area.The retention time of riboflavin is about 6 minutes.

By peak area to riboflavin concentration in the urine and the drawing standard curve.Sensitivity for analysis is 1 μ g/ml, the riboflavin concentration linear correlation (R of peak area and 1 to 10 μ g/ml ²=0.9971).The representative standard curve of riboflavin as shown in figure 29 in the urine.Consider endogenous riboflavin, the area of urine sample gained when from all test standard samples and sample, deducting blank urinalysis or zero.

5) sample analysis:

The urine of about 10ml centrifugal 10 minutes at 4000rpm.Part supernatant (150 μ l) is transferred to HPLC pipe and sample introduction 50 μ L to the HPLC post.Riboflavin 6 minutes eluting behind sample introduction come out.

Embodiment 15

This section relates to the pharmacokinetic analysis of HPLC data

As embodiment 14B, the described riboflavin that obtains of 1-5 part is drained data.Use back recovery, recovery from urine in preceding 24 hours according to riboflavin _0-24, maximum homaluria rate, R _MaxWith the time, reach R _MaxThe T that needs _MaxAnd relatively more different treatments.Measure all parameters from individual homaluria rate-time graph, promptly the homaluria rate is to urine collecting mid point mapping at interval.Individual accumulation urine Chinese medicine drainage-time graph is measured and is reclaimed _0-24h, promptly cumulative excretion of drug is mapped at interval to acquisition time.

Embodiment 16

This section relates to the statistical analysis of HPLC data.

As embodiment 14B, the described acquisition riboflavin of 1-5 part is drained data.Use the pharmacokinetic parameter difference between the different treatments of bilateral Xue Shengshi t check examination.With null hypothesis Ho: μ _T-μ _R=0 is the basis, carries out bilateral Xue Shengshi t check in α=0.05, to obtain the urine data collection: reclaim _0-24h, R _MaxAnd T _MaxNull hypothesis (H _o) the qualified mean parameter that shows the mean parameter that do not have enough evidences to draw the GRD preparation and corresponding immediate release formulation between have the conclusion of significant difference, that is, parameter equates.The rejection of null hypothesis is the strong proof that the test parameters of two kinds of preparations has significant difference.

Embodiment 17

What this section related to homaluria rate data removes flatung (deconvolution).

Use the computer software PCDCON of Williams Gillespie to measure and remove the flatung input function from the biological study data.Go flatung to reply with the characteristic pulse of medicine and reply function generation input function (dissolved cumulant-time in the body) by input.By going the cumulative in time medicine input of flatung prediction data to be used to measure the gastric retention time of the GRD of different size.From going convoluted curve to calculate observed time when stopping gastric retention time as absorption.It is the excretion rate (dU/dt) of riboflavin in urine that derives from different preparations that the input of using is replied, and the impulse response of using is the elimination rate constant that comes from document, and described constant is measured from the vein single dose (bolus dose) of riboflavin.

Embodiment 18

This section relates to the drug absorption of people experimenter to GRD.

A. as GRD being applied to the experimenter as described in the embodiment 13A and draining according to the amoxicillin after the analysis as described in the embodiment 14A.

The bioavailability of the amoxicillin (a kind of beta-Lactam antibiotic) of GRD is introduced in detection with the scrotiform tablet form.The raising of beta-lactam concentration shows that more antibacterials are killed, and up to a qualified point of 4 times that is about minimum inhibitory concentration (MIC), it is called as treatment concentration.Further raising can not cause the increase (18, for example the MIC of Diplococcus pneumoniae (Strep.pneumococci) is 0.02mcg/ml, and treatment concentration is 0.08mcg/ml) of fungicidal effectiveness.Keep beta-Lactam antibiotic concentration above having positive correlation between time for the treatment of concentration and the clinical effect.Antibacterial regenerates rapidly drop under the minimal inhibitory concentration of antibacterial when these concentration after.Therefore, the no medicine between the dosage regimen of every kind of independent beta-lactam should prevent to put in poison is at interval greatly to making bacterial pathogen can restart growth.

Half-life after the amoxicillin is oral is very short, is about 1 hour, has limited " absorption window ".Medicine has good absorption at duodenum and small intestinal stage casing, but reduces and be rate dependent in the absorption of ileum.Absorb very poor in all colon regions.Therefore, compare, use GRD to send beta-Lactam antibiotic and for example can prolong the intravital MIC time in the amoxicillin with conventional IR preparation.Also therefore prevented to reach capacity because arrival absorbs the time period prolongation of the medication amount of position, therefore also improved bioavailability in the absorption position.

When under fasted conditions, the amoxicillin being applied to the experimenter of embodiment 13A, find that according to the methods analyst of embodiment 14A the medicine that is incorporated in the GRD is compared with the medicine that lacks GRD, the excretion rate area under curve (AUC) of medicine increases by 30%.When lacking GRD, maximal excretion rate (C _Max) be 34.2mg/hr, and when GRD exists, C _MaxBe 29.0mg/hr, these values do not have significant difference.Both T _MaxBe worth identical.The compared bioavailability of two kinds of preparations as shown in figure 21.

On the feed in the research of carrying out under the condition, AUC or C _MaxWithout any significant difference.Yet the T that contains GRD _MaxWith the T that lacks GRD _MaxThe time relatively, T _MaxMove right.Find the T of GRD _MaxBe 4 hours, and be 2 hours when lacking GRD.Figure 22 represents the comparison of the bioavailability under the condition on the feed of two kinds of preparations.

These results of amoxicillin and food when the experimenter takes food slow down that medicine is transported in from the stomach to the intestinal and when experimenter's fasting GRD slow down medicine and be delivered in the intestinal and be consistent.In addition, food can not discharge from GRD medicine adverse influence.

B. as GRD being applied to the experimenter as described in the embodiment 13B and according to embodiment 14B, the riboflavin drainage after 1-5 part and embodiment 15, the 16 and 17 described analyses.

The urine Chinese medicine is drained data and be can be used for estimating bioavailability, because the excretory cumulant of urine Chinese medicine is with absorption and then by the excretory medicine total amount of first order elimination process positive correlation.In order to obtain effective estimation, medicine must be excreted in the urine with significant quantity, and must collect the full sample of urine.

Under fasted conditions, measure the purpose that size also is this biological study of holding back of GRD gastric emptying.Riboflavin partially absorbs relatively from the different preparations of homaluria data evaluation.Following table represents to be used for the average pharmacokinetic parameter of different treatments.

Table 6: in the fasting volunteer oral administration immediate release capsule or the riboflavin pharmacokinetic parameter behind the 100mg riboflavin in the GRD capsule.

Treatment

(IR)??????????(SGRD)???????(IGRD)????????(LGRD)

0-24h reclaims (mg) 5.33 ± 1.74 4.09 ± 1.67 9.3 ± 5.27 17.36 ± 9.7

Maximum homaluria rate (mg/h) 1.36 ± 0.42 1.14 ± 0.59 2.05 ± 0.99 2.52 ± 0.98

The maximal excretion rate time (h) 2.5 ± 0.6 2.33 ± 0.97 3.25 ± 1.1 5.08 ± 2.4

Mean residence time (h) 4.73 ± 0.83 5.98 ± 1.06 5.27 ± 1.7 6.99 ± 1.18

Data are meansigma methods ± SE

Following table 7-12 represents that each experimenter accepts the independent pharmacokinetic parameter of four kinds of treatments.

Figure 23 represents the LGRD capsule, is IGRD capsule, IR capsule and the capsular recovery of SGRD then _{0-24 hour}Maximum average value.Measure the average recovery of LGRD capsule (17.3mg) _{0-24 hour}Estimated value is greater than 225%, has significant significant difference (P＜0.05) with respect to the meansigma methods of IR capsule (5.33mg).The average recovery of SGRD capsule (4.09mg) _{0-24 hour}Estimated value is less, does not have significant significant difference (P＜0.05) with respect to the meansigma methods of IR capsule (5.33mg).The average recovery of IGRD capsule (9.3mg) _{0-24 hour}Estimated value is higher, does not have significant significant difference with respect to the meansigma methods of IR capsule (5.33mg).This may be (among the experimenter 1 and 2, to derive from the capsular urine of IGRD and reclaim because device only has the gastric transit time of prolongation in some volunteers _0-24hReclaim than deriving from the capsular urine of IR _0-24hSignificantly improve).

R _MaxAnd T _MaxThe statistics of parameter more also shows between the result of LGRD capsule (be respectively 2.5 ± 0.98mg/h and 5.08 ± 2.4 hours) and IR capsule (be respectively 1.36 ± 0.4mg/h and 2.5 ± 0.63 hours) to have significant difference (P＜0.05).The capsular R of IGRD and SGRD _MaxAnd T _MaxParameter and IR capsule do not have significant difference.These results as shown in figure 24.

The bioavailability of the capsular riboflavin of LGRD that obtains in this research improves (it is more than three times of institute's survey time receipts behind the administration IR capsule that urine reclaims) and shows that device keeps at gastric.LGRD stops time enough with its vitamin content of slow release at gastric, and the vitamin of release little by little more effectively absorbs by absorption window subsequently.

On the other hand, using the SGRD capsule uses the IR capsule and causes riboflavin absorb to reduce.This may be because small device sizes produces few relatively drug release by the III phase myoelectricity contraction movement of dividing a word with a hyphen at the end of a line from gastric emptying.In case device by absorption window, does not just have to absorb and takes place.

Figure 25 represents to go from the biological study data that IR, SGRD, IGRD and LGRD capsule obtain the cumulant-time of the drug absorption behind the flatung.For the LGRD capsule, its absorption is extended to and mostly is 15 hours most before it stops.This can show that LGRD also discharged medicine about 15 hours lentamente in the gastric stop.On the other hand, become constantly after the capsular absorption of IGRD continues about 9 hours, show that device does not stop the sufficiently long time to discharge its all drug substance contents at gastric.The capsular absorption of SGRD only continues 3 hours, show device with the IR dosage form equally promptly by house keeper's ripple from gastric emptying (because its small size).

These results show, the inflatable system that contains the different medicines with limited absorption position for example GRD can be estimated by the bioavailability of comparative drug in the holdup time of gastric, and the bioavailability of medicine can be by using the inflatable system that contains the same amount medicine and measuring AUC or urine immediately behind the delivery systme and reclaim and measure.

Table 7: to the riboflavin pharmacokinetic parameter behind the 100mg riboflavin in experimenter's 1 oral administration immediate release capsule or the GRD capsule

Treatment
						??(IR)	??(SGRD)	??(IGRD)	???(LGRD)
0-24h reclaims (mg) maximum homaluria rate (mg/h) maximum homaluria rate time (h) mean residence time (h)	??8.001 ??1.93 ??2.5 ??4.08	??6.0 ??1.94 ??3.5 ??5.421	??17.92 ??2.27 ??5 ??6.49	????33.75 ????4.06 ????9 ????7.59

Table 8: to the riboflavin pharmacokinetic parameter behind the 100mg riboflavin in experimenter's 2 oral administration immediate release capsules or the GRD capsule

Treatment
						??(IR)	??(SGRD)	??(IGRD)	????(LGRD)
0-24h reclaims (mg) maximum homaluria rate (mg/h) maximum homaluria rate time (h) mean residence time (h)	??4.67 ??1.44 ??1.5 ??3.40	??5.57 ??0.95 ??2.5 ??7.52	??12.87 ??2.82 ??5 ??5.90	????23.89 ????2.05 ????11 ????8.70

Table 9: to the riboflavin pharmacokinetic parameter behind the 100mg riboflavin in experimenter's 3 oral administration immediate release capsules or the GRD capsule

Treatment
						??(IR)	??(SGRD)	????(IGRD)	????(LGRD)
0-24h reclaims (mg) maximum homaluria rate (mg/h) maximum homaluria rate time (h) mean residence time (h)	??6.3 ??1.26 ??2.5 ??5.61	??3.89 ??1.62 ??1.5 ??4.38	????6.86 ????2.64 ????1.5 ????3.17	????14.12 ????2.46 ????3.5 ????5.73

Table 10: to the riboflavin pharmacokinetic parameter behind the 100mg riboflavin in experimenter's 4 oral administration immediate release capsules or the GRD capsule

Treatment
						??(IR)	??(SGRD)	??(IGRD)	??(LGRD)
0-24h reclaims (mg) maximum homaluria rate (mg/h) maximum homaluria rate time (h) mean residence time (h)	??3.47 ??0.91 ??3.5 ??4.91	??4.34 ??1.34 ??3.5 ??6.13	??6.51 ??1.52 ??3.5 ??5.01	??12.50 ??1.55 ??7 ??7.13

Table 11: to the riboflavin pharmacokinetic parameter behind the 100mg riboflavin in experimenter's 5 oral administration immediate release capsules or the GRD capsule

Treatment
						??(IR)	????(SGRD)	????(IGRD)	????(LGRD)
0-24h reclaims (mg) maximum homaluria rate (mg/h) maximum homaluria rate time (h) mean residence time (h)	??3.63 ??0.907 ??2.5 ??5.33	????1.30 ????0.43 ????1.5 ????5.86	????3.11 ????0.42 ????2.5 ????7.55	????6.46 ????1.4 ????2.5 ????5.55

Table 12: to the riboflavin pharmacokinetic parameter behind the 100mg riboflavin in experimenter's 6 oral administration immediate release capsules or the GRD capsule

Treatment
						??(IR)	??(SGRD)	????(IGRD)	????(LGRD)
0-24h reclaims (mg) maximum homaluria rate (mg/h) maximum homaluria rate time (h) mean residence time (h)	??5.96 ??1.77 ??2.5 ??5.06	??3.45 ??0.58 ??1.5 ??6.62	????8.81 ????1.88 ????3.5 ????3.53	????13.53 ????3.06 ????5 ????7.28

Embodiment 19

This section relates to the production of the gastric retention device that contains Hydrochlorothiazide

Preparation all the components and mould (use can stand the 1*1.5*7.5 cuboid container of hot solution).Weigh up 0.75g XG (xanthan gum) and LBG (locust bean gum) respectively, fully mix each other, be dissolved in then in the 100ml deionized water (DIW).Be distributed in them among the DIW well then and let alone swelling 3-4 hour.

Prepare independent foam solution:

● warm 25ml deionized water (about 26ml is with compensate for evaporation) also dissolves 0.125g SLS (sodium lauryl sulfonate), then at magnetic stirrer low suspension 0.075g carbopol.Stir and continue about 3 hours.

● after 3 hours, adjust pH to 7 to 7.5 (variation of pH reagent paper: yellowish-brown is to bottle greens) with Neutral (denier), then the beaker of foam solution is put into ice-water bath and make foamed set (Neutral is used to adjust the pH of carbopol solution and makes this solution becomes get extremely condensed excipient or composition, also can use other antalkali).

● the gum-solution of heating above-mentioned steps 1 also stirs every now and then, at full throttle stirs the foam solution of above-mentioned steps 3 simultaneously with magnetic stirring apparatus.

● the heating gum-solution adds 5.5ml PEG400 then and stirred 10 seconds up to 80 ℃.

● shift out magnetic stirring apparatus from gum-solution and also foam impouring gum-solution and with scraper they are mixed with scraper.

● make an appointment with half being full of in natural gum/each mould of foam mixture impouring, the mould remainder that adds the medicine globule then and be full of with natural gum/foam mixture, before cooling, promptly mix them then, gelling takes place make medicine globule uniform distribution.

● in room temperature it was solidified about 2 to 4 hours.

● refrigerative gel is put into refrigerator (usually above 10 hours (spending the night), but the time can change for convenience's sake).

● each gel is taken out from container and is placed on wax disk(-sc) or the plastic sheet.

● gel in the laboratory vacuum drying oven 53 ℃ dry 4.5 to 5 hours down.Depend on definite vacuum, temperature and drying time that available equipment all is variable.These conditions make the water vacuum obtain good result.

Embodiment 20

This section relates to the production of the slow releasing preparation of Hydrochlorothiazide

1. make with the Hydrochlorothiazide suspension and be of a size of the layering of 18-20 purpose sugar ball.At room temperature, with 9 gram PVP (Povidone K-30), 3 gram Klucel ^(HPC), 3g (both as binding agent) and 40 restrains HCTZ and is suspended in and spends the night in the 100ml deionized water and prepare the Hydrochlorothiazide suspension.

2. in bottom spray, Wurster post, spray booth, carry out layering.

Table 13: spraying condition

	Unit
		Inlet temperature (℃)	????55-60
Air pressure (psi)	????18
		Medicine layering nozzle (mm)	????1.0
Sustained release coating nozzle (mm)	????1.0

3.HCTZ the layering spheroid suspension coating of Surelease and Opadry mixture.Coating in the suspension of the 10ml deionized water of 100g medicine layering spheroid usefulness 1g Opadry and 8.06g Surelease.The total percentage that is applied to the coating on the HCTZ layering spheroid is 3%, and it is made up of 66.3%Surelease and 33.3%Opadry.

4. after layering is finished, spheroid in the chamber dry about 30 minutes.

Embodiment 21

This section relates to uses the GRD that contains Hydrochlorothiazide to people experimenter.

Two kinds of preparations (a kind of immediate release formulation (IR) and a kind of gastric retention device (GRD)) of using the Hydrochlorothiazide that contains slow releasing preparation (SR) carry out biological study (bioavailability research).The marketed tablet that contains 50mg HCTZ is made the spraying globule that is equivalent to 50mg HCTZ at laboratory and is used for SR as the IR contrast.The preparation process of SR as mentioned above.Carry out biological study to estimate the HCTZ that from GRD, discharges and the bioavailability of comparing and the pharmacokinetics that from IR, discharge.

Monitor the concentration of Hydrochlorothiazide in the adult healthy volunteers urine, be used for the relative bioavailability of the Hydrochlorothiazide of comparison GRD preparation and conventional tablet.The participation time of each treatment is at least two days, and each treatment has at least 72 hours eccysis phase between prescribe medicine.Disposable employed IR and GRD repetitive administration twice are with the repeatability of test novel form GRD.Selecting 50mg dosage to be used for research is because this dosage is within the dosage range of PDR (physician's prescription handbook) recommendation, and can produce sufficiently high concentration and analyze to carry out effective HPLC.There are six experimenters to participate in research, four healthy males and two healthy womens.Do not allow them to accept any food or beverage that contains caffeine, alcohols or other medicines.Do not comprise smoker and vegetarian.Experimenter's overnight fasting and fasting at least 2 hours behind prescribe medicine.In each research, the experimenter emptied their bladder before accepting the Hydrochlorothiazide of single dose, and took this dosage with 12 ounces of water.Behind the prescribe medicine, the experimenter obtains one group in order to the container of collecting their urine and the timetable that writes down urination time.The experimenter collects all urines in during 24 hours behind oral formulations.In 0-1,1-2,2-3,3-4,4-6,6-8,8-10,10-12,12-24,24-36 and 36-48 hour, collect urine sample.Urine sample cold preservation is up to giving research worker.The volume of urine of measurement collection is to calculate the medicine recovery total.Medicament contg in the urine sample of analyzing aliquot of improving one's methods that people's such as use Paradoynnis HPLC (high performance liquid chromatography) analyzes.

Embodiment 22

This section relates to pharmacokinetic parameter and the voided volume data analysis of using behind the GRD that contains Hydrochlorothiazide.

As described in embodiment 21, the GRD that contains the Hydrochlorothiazide medicine is applied to people experimenter.Under fasted conditions, the average pharmacokinetic parameter of each treatment provides in following table 14.Figure 26 represents excretory drug accumulation amount-time diagram.Eliminate half-life (t _1/2) be about 7 hours.Compare A _0-36Value is used for statistical analysis, because the IR half-life is short, can not obtain the value of the IR 48 hours the time from an experimenter.

Embodiment 23

This section relates to the effect of fasted subjects being used the GRD that contains Hydrochlorothiazide.

As described in embodiment 21, people experimenter is used the GRD that contains the Hydrochlorothiazide medicine and as described in the embodiment 23, analyzes the average pharmacokinetic parameter of each treatment.Discovery under fasted conditions, the average A of IR (33.3mg, 66.6%) _0-36hAverage A with GRD (37mg, 75.4%) _0-36hThere were significant differences (P＜0.05), although difference is in 10%.From the FDABA/BE guide as can be known, be considered to insignificant usually less than 20% difference.From Figure 26 and table 14 as can be known, absorb and urine in the meansigma methods of total medicine of collecting equate the meansigma methods (A of IR and GRD under fasted conditions _0-48h) be respectively 38.12mg (76.2%) and 38.95mg (77.9%).A _0-48Be to suppose that 50% absorbed dose appear as the basis with original shape in urine.Thereby in fasted subjects, when mostly being most 48 hours, GRD and IR obtain the drug absorption of same amount basically.Yet the influence to homaluria but is different fully surprisingly.

Pharmacokinetic parameter and the voided volume data of table 14:IR

AVG(IR)

Time drain volume/accumulated time amount cumulative volume water take the photograph water take the photograph output/

Mid point rate (ml) is gone into (ml) and is gone into/the hr input rate

(mg/hr)

0.5??????2.109834???270.3333?????2.109834???257.5??????355?????????355???????????0.725352113

1.5??????3.94137????363.4618?????5.860838???628.333????710?????????355???????????0.884976526

2.5??????4.838802???311.3587?????10.61732???940????????1098.33333??388.333333????0.855842185

3.5??????3.587672???310.75???????14.43554???1204.67????1486.66667??388.333333????0.810313901

5????????1.44891????323.8361?????17.30009???1856.6?????1866????????189.666667????0.994962487

7????????1.59156????284.3054?????20.60636???2281.33????2398.33333??266.166667????0.951216122

9????????1.017416???206.9508?????22.53981???2628???????3023.33333??312.5?????????0.86923925

11???????0.816937???145.1????????24.34742???3006.33????3496.66667??236.666667????0.859771211

18???????0.489007???108.4572?????29.01896???4535???????4315.83333??68.2638889????1.050782004

30???????0.316279???79.62282?????33.26785???5560.83????5617.5??????108.472222????0.989912476

42???????0.204944???81.23696?????38.12199???6068.67????6013.33333??32.9861111????1.009201774

AVG(GRD)

Time drain volume/accumulated time amount cumulative volume water take the photograph water take the photograph output/

Mid point rate (ml) is gone into (ml) and is gone into/the hr input rate

(mg/hr)

0.5????0.438872?????214.8434?????0.483118???200.556????355?????????355???????????0.564945227

1.5????1.155346?????379.355??????1.708467???529.273????603.75??????248.75????????0.876642198

2.5????1.86002??????367.5????????3.304097???942.909????916.818182??313.068182????1.028458106

3.5????2.195914?????390.6247?????5.698541???1311.55????1254.58333??337.765152????1.045403219

5??????2.46914??????356.0098?????10.43505???1927.67????1820.45455??282.935606????1.05889305

7??????2.151739?????317.013??????14.18478???2592.25????2484.16667??331.856061????1.04350889

9??????1.627401?????264.23???????17.92668???2975.18????3062.91667??289.375???????0.971355783

11?????1.552815?????276.3023?????21.32656???3598.92????3612.08333??274.583333????0.996354828

13.5???1.144381?????214.9586?????24.04283???4217.29????4307.29167??231.736111????0.9791052

18?????0.79889??????114.8045?????31.00009???5003.18????4972.91667??73.9583333????1.006085996

30?????0.487425?????100.6936?????37.71256???6378.5?????6481.66667??125.729167????0.984083312

42?????0.265091?????93.9158??????38.95911???7466.78????7380????????74.8611111????1.011758506

As expected, Figure 27 represent to discharge immediately (IR) capsule than new formulation (GRD) at more Zao time (t _Max) the higher maximum excretion of drug rate (R of appearance _Max) (was 4.84mg/hr and be 2.5mg/hr at 5 hours (hr) at 2.5 hours (hr)).

Embodiment 24

This section relates in the fasted subjects body figure of HCTZ-50mg in 48 hours.

As described in embodiment 21, people experimenter is used the GRD that contains the Hydrochlorothiazide medicine, and as the average pharmacokinetic parameter of each treatment of analysis as described in the embodiment 23.As analyzing cumulant-time of HCTZ-50mg as described in the embodiment 23.

● the C of IR and GRD _MaxAnd T _MaxBe respectively 4.84 and 2.46 (mg/ml) and 2.5 and 5 (hour).

● T _1/2It is 7 hours.

Behind the prescribe medicine during up to 10 hours, IR is similar with the speed that GRD produces urine.This is fully unexpected, because GRD of the present invention compares with commercially available IR capsule, and drug absorption and drug level is less in vivo.And behind prescribe medicine 10 hours, the capsular polyuria of IR begins to reduce, and for GRD, measures high polyuria and keep the longer time.

The polyuria of initial equivalent is unexpected because at first the medicine that absorbs from GRD less (under fasted conditions, IR and GRD are respectively t _Max2.5 hour R _MaxBe 4.8 (μ g/ml) and t _Max5 hours R _MaxBe 2.5 (μ g/ml)), the less medicine of this instruction can be more effective at present, and this is uncommon for medicine.In fact, if take in more a spot of medicine, expection can produce less effect, but for this novel GRD and diuretic opposite effect has taken place.

The uropoietic drug effect of also clearly observing GRD continues up to about 15 hours (referring to data in the top table).Figure 28 has compared urine generation and water intake, urine generating rate and water intake speed, and in IR and GRD, the accumulation voided volume that Hydrochlorothiazide causes is all consistent with water intake.

Body fluid healthy, the normal subjects is drained to increase and is stimulated water intake.The GRD of same dose produces higher urine than IR and generates total amount, but this attribution is the medicine input prolongation of GRD, causes the feedback of water intake amount to increase, thus the unexpected drug effect that increases of compensation.

This effect that comprehensively increases is unexpected (except aforementioned less medicine input produces the initial greater role), because knownly will increase the diuretic effect and must increase drug dose.In fact, most drug reaction curve is a log-linear, this means after crossing the initial communication threshold value, and the increase of effect is usually less than the increase of (littler percentage ratio) dosage.But in this case, the bioavailability of medicine comes down to equate under the fasted conditions, but diuresis increases by 27%, shown in Figure 38 and the above table that provides.

Confirm that from the result of the bioavailability of Hydrochlorothiazide research device keeps the sufficiently long time discharging whole or most medicine at gastric, but the release that also confirms described dosage form control medicine is to prolong drug effect.Therefore, GRD is excellent device for using the diuretic that Hydrochlorothiazide and other the top at intestinal shows limited absorption position.This dosage form is by avoiding inducing the high medicine peak concentration of adverse side effect (referring to following side effect information) to improve patient's health care, the drug effect that increases the drug effect behind each dosage and realize prolonging.

Embodiment 25

This section relates to the intravital side effect of Hydrochlorothiazide descendant experimenter of using among the GRD

Contain Hydrochlorothiazide medicine GRD as people experimenter being used as described in the embodiment 21, obtain following side effect report then:

● after prescribe medicine IR dosage form, there are three reports that side effect is arranged among seven experimenters between 4-6 hour.

● the untoward reaction of report is severe or medium headache, dehydration and fatigue.

● an experimenter is because severe headache, dehydration and fatigue can not be proceeded research.

● the Hydrochlorothiazide about same dose among the GRD does not have the untoward reaction report.

● can cause dehydration owing to recognize HCTZ, encourage the experimenter to drink more water after the IR research in the first time.

Can change or improve the fine detail of described method and not break away from spirit of the present invention will be that an order is understood.Our claimed all these modifications and changing all fall within the scope and spirit of claims.

Claims (109)

1. gastric retention device, it comprises the gel that is formed by polysaccharide, this device forms the size that is suitable for experimenter's administration.

2. the gastric retention device of claim 1, it has the coating that is applied to its outer surface or is loaded into and can absorb in the capsule.

3. the gastric retention device of claim 2, wherein coating or capsule are that to be subject to gastric juice erosive.

4. the gastric retention device of claim 2, wherein coating or capsule are enteric coatings.

5. the gastric retention device of claim 1, wherein polysaccharide comprises xanthan gum.

6. the gastric retention device of claim 1, wherein polysaccharide comprises locust bean gum.

7. the gastric retention device of claim 1, wherein polysaccharide comprises the mixture of xanthan gum and locust bean gum.

8. the gastric retention device of claim 1, it further comprises the material that is selected from plasticizer, pH regulator agent, GI wriggling regulator, viscosity modifier, therapeutic agent, diagnostic agent, preparation, extender, surfactant and composition thereof.

9. the gastric retention device of claim 1, it is compressed to the size that is suitable for oral administration.

10. the gastric retention device of claim 1, wherein administration comprises oral administration, rectally, vagina administration, nose administration or oral administration.

11. the gastric retention device of claim 1, it expands after administration, and wherein said device is cube, cone (noting except the cone), cylinder, pyramid (noting except the cone), spheroid, cylinder or parallelepiped after expansion.

12. the gastric retention device of claim 8, wherein diagnostic agent or therapeutic agent are selected from nucleic acid, protein and combination thereof.

13. the gastric retention device of claim 1, it further comprises the material that is selected from following material: the AIDS adjuvant; the alcohol abuse preparation; the Alzheimer inorganic agent; the amyotrophic lateral sclerosis therapeutic agent; analgesic; anesthetis; antacid; anti-arrhythmia agent; antibiotic; anticonvulsant; antidepressant; the anti-diabetic medicament; antiemetic; antidote; the fibrosis therapeutic agent; antifungal; hydryllin; hypotensive agent; anti-infective; antibacterial; antineoplastic agent; tranquilizer; the anti-Parkinson medicament; antirheumatic; appetite stimulator; appetite suppressant; biological respinse modifier; biological preparation; Hemoregulatory; the bone modulators of metabolism; heart protective agent; cardiovascular agents; central nervous system's stimulant; cholinesterase inhibitor; contraceptive; the cystic fibrosis inorganic agent; deodorizer; diagnostic agent; nutritional supplement; diuretic; dopamine-receptor antagonist; the endometriosis inorganic agent; enzyme; therapeutic agent for erection failure; fatty acid; gastrointestinal agent; ceramide glucoside enzyme deficiency disease inorganic agent; the gout preparation; homeopathic drug; hormone; the hypercalcemia inorganic agent; somnifacient; hypocalcemia disease inorganic agent; immunomodulator; immunosuppressant; ion exchange resin; levocarnitine lacks inorganic agent; mast cell stabilizers; the migraine preparation; the motion sickness goods; the multiple sclerosis inorganic agent; muscle relaxant; the anesthetics antidote; anesthetis; nucleoside analog; NSAID (non-steroidal anti-inflammatory drug); fat inorganic agent; the osteoporosis preparation; odinagogue; parasympathomimetic agent; parasympatholytic; phosphate binder; the hematoporphyria medicament; psychotherapy's agent; the radiopaque medicament; treatment psychosis medicament; sclerosing agent; tranquilizer; the sickle cell disease inorganic agent; the aiding smoking cessation medicament; steroid; analeptic; sympatholytic; sympathomimetic; Tourette syndrome medicine; preparation trembles; the urinary tract medicament; vagina preparation; vasodilation; dizzy medicine; anoretic; wilson disease inorganic agent and composition thereof.

14. the gastric retention device of claim 8, wherein diagnostic agent or therapeutic agent provide by the form of tablet, capsule, powder, globule, piller, granule, solid dispersion or its combination.

15. the gastric retention device of claim 8, wherein diagnostic agent or therapeutic agent are easier to be molten in gastric juice than in intestinal juice.

16. the gastric retention device of claim 8, wherein diagnostic agent or therapeutic agent are easier to be molten in intestinal juice than in gastric juice.

17. the gastric retention device of claim 8, wherein diagnostic agent or therapeutic agent absorb in intestinal fluid than in large intestine better.

18. the gastric retention device of claim 8, wherein diagnostic agent or therapeutic agent are better than absorbing in intestinal at gastric.

19. the gastric retention device of claim 8, wherein diagnostic agent or therapeutic agent are better than absorbing at gastric in intestinal.

20. the gastric retention device of claim 8, wherein diagnostic agent or therapeutic agent are abacavir sulfate, abacavir sulfate/lamivudine/zidovudine, acetazolamide, acycloguanosine, albendazole, salbutamol, spironolactone, allopurinol BP, the amoxicillin, amoxicillin/clavulanate potassium, amprenavir, atropic cuts down ketone, atropic cuts down ketone and proguanil hydrochlorate, the atracurium benzene sulfonate, beclomethasone dipropionate, the berlactone Betamethasone 17 valerate, the BUP hydrochlorate, BUP hydrochlorate SR, carvedilol, caspofungin acetate, cefazolin sodium, ceftazidime, cefuroxime (non-sulfuric acid salt), chlorambucil, chlorpromazine, cimetidine, the cimetidine hydrochlorate, the cisatracurium benzene sulfonate, CBP, bactrim, the colfosceril palmitate, dextroamphetamie sulfate, digoxin, English sodium Puli maleate, epoprostenol, esomeprazole magnesium, fluticasone propionate, furosemide, Hydrochlorothiazide/triamterene, lamivudine, lamotrigine, lithium carbonate, LOSARTAN POTASSIUM, melphalan, purinethol, mesalazine, the mupirocin calcium cream, Na Biemin, naratriptan, omeprazole, ondansetron hydrochloride, ovine, oxiconazole nitrate, paroxetine hydrochloride, prochlorperazine mesylate, the kemadrin hydrochlorate, pyrimethamine, the ranitidine bismuth citrate, ranitidine hydrochloride, Luo Fukaoxi, the ropinirole hydrochlorate, the rosiglitazone maleate, salmeterol xinafoate, salmaterol, FLUTICASONE PROPIONATE, aseptic ticarcillin disodium/clavulanate potassium, suffering is cut down its spit of fland, spironolactone, succinylcholine chloride, sumatriptan, 2-am-inopurine-6-thiol, tirofiban HCI, the topotecan hydrochlorate, tranylcypromine sulfate, trifluoperazine hydrochloride, the valaciclovir hydrochlorate, nvelbine, Zha Namiwei, azidothymidine AZT, azidothymidine AZT, rummy husband fourth or its mixture.

21. a gastric retention device, it comprises compressor, and this compressor is enough firm when being taken in the back by the experimenter and fully expand and expand, to stop this device still to allow food to pass through by experimenter's pylorus in reaching 24 hours preset time.

22. the gastric retention device of claim 21, it further is included in therapeutic agent or the diagnostic agent of gastric than easier absorption in intestinal.

23. the gastric retention device of claim 21, its coefficient of expansion is at least 3.0.

24. the gastric retention device of claim 21, its coefficient of expansion is at least 6.0.

25. the gastric retention device of claim 21, its coefficient of expansion is at least 8.0.

26. a gastric retention device, it is formed by the mixture that comprises sugar, polysaccharide or its combination.

27. the gastric retention device of claim 1, wherein gel is a heat-induced gelation.

28. the gastric retention device of claim 1, wherein gel is the chemical induction gel.

29. the gastric retention device of claim 1, and further comprise Hydrochlorothiazide, ranitidine hydrochloride or amoxicillin.

30. the gastric retention device of claim 21, and further comprise Hydrochlorothiazide, ranitidine hydrochloride or amoxicillin.

31. the gastric retention device of claim 21, and further be included in device absorption back help coating, capsule or install erosive enzyme.

32. a gastric retention device, it comprises:

Compressor, it is enough firm when being taken in abundant expansion in back and expansion by the experimenter, to prevent that this device from still allowing food to pass through by experimenter's pylorus in reaching 24 hours preset time, this compressor further comprises the material that is selected from plasticizer, pH regulator agent, GI wriggling regulator, viscosity modifier, therapeutic agent, diagnostic agent, extender, surfactant and composition thereof; And

Be applied to the compressor outer surface be subject to the erosive coating of gastric juice or the compression gel be housed be subject to the erosive capsule of gastric juice.

33. an expandable gastric retention device, it is by the mixture preparation that comprises xanthan gum and locust bean gum, and this device is compressed the formation compressor, and this compressor has the coating that is applied to its outer surface or is loaded into and is subject in the erosive capsule of gastric juice.

34. the gastric retention device of claim 33, wherein device dewaters basically.

35. the gastric retention device of claim 33, wherein device is cryodesiccated.

36. the gastric retention device of claim 33, its coefficient of expansion that has is at least 3.0.

37. the gastric retention device of claim 33, wherein the weight ratio of xanthan gum and locust bean gum is about 1: 4 to about 4: 1.

38. the gastric retention device of claim 33, wherein the weight ratio of xanthan gum and locust bean gum is about 1: 1.

39. the gastric retention device of claim 33, it further comprises the material that is selected from plasticizer, pH regulator agent, GI wriggling regulator, viscosity modifier, therapeutic agent, diagnostic agent, extender, surfactant and composition thereof.

40. the gastric retention device of claim 39, wherein plasticizer is a Polyethylene Glycol.

41. the gastric retention device of claim 39, wherein the pH regulator agent is sodium phosphate or sodium hydrogen phosphate.

42. the gastric retention device of claim 39, wherein extender is a sodium lauryl sulphate.

43. the gastric retention device of claim 39, wherein viscosity modifier is a carbopol.

44. the gastric retention device of claim 39, wherein viscosity modifier is a polyvinylpyrrolidone.

45. the gastric retention device of claim 33, wherein this device is cube, cone (noting except the cone), cylinder, pyramid (noting except the cone), spheroid, cylinder or parallelepiped after expansion.

46. the gastric retention device of claim 33, wherein the weight ratio of xanthan gum and locust bean gum is about 1: 4 to about 4: 1, and this device further comprises the material that is selected from carbopol, sodium lauryl sulphate, PEG400 and composition thereof.

47. the gastric retention device of claim 46, wherein the weight ratio of xanthan gum and locust bean gum is about 1: 1.

48. the gastric retention device of claim 33, it further comprises the material that is selected from diagnostic agent, therapeutic agent and composition thereof.

49. the gastric retention device of claim 48, wherein medicament is selected from nucleic acid; protein; the AIDS adjuvant; the alcohol abuse preparation; the Alzheimer inorganic agent; the amyotrophic lateral sclerosis therapeutic agent; analgesic; anesthetis; antacid; anti-arrhythmia agent; antibiotic; anticonvulsant; antidepressant; the anti-diabetic medicament; antiemetic; antidote; the fibrosis therapeutic agent; antifungal; hydryllin; hypotensive agent; anti-infective; antibacterial; antineoplastic agent; tranquilizer; the anti-Parkinson medicament; antirheumatic; appetite stimulator; appetite suppressant; biological respinse modifier; biological preparation; Hemoregulatory; the bone modulators of metabolism; heart protective agent; cardiovascular agents; central nervous system stimulant; cholinesterase inhibitor; contraceptive; the cystic fibrosis inorganic agent; deodorizer; diagnostic agent; nutritional supplement; diuretic; dopamine-receptor antagonist; the endometriosis inorganic agent; enzyme; therapeutic agent for erection failure; fatty acid; gastrointestinal agent; ceramide glucoside enzyme deficiency disease inorganic agent; the gout preparation; homeopathic drug; hormone; the hypercalcemia inorganic agent; somnifacient; hypocalcemia disease inorganic agent; immunomodulator; immunosuppressant; ion exchange resin; levocarnitine lacks inorganic agent; mast cell stabilizers; the migraine preparation; the motion sickness goods; the multiple sclerosis inorganic agent; muscle relaxant; the anesthetics antidote; anesthetis; nucleoside analog; NSAID (non-steroidal anti-inflammatory drug); fat inorganic agent; the osteoporosis preparation; odinagogue; parasympathomimetic agent; parasympatholytic; phosphate binder; the hematoporphyria medicament; psychotherapy's agent; the radiopaque medicament; treatment psychosis medicament; sclerosing agent; tranquilizer; the sickle cell disease inorganic agent; the aiding smoking cessation medicament; steroid; analeptic; sympatholytic; sympathomimetic; Tourette syndrome medicine; preparation trembles; the urinary tract medicament; vagina preparation; vasodilation; dizzy medicine; anoretic; wilson disease inorganic agent and composition thereof.

50. the gastric retention device of claim 48, wherein medicament provides with the form of tablet, capsule, powder, globule, piller, granule, solid dispersion or its combination.

51. the gastric retention device of claim 48, wherein medicament is easier to be molten in gastric juice than in intestinal juice.

52. the gastric retention device of claim 48, wherein medicament absorbs in small intestinal than in large intestine better.

53. the gastric retention device of claim 48, wherein medicament is Hydrochlorothiazide, amoxicillin or ranitidine hydrochloride.

54. the gastric retention device of claim 33, wherein gel expand into its final size in 2 hours in aqueous environments.

55. the gastric retention device of claim 33, wherein gel expand into 60% of its final size in 2 hours in aqueous environments.

56. the gastric retention device of claim 33, wherein gel expand into 80% of its final size in 2 hours in aqueous environments.

57. the gastric retention device of claim 33, wherein gel expand into its final size basically and forms the expansion gel after being taken in by the experimenter in 2 hours.

58. the gastric retention device of claim 57, the gel that wherein expands prevents that gastric retention device from passing through pylorus in preset time.

59. the gastric retention device of claim 57, the gel that wherein expands has at least a size greater than the pylorus diameter.

60. the gastric retention device of claim 58, wherein device allows food to pass through pylorus.

61. the gastric retention device of claim 58, wherein gel corrodes in the presence of gastric juice and pass through pylorus behind preset time.

62. the gastric retention device of claim 33 wherein installs at experimenter's gastric and kept basically at least 2 hours.

63. the gastric retention device of claim 33 wherein installs at experimenter's gastric and kept basically at least 9 hours.

64. the gastric retention device of claim 33 wherein installs at experimenter's gastric and kept basically at least 24 hours.

65. the gastric retention device of claim 33, it further includes and helps the enzyme that stomach corrodes gel.

66. an energy is at least 24 hours gastric retention device of gastric stop, it comprises the inflatable device by the mixture preparation, described mixture comprises (a) carbohydrate natural gum, (b) be selected from the material of therapeutic agent, diagnostic agent, plasticizer, pH regulator agent, GI wriggling regulator, viscosity modifier, extender, surfactant and composition thereof, this device can fully compress and form a kind of shape that is subject in the erosive capsule of gastric acid that is suitable for embedding.

67. an energy is at least 9 hours gastric retention device of gastric stop, it comprises the inflatable device by the mixture preparation, described mixture comprises (a) xanthan gum and locust bean gum, (b) be selected from the material of therapeutic agent, diagnostic agent, plasticizer, pH regulator agent, GI wriggling regulator, viscosity modifier, extender, surfactant and composition thereof, this device can fully compress and form a kind of shape that is subject in the erosive capsule of gastric acid that is suitable for embedding.

68. an energy is at least 9 hours gastric retention device of gastric stop, it comprises the inflatable device by the mixture preparation, described mixture comprises about 0.1% xanthan gum to about 2.0% weight, about 0.1% locust bean gum to about 2.0% weight, be lower than the Polyethylene Glycol of 5% weight, be lower than 1% weight sodium lauryl sulphate, be lower than the carbopol of 1% weight, and therapeutic agent, diagnostic agent and the combination thereof of effective dose biologically, this device can fully compress and form a kind of shape that is subject in the erosive capsule of gastric acid that is suitable for embedding.

69. a method of making gastric retention device comprises:

Form a kind of mixture that comprises polysaccharide;

Mixture is processed to form the desiccant gel that is suitable for the form of experimenter's administration; With

Be subject in the erosive capsule of waterborne liquid with being subject to that the erosive material of gastric juice carries out coating to desiccant gel or gel placed.

70. the method for claim 69, wherein mixture comprises locust bean gum.

71. the method for claim 69, wherein mixture comprises xanthan gum.

72. the method for claim 69, wherein mixture comprises polysaccharide, locust bean gum and water.

73. the method for claim 69, wherein xanthan gum and locust bean gum account for about 1% to about 5% of mixture weight.

74. the method for claim 74, wherein mixture further comprises the material that is selected from therapeutic agent, diagnostic agent, plasticizer, pH regulator agent, GI wriggling regulator, viscosity modifier, extender, surfactant and composition thereof.

75. the method for claim 74, wherein medicament is selected from nucleic acid; protein; the AIDS adjuvant; the alcohol abuse preparation; the Alzheimer inorganic agent; the amyotrophic lateral sclerosis therapeutic agent; analgesic; anesthetis; antacid; anti-arrhythmia agent; antibiotic; anticonvulsant; antidepressant; the anti-diabetic medicament; antiemetic; antidote; the fibrosis therapeutic agent; antifungal; hydryllin; hypotensive agent; anti-infective; antibacterial; antineoplastic agent; tranquilizer; the anti-Parkinson medicament; antirheumatic; appetite stimulator; appetite suppressant; biological respinse modifier; the biological preparation Hemoregulatory; the bone modulators of metabolism; heart protective agent; cardiovascular agents; central nervous system stimulant; cholinesterase inhibitor; contraceptive; the cystic fibrosis inorganic agent; deodorizer; diagnostic agent; nutritional supplement; diuretic; dopamine-receptor antagonist; the endometriosis inorganic agent; enzyme; therapeutic agent for erection failure; fatty acid; gastrointestinal agent; ceramide glucoside enzyme deficiency disease inorganic agent; the gout preparation; homeopathic drug; hormone; the hypercalcemia inorganic agent; somnifacient; hypocalcemia disease inorganic agent; immunomodulator; immunosuppressant; ion exchange resin; levocarnitine lacks inorganic agent; mast cell stabilizers; the migraine preparation; the motion sickness goods; the multiple sclerosis inorganic agent; muscle relaxant; the anesthetics antidote; anesthetis; nucleoside analog; NSAID (non-steroidal anti-inflammatory drug); fat inorganic agent; the osteoporosis preparation; odinagogue; parasympathomimetic agent; parasympatholytic; phosphate binder; the hematoporphyria medicament; psychotherapy's agent; the radiopaque medicament; treatment psychosis medicament; sclerosing agent; tranquilizer; the sickle cell disease inorganic agent; the aiding smoking cessation medicament; steroid; analeptic; sympatholytic; sympathomimetic; Tourette syndrome medicine; preparation trembles; the urinary tract medicament; vagina preparation; vasodilation; dizzy medicine; anoretic; wilson disease inorganic agent and composition thereof.

76. the method for claim 74, wherein mixture further comprises Hydrochlorothiazide.

77. the method for claim 74, wherein processing comprises gel is carried out lyophilization.

78. the method for claim 69, wherein process mixture comprises that heating blends forms gel with the gelation of thermal induction mixture effectively.

79. the method for claim 69, it is compressed into size and the shape that is suitable for experimenter's administration to desiccant gel before further being included in gel being carried out coating or put it into capsule.

80. the method for claim 74, wherein medicament provides by the form of tablet, capsule, powder, globule, piller, granule, solid dispersion or its combination.

81. a method of making gastric retention device comprises:

Form a kind of mixture, this mixture comprise polysaccharide and be selected from plasticizer, pH-meter, GI wriggling regulator, viscosity modifier, therapeutic agent, diagnostic agent, extender, surfactant, and composition thereof material;

Heating blends is to being enough to induce the mixture gelation to form the temperature of gel;

Gel drying is formed desciccator diaphragm;

The desciccator diaphragm compression is formed compressive films; With

Be subject in the erosive capsule of gastric juice with being subject to that the erosive material of gastric juice carries out coating to compressive films or gel placed.

82. the method for claim 81, it further is included in and introduces abacavir sulfate in the gel, abacavir sulfate/lamivudine/zidovudine, acetazolamide, acycloguanosine, albendazole, salbutamol, spironolactone, allopurinol BP, the amoxicillin, amoxicillin/clavulanate potassium, amprenavir, atropic cuts down ketone, atropic cuts down ketone and proguanil hydrochlorate, the atracurium benzene sulfonate, beclomethasone dipropionate, the berlactone Betamethasone 17 valerate, the BUP hydrochlorate, BUP hydrochlorate SR, carvedilol, caspofungin acetate, cefazolin sodium, ceftazidime, cefuroxime (non-sulfuric acid salt), chlorambucil, chlorpromazine, cimetidine, the cimetidine hydrochlorate, the cisatracurium benzene sulfonate, CBP, bactrim, the colfosceril palmitate, dextroamphetamie sulfate, digoxin, English sodium Puli maleate, epoprostenol, esomeprazole magnesium, fluticasone propionate, furosemide, Hydrochlorothiazide/triamterene, lamivudine, lamotrigine, lithium carbonate, LOSARTAN POTASSIUM, melphalan, purinethol, mesalazine, the mupirocin calcium cream, Na Biemin, naratriptan, omeprazole, ondansetron hydrochloride, ovine, oxiconazole nitrate, paroxetine hydrochloride, prochlorperazine mesylate, the kemadrin hydrochlorate, pyrimethamine, the ranitidine bismuth citrate, ranitidine hydrochloride, Luo Fukaoxi, the ropinirole hydrochlorate, the rosiglitazone maleate, salmeterol xinafoate, salmaterol, FLUTICASONE PROPIONATE, aseptic ticarcillin disodium/clavulanate potassium, suffering is cut down its spit of fland, spironolactone, succinylcholine chloride, sumatriptan, 2-am-inopurine-6-thiol, tirofiban HCI, the topotecan hydrochlorate, tranylcypromine sulfate, trifluoperazine hydrochloride, the valaciclovir hydrochlorate, nvelbine, Zha Namiwei, azidothymidine AZT, azidothymidine AZT, rummy husband fourth or its mixture.

83. a method of using gastric retention device, it comprises:

A kind of gastric retention device is provided; With

Use gastric retention device to the experimenter.

84. the method for claim 83, wherein gastric retention device further comprises therapeutic agent, diagnostic agent or its mixture.

85. the method for claim 83, wherein therapeutic agent or diagnostic agent are abacavir sulfate, abacavir sulfate/lamivudine/zidovudine, acetazolamide, acycloguanosine, albendazole, salbutamol, spironolactone, allopurinol BP, the amoxicillin, amoxicillin/clavulanate potassium, amprenavir, atropic cuts down ketone, atropic cuts down ketone and proguanil hydrochlorate, the atracurium benzene sulfonate, beclomethasone dipropionate, the berlactone Betamethasone 17 valerate, the BUP hydrochlorate, BUP hydrochlorate SR, carvedilol, caspofungin acetate, cefazolin sodium, ceftazidime, cefuroxime (non-sulfuric acid salt), chlorambucil, chlorpromazine, cimetidine, the cimetidine hydrochlorate, the cisatracurium benzene sulfonate, CBP, bactrim, the colfosceril palmitate, dextroamphetamie sulfate, digoxin, English sodium Puli maleate, epoprostenol, esomeprazole magnesium, fluticasone propionate, furosemide, Hydrochlorothiazide/triamterene, lamivudine, lamotrigine, lithium carbonate, LOSARTAN POTASSIUM, melphalan, purinethol, mesalazine, the mupirocin calcium cream, Na Biemin, naratriptan, omeprazole, ondansetron hydrochloride, ovine, oxiconazole nitrate, paroxetine hydrochloride, prochlorperazine mesylate, the kemadrin hydrochlorate, pyrimethamine, the ranitidine bismuth citrate, ranitidine hydrochloride, Luo Fukaoxi, the ropinirole hydrochlorate, the rosiglitazone maleate, salmeterol xinafoate, salmaterol, FLUTICASONE PROPIONATE, aseptic ticarcillin disodium/clavulanate potassium, suffering is cut down its spit of fland, spironolactone, succinylcholine chloride, sumatriptan, 2-am-inopurine-6-thiol, tirofiban HCI, the topotecan hydrochlorate, tranylcypromine sulfate, trifluoperazine hydrochloride, the valaciclovir hydrochlorate, nvelbine, Zha Namiwei, azidothymidine AZT, azidothymidine AZT, rummy husband fourth or its mixture.

86. the method for claim 83, wherein gastric retention device comprises a kind of inflatable device by the mixture preparation that contains polysaccharide and locust bean gum, this inflatable device is compressed forms the compressor that size is suitable for swallowing, this compressor scribbles at its outer surface and is subject to the erosive coating of gastric juice or is loaded into be subject to that gastric juice is erosive to be absorbed in the capsule.

87. the method for claim 86, wherein gastric retention device comprises a kind of compressor, enough firm when fully expanding when this compressor is ingested and expanding, to prevent that this device from still allowing food to pass through by experimenter's pylorus in reaching at least 24 hours preset time, this compressor further comprises and is selected from therapeutic agent, diagnostic agent, plasticizer, the pH regulator agent, the GI regulator of wriggling, viscosity modifier, extender, the material of surfactant and composition thereof, compressor scribble at its outer surface and are subject to the erosive coating of gastric juice or are loaded into be subject in the erosive capsule of gastric juice.

88. the method for claim 83, wherein gastric retention device comprises a kind of inflatable device by the mixture preparation that contains xanthan gum and locust bean gum, inflatable device is compressed the formation compressor, and this compressor scribbles coating or is loaded at its outer surface and is subject in the erosive capsule of gastric juice.

89. the method for claim 84, wherein the size of GRD enough also can arrive colon with diagnostic agent and/or therapeutic agent delivery by pylorus.

90. the method for claim 84, wherein GRD further comprises enteric coating and diagnostic agent and/or therapeutic agent delivery can be arrived colon.

91. the method for an appetite-suppressing, it comprises:

A kind of gastric retention device is provided, and this device fully expands to suppress experimenter's appetite at least in part at experimenter's gastric; With

The experimenter is used gastric retention device.

92. the method for claim 91, wherein device further comprises fatty acid, appetite suppressant, anoretic or its combination of effective dose.

93. the method for an appetite-suppressing, it comprises:

A kind of gastric retention device is provided, and this device fully expands in experimenter's intestinal to suppress experimenter's appetite at least in part; With

The experimenter is used gastric retention device.

94. the method for claim 93, wherein device further comprises fatty acid, appetite suppressant, anoretic or its combination of effective dose.

95. a peroral dosage form, it comprises and forms the dehydrated polymer gel that size is suitable for swallowing, and contains excipient, and the weight of described dehydrated polymer is 1 gram or still less.

96. the peroral dosage form of claim 95, its formation is suitable for the size of nose administration.

97. the peroral dosage form of claim 95, its formation is suitable for the size of vagina administration.

98. the peroral dosage form of claim 95, its formation is suitable for the size of rectally.

99. the peroral dosage form of claim 95, its formation is suitable for the size through enteral administration.

100. the peroral dosage form of claim 95 forms the size that is suitable for oral administration.

101. the method for claim 83, it further comprises diagnostic agent or therapeutic agent, wherein the medicament of in two hours, sending be the total medicament sent about 2% to about 70%, and the medicament of sending in twenty four hours is about 35% to about 100% of total diagnostic agent sent or a therapeutic agent.

102. the method for claim 83, it further comprises ranitidine hydrochloride, wherein suitably sending by USP oar formula agitating device in-vitro measurements in the aqueous medium under 37 ℃, and the ranitidine hydrochloride of wherein sending in two hours is the about 70% of the total ranitidine hydrochloride sent, and the ranitidine hydrochloride of sending in twenty four hours is about 100% of the total ranitidine hydrochloride sent.

103. the method for claim 83, it further comprises riboflavin, wherein suitably sending by USP oar formula agitating device in-vitro measurements in the aqueous medium under 37 ℃, and the riboflavin of wherein sending in two hours is the about 2% of the total riboflavin sent, and the riboflavin of sending in twenty four hours is about 35% of the total riboflavin sent.

104. the method for claim 83, wherein diagnostic agent or therapeutic agent are riboflavin, wherein send in the homaluria measuring body by riboflavin, and wherein the riboflavin of sending in two hours is the about 15% of the total riboflavin sent, and the riboflavin of sending in twenty four hours is about 100% of the total riboflavin sent.

105. the method for claim 83, wherein diagnostic agent or therapeutic agent are Hydrochlorothiazide, and sending by measuring voided volume of Hydrochlorothiazide assessed, and wherein the voided volume in two hours is the about 10% of 42 hours tatol emiction quantities, and the voided volume of twenty four hours is about 75% of 42 hours tatol emiction quantities.

106. method of using the gastric retention device of claim 83, wherein use the diagnostic agent or the therapeutic agent that are positioned at gastric retention device and produce first result, when with second result who uses the diagnostic agent that do not have gastric retention device or therapeutic agent gained relatively the time, first result produces the biological action that needs.

107. the method for claim 106, wherein diagnostic agent or therapeutic agent are Hydrochlorothiazides, and the biological action that needs is to increase total voided volume.

108. the method for claim 83, it is used to measure the GI absorption position of diagnostic agent or therapeutic agent, wherein administration comprises and uses a kind of GRD, and this GRD has enough sizes and passes through pylorus to prevent GRD, and comprises that further the GI that measures diagnostic agent or therapeutic agent absorbs the position.

109. the method for claim 83, its GI that is used to measure diagnostic agent or therapeutic agent absorbs the position, and wherein administration comprises and uses a kind of GRD, and this GRD has enough sizes with by pylorus, and comprises that further the GI that measures diagnostic agent or therapeutic agent absorbs the position.

Images