CN112807283A - Novel oral pellet drug delivery system for gastrointestinal tract - Google Patents

Abstract

The present invention relates to a drug delivery system in the form of a drug delivery system. More particularly, the present invention relates to a drug delivery system for prolonged residence in the stomach comprising a reservoir of an expandable material containing tiny pills. A pellet delivery system for delivering an effective drug into a living organism is disclosed. The drug delivery system includes a hydrogel reservoir containing tiny pills (pellets for short). The pellet comprises a wall surrounding a core containing the drug. The advantages are that: delivery systems that retain in the stomach and controllably release drugs to achieve therapeutic blood concentrations are useful in clinical medical applications.

Description

Novel oral pellet drug delivery system for gastrointestinal tract

Technical Field

The present invention relates to a drug delivery system in the form of a drug delivery system. More particularly, the present invention relates to a drug delivery system for prolonged residence in the stomach comprising a reservoir of an expandable material containing tiny pills.

Background

There is an urgent need for a drug delivery system that can be retained in the stomach for a long period of time. The system requires retention in the stomach and as an in vivo reservoir that controls the release of the drug and provides sustained absorption (a) in the stomach or (b) into the intestinal tract where it is absorbed. Drug delivery systems are used clinically for the administration of effective drugs, usually drugs are administered either (1) through a delivery system that releases the drug at different sites normally followed by evacuation of the gastrointestinal tract or (2) through a delivery system that resides and releases the drug in the stomach. The delivery system is used because it eliminates the inconvenience of multiple repeat administrations of a single dose of an immediate release formulation. The convenience of using drug delivery systems that release drug over an extended period of time as opposed to multiple administrations of a single immediate release formulation has long been recognized in pharmaceutical applications. This regimen, which is popular with patients and clinicians, is controllable to optimize the plasma concentration of the drug over the time it is released from the delivery system. This regimen is benefited by a delivery system that continuously releases the drug for absorption into the blood stream to replace the drug that the patient has used, cleared, or metabolically inactivated.

The above introduction teaches that in the field of health care management, delivery systems are available for the sustained delivery of drugs for better treatment. For example, patentee Blythe discloses in U.S. Pat. No. 2,738,303 a system for sustained release of a drug over an extended period of time. The delivery system disclosed in this patent consists essentially of a capsule containing uncoated pellets and pellets of different coating thicknesses. Upon release from the capsule, the uncoated pellets provide an initial dose of the drug and the coated pellets provide a subsequent dose of the drug. Another delivery system is disclosed in U.S. Pat. Nos. 4,140,775 and 4,167,558, which systems are primarily composed of tablets compressed from a polymer containing a dispersed drug. The system is capable of maintaining hydrodynamic equilibrium and retaining in the stomach for sustained release of the drug in the stomach.

Although the above-described delivery systems are designed to provide a continuous supply of medication, there are inherent disadvantages associated with these delivery systems themselves. For example, pills often pass rapidly through the gastrointestinal tract, which often restricts the supply of medication to maintain the desired blood concentration. In addition, since the pills can be emptied with the stomach in a first flight like a liquid, the pills cannot be retained in the stomach for a long time. The tablets release the drug at an uncontrolled and decreasing rate upon exposure to gastric fluid, thereby limiting their use as controlled release delivery systems during gastric residence.

In view of the above, those skilled in the art will recognize that if a delivery system is provided that can be retained in the stomach and act as a drug reservoir in the body while releasing the drug in the stomach (a) for absorption by the stomach, or (b) into and for absorption in the intestine, without substantially disrupting the normal emptying of ingested food and fluids. Such a delivery system would have positive significance and represent a significant contribution to the art. Likewise, those skilled in the art will recognize that such delivery systems would be useful in clinical medicine applications if they could provide a delivery system that resides in the stomach and controllably releases drugs to achieve therapeutic blood concentrations.

Disclosure of Invention

In view of the above, it is a direct object of the present invention to provide a novel and useful drug delivery system which fulfils a long-felt need and overcomes the drawbacks known from the prior art.

It is another object of the present invention to provide a drug delivery system which is simple in construction and which actually exhibits the beneficial effects of controlled and sustained drug delivery over a prolonged period of time in animals and humans.

It is another object of the present invention to provide a drug delivery system which is manufactured in the form of a drug delivery system, which is capable of staying in the stomach for a long period of time and exerting a therapeutic effect therein.

It is a further object of the present invention to provide a drug delivery system comprising a reservoir formed of an expandable material containing tiny pills, which can be used to maintain the stomach in a fed state and/or simultaneously vacate a retention space of the delivery system in the stomach.

It is a further object of the present invention to provide a drug delivery system which includes a swellable reservoir containing tiny pills which stay in the stomach for extended periods of time for the drug to be effective in the stomach or subsequently enter the intestinal tract.

It is a further object of the present invention to provide a drug delivery system which, by virtue of its size, will stay in the stomach during eating, where it will enter the small intestine after prolonged erosion.

It is a further object of the present invention to provide a drug delivery system that is sized to be retained in the stomach, releasing the drug into the stomach and subsequently into the intestine.

The above objects as well as other objects, features and advantages of the present invention will become apparent from the following detailed description of the invention, the accompanying drawings and the appended claims.

Drawings

Fig. 1 is a profile view of an oral drug delivery device of the present invention.

Fig. 2 is a view taken at section 2-2 of fig. 1.

Fig. 3 is a corresponding view of fig. 2 after swelling/expansion of the device.

Fig. 4 is a cross-sectional view of individual pellets as released by the devices shown in fig. 1-3.

Detailed Description

Examples

The delivery system of this embodiment may be comprised of a reservoir formed of a material that does not adversely affect the medicament, animal or other subject. Presently preferred materials for forming reservoirs include hydrogels that have the ability to swell in water and retain a large amount of water within their structure. The hydrogel may be non-crosslinked or may be crosslinked by labile covalent or ionic bonds. Hydrogels can be of plant or animal origin, can be prepared by modifying naturally occurring structures, and synthetic polymer hydrogels. Polymer hydrogels are capable of swelling or expanding, typically increasing in volume by 2 to 50 times. Hydrophilic polymeric materials useful for this purpose include poly (hydroxyalkyl methacrylates), poly (electrolyte complexes), hydrolyzable crosslinked poly (vinyl acetate), water swellable N-vinyl lactam polysaccharides, natural gums, agar, agarose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, salsa, Eucheuma, acacia, ghatti gum, karaya gum, tragacanth gum, locust bean gum, arabinogalactan, pectin, pullulan, gelatin, hydrophilic colloids (e.g., carboxymethylcellulose gum or alginate gum crosslinked with a polyol such as propylene glycol), and the like.

Other hydrogels include the following hydrophilic hydrogels: carbopol acid carboxyl polymer, Cyanamer polyacrylamide, Good-rite polyacrylic acid, polyethylene oxide, starch graft copolymer, Aqua-Keeps acrylic ester polymer, ester cross-linked polyglucan and the like.

In the minipill, the wall surrounding the drug may be a wall-forming composition consisting essentially of a fatty acid ester mixed with a wax, such as a triglyceride, which may be selected from the group consisting of glyceryl distearate, glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monolaurate, glyceryl dibehenate, glyceryl tribehenate, glyceryl monobehenate, glyceryl monocaprate, glyceryl didecanoate, glyceryl tricaprate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecanoate, glyceryl didecanoate, and glyceryl tridecanoate.

The wax comprising the composition formed in the wall is selected substantially from the group consisting of beeswax, cetyl palmitate, ceresin, carnauba wax, cetyl myristate, cetyl palmitate, cetyl cerolate, stearyl palmitate, stearyl myristate and lauryl laurate.

The combination of ester and wax may be wrapped around the drug using an organic solvent such as selected from carbon tetrachloride, chloroform, trichloroethylene, ethers, benzene, ethyl acetate, methyl ethyl ketone, isopropyl alcohol, and the like. Us patent 2,793,979 discloses the use of fatty esters, waxes, solvents and processes for preparing pellets that disintegrate slowly and release drug continuously over a period of 10 to 12 hours.

In another embodiment, the wall of the pellet is formed of an osmotic material that provides controlled release of the drug by permeation over time. In this embodiment, the drug is present in the form of a solute, such as a therapeutically acceptable salt, and an osmotic pressure differential is created across the wall to the external fluid. The membrane material used to form the wall is permeable to external liquids and substantially impermeable to the drug. Commonly used materials include one selected from: cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate having a degree of substitution of about 1 and 21% of acetyl content, cellulose diacetate having a degree of substitution of 1 to 2 and 21 to 35% of acetyl content, cellulose triacetate having a degree of substitution of 2 to 3 and 35 to 44.8% of acetyl content, cellulose acetopropionate, cellulose acetate butyrate and the like. The osmotic wall may be coated around the drug to varying thicknesses by pan coating, spray coating, fluidized bed coating, and the like. The coating is carried out using an organic solvent including the above-mentioned solvents, and a solvent system such as dichloromethane-methanol, dichloromethane-acetone, methanol-acetone, dichloroethane-acetone, etc. to form a wall.

In another embodiment, the wall 1 may be made of a controlled drug release material. I.e. the drug dissolves within the wall and is controllably released over time and passes through the wall. Exemplary materials that can be used to form the controlled release wall are ethylene vinyl acetate, ethyl cellulose, polyethylene, cross-linked polyvinylpyrrolidone, vinylidene chloride-acrylonitrile copolymer, polypropylene, silicone, and the like.

In yet another embodiment, the wall is made of a bioerodible material that bioerodes at a controlled rate and releases the drug into the biological environment of use. Materials for forming the wall bioerodible degradation include polyacidic or basic mobile crosslinked polyelectrolytes, polycarboxylic acids, polyesters, polyamides, polyimides, polylactic acids, polyglycolic acids, polyorthoesters, and polyorthocarbonates.

In the specification and the appended claims, the term drug includes pharmacologically active substances that produce a local or systemic effect in an animal. Animals include warm-blooded mammals, such as humans. Active agents that may be delivered include agents that act on the central nervous system, inhibitors, hypnotics, sedatives, stimulants, tranquilizers, anticonvulsants, muscle relaxants, antiparkinsonian agents, analgesics, anti-inflammatories, hormonal agents, contraceptives, sympathomimetics, diuretics, antiparasitics, neoplasms, hypoglycemic agents, ocular agents, electrolytes, cardiovascular agents, and the like.

Drugs that are soluble in water and can be delivered by the delivery system of the present invention, such as prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, benzphetamine hydrochloride, isoproterenol sulfate, methamphetamine hydrochloride, phenmetrazine hydrochloride, becylcholine chloride, methacholine chloride, atropine sulfate, scopolamine methylbromide, iodoipramine, triamcinolone, oxprenolol hydrochloride, metoprolol hydrochloride, cimetidine hydrochloride, and the like.

Drugs having limited solubility in water and which can be delivered by the delivery system of the present invention, such as meclizine hydrochloride, phenoxybenzamine, ethiprole maleate, anisindione, tetranitrated esters, dezocine, reserpine, acetazolamide, mechloraz, natriuretic, chlorpropamide, tolazamide, chlormaderamide acetate, aspirin aluminum, methotrexate, sulfacetamide, erythromycin, progestins, estrogens, progestogens, corticosteroids, and the like.

Other drugs that may be delivered by the delivery system of the present invention, such as aspirin, indomethacin, naproxen, fenoprofen, sulindac, diclofenac, indoprofen, propranolol, metoprolol, oxprenolol, timolol, clonidine, theophylline, ferrous lactate, phenoxybenzamine, baclofen, furantoin, and the like.

The drug may be present in the pellet in various forms, such as unaltered molecules, molecular complexes, therapeutically acceptable salts, such as hydrochloride, hydrobromide, sulfate, oleate, and the like. For acid drugs, such as metal salts, amine salts or organic cations, quaternary ammonium salts may be used. Derivatives of the drug, such as esters, ethers, and amides, may also be used. Similarly, water-insoluble drugs may be used in the solute form of their water-soluble derivatives, which, when released from the delivery system, are converted enzymatically, hydrolyzed by the body's pH environment, or other metabolic pathways into the originally biologically active form. Typically, the amount of drug in the pellets is from about 10 ng to about 20 mg, and the number of pellets in an oral delivery system is from about 10 to about 1000, preferably from about 100 to about 150. The pellets are at least 100 microns in diameter, and in a presently preferred embodiment, at least 2000 microns in diameter. The delivery system comprises a reservoir and micro-pills uniformly or heterogeneously distributed therein, and can be made into conventional shapes such as round, oval and the like for oral administration. The delivery system may have a diameter of 3/16 inches to 1/2 inches, etc.

The following examples further illustrate the invention. An oral tablet containing sympathomimetic pellets was prepared as follows: the powdered drug is mixed with sucrose and the mixture is passed through a 15 to 30 mesh screen to granulate into drug pellet cores. A composition of 85% glyceryl monostearate and 15% beeswax, as a wall forming material, was then dissolved in hot carbon tetrachloride and sprayed through the coating pan onto the pellet cores until a coated wall was formed on each pellet core. Next, after coating of the pellets was complete, about 50 pellets were mixed with about 200 mg of crushed carboxyvinyl polymer (Carbopol polymers) to form a depot and compressed into a series of oral tablets on a tablet press at 4kg pressure.

Another drug delivery system is the preparation of pellets by coating the pellets with a coating, such as procainamide hydrochloride, using an ethylcellulose composition dissolved in ethanol, in a fluidized bed, and coating the drug pellet cores with the procainamide hydrochloride. After the pellets were vacuum stripped of solvent, they were mixed with ground lightly cross-linked polyacrylamide and compressed into oral tablets.

The above product preparation can be reproduced by replacing ethylcellulose and ethanol, respectively, with cellulose acetate having an acetyl content of 32% and dichloromethane methanol solvent, or by coating the periphery of the drug pellet core with a bioerodible poly (2, 2-dioxo-trans-1, 4-cyclohexanedimethylenetetrahydrofuran) wall. The latter may be coated by heating the polymer to 80-90 ℃ and then dispersing the drug pellet core in the polymer.

In another example, a sustained release drug pellet core is first prepared prior to preparation of the delivery system by mixing 400ml of ethylcellulose-water (70: 30%, 7.5% w: v) with 375g theophylline, 150g mannitol, and 475g magnesium stearate, kneading the mixture and passing through an extrusion granulator. After drying at 115-120F, the drug pellet cores were passed through a 20 mesh screen and coated with ethylcellulose in a fluidized bed to form a wrap to prepare controlled release pellets. Next, a plurality of pellets were mixed with a hydrogel polymer as a reservoir matrix, which polymer consisted essentially of alginate gel powder cross-linked with propylene glycol with an adhesive network that absorbs and immobilizes moisture, and the mixture was then compressed in a tablet press using an 11/32 inch deep concave die to prepare a drug delivery system. The delivery system can be used as bronchodilator for oral administration to treat asthma, and can also be used as pulmonary vasodilator and smooth muscle relaxant. Other forms of theophylline may also be used in the preparation of delivery systems, such as sodium theophylline acetate, sodium theophylline glycinate, [7 (2, 3-dihydroxypropyl) ] theophylline, theophylline meglumine and theophylline monoethanolamine.

Other drug delivery systems are prepared by spraying an edible binder onto a blank pellet core while the drug is being spread. Coating the pill core after being loaded with the medicine with a proper amount of edible enteric coating to obtain the enteric-coated pellet. The number of enteric coating layers is variable and is usually at least 1-10 coatings for this purpose. Finally, the mini-pill is loaded into a hydrogel reservoir.

Similarly, these micropellets may be prepared from a blank pellet core of carbohydrate (e.g., sucrose) on which a mixture of talc, starch and galactose is sprayed together, moistened with distilled or deionized water, and the desired drug (e.g., antibiotic: amoxicillin) is applied. The pill is dried and then coated with a layer of nontoxic and acidic enteric-coated wall. The enteric material is typically selected from, for example, keratin, calcium alginate, shellac, partially hydrolyzed styrene-maleic acid copolymer, polyvinyl acetate phthalate, polyvinyl hydrogen phthalate, and the like. Finally, the pellets are dispersed in a hydrogel reservoir matrix, the reservoir being sized and shaped for oral entry into the gastrointestinal tract.

This example provides a schematic representation of various drug delivery systems and should not be construed as limiting the patent. A schematic view of the drug delivery system as a whole is shown in figures 1 to 3 and is indicated generally by the numeral 10. In fig. 1-3, it can be seen that delivery system 10 includes a body 11, body 11 being of a suitable shape and size to facilitate entry into the gastrointestinal tract from the mouth and to extend residence time in the stomach. In fig. 2 and 3, seen in cross-section, the body 11 comprises a reservoir 12 formed of a non-toxic material which swells and expands in the presence of a liquid in the environment of use, such as water or gastric fluid. In a presently preferred embodiment, the material forming the reservoir 12 is a hydrophilic polymer, such as a hydrogel. In fig. 2, the reservoir 12 made of hydrophilic material is in a non-hydrated state, while in fig. 3, the post-distended state of the reservoir 12 is shown. The material absorbs liquid from the environment of use and swells or expands to equilibrium. The drug delivery system 10 is retained in the stomach for a long period of time after the size increase. During and at the end of drug delivery, the reservoir 12 is less susceptible to degradation by constant hydrolysis or bioerosion and thus is removed from the environment of use. Materials that may be used to form the reservoir 12 are described in later sections of the specification.

In the drug delivery system 10 depicted in fig. 1-3, it can be seen from the cross-sectional views of fig. 2 and 3 that it contains a plurality of pellets 13 for controlled release of the drug. The pellet 13 structure shown in fig. 4, inside which is a core of drug 14 pellets, is surrounded by a wall 15 formed of a controlled release material. The wall 15 of the pellet 13 may be made of a material that releases the drug 14 in the stomach, or may be made of an enteric material. The enteric material may prevent release of the drug 14 in the stomach, but may release the drug 14 in the intestine. In addition, the material forming the wall 15 may also be selected from materials that release the drug 14 by different physico-chemical mechanisms. These mechanisms include erosion, diffusion, osmosis, metabolism, and the like. The wall 15 may have different thicknesses to assist in the controlled release of the drug. A description of the materials forming the wall will appear later in this specification.

In use, the drug delivery system 10 is able to stay in the stomach for a longer period of time by simultaneously (1) expanding in the stomach and (2) maintaining the stomach in a fed state. (a) The drug delivery system 10 releases the drug 14 to the stomach over a long period of time via the non-enteric pellets 13, or (b) the drug delivery system 10 releases the enteric pellets 13 first, and the pellets 13 release the drug 14 when flowing through the intestinal tract, so as to achieve the effect of releasing the drug 14 in a delayed manner.

Those skilled in the art will recognize that the present invention provides a novel and useful delivery and drug delivery system for delivering effective drugs over an extended period of time. As such, those skilled in the art will appreciate that many embodiments of the invention can be made without departing from the spirit and scope of the invention, and that the invention is not to be considered as limiting, but rather to encompass all equivalents therein.

Claims (4)

1. An oral delivery system for controlled release of an effective drug to the gastrointestinal tract over an extended period of time, the oral delivery system comprising:

(a) a suitable shape and size to facilitate entry into the gastrointestinal tract and comprising a pharmaceutically acceptable, non-toxic, unhydrated cellulose gum which absorbs fluid from within the gastrointestinal tract, swells and increases in volume by a factor of 2 to 50 for prolonged residence time in the gastrointestinal tract, said cellulose gum being selected from the group consisting of non-crosslinked, covalently crosslinked and ionically crosslinked cellulose gums selected from the group consisting of natural and synthetic cellulose gum materials;

(b) micro-pills dispersed throughout a cellulosic matrix, the micro-pills comprising:

(1) an orally effective dose of the drug;

(2) a wall comprising a biodegradable material having a pharmaceutically acceptable release rate for releasing a drug in the gastrointestinal tract;

the material is selected from the group consisting of polyesters, polyimides, and polyorthoesters, said material substantially surrounding an effective administered dose of the drug;

(c) when the delivery system is in the gastrointestinal tract, the delivery system delivers the treatment by delivering an effective drug.

2. An oral delivery system for controlled release of an effective drug to the gastrointestinal tract over an extended period of time, said oral delivery system comprising

(1) The body is suitably shaped and sized to enter the gastrointestinal tract and to be retained in the stomach for a prolonged period of time;

as an in vivo depot for delivering an orally effective dose of a drug to and effecting treatment in the gastrointestinal tract, the body comprising:

(2) a pharmaceutically acceptable non-toxic cellulose gum having the ability to retain fluid within its cellulose gum structure, absorb fluid from the gastrointestinal tract, swell and increase in volume by at least 2 times, so as to retain the delivery system in the stomach for an extended period of time;

(3) micro-pills distributed within the body, the micro-pills comprising:

(a) an orally effective dose of the drug;

(b) a wall comprised of a controlled release composition of a drug, said composition comprising polylactic acid surrounding an administered dose of the drug;

(4) when the delivery system is in a fluid environment in the gastrointestinal tract, and the treatment is effected by:

(a) the micro pills release the medicine in the stomach, and the medicine is absorbed by the stomach and the intestinal tract when reaching the intestine;

(b) the micro-pills release the drug for a long time after entering the intestinal tract.

3. An oral delivery system for controlled release of an effective drug to the gastrointestinal tract over an extended period of time, the oral delivery system comprising:

(1) the body is suitably shaped and sized to enter the gastrointestinal tract and to be retained in the stomach for a prolonged period of time; as an in vivo depot for delivering an orally effective dose of a drug to and effecting treatment in the gastrointestinal tract, the body comprising

(2) A pharmaceutically acceptable non-toxic cellulose gum having the ability to retain fluid within its cellulose gum structure, absorb fluid from the gastrointestinal tract, swell and increase in volume by at least 2 times, so as to retain the delivery system in the stomach for an extended period of time;

(3) micro-pills distributed within the body, the micro-pills comprising:

(a) an orally effective dose of the drug;

(b) a wall comprised of a controlled release composition of a drug, said composition comprising polyglycolic acid surrounding an administered dose of the drug;

(4) when the delivery system is in a fluid environment in the gastrointestinal tract, and the treatment is effected by:

(c) the micro pills release the medicine in the stomach, and the medicine is absorbed by the stomach and the intestinal tract when reaching the intestine;

(d) the micro-pills release the drug for a long time after entering the intestinal tract.

4. An oral device for controlled release of an effective drug to the gastrointestinal tract over an extended period of time, said oral delivery system comprising:

(1) the body is suitably shaped and sized to enter the gastrointestinal tract and to be retained in the stomach for a prolonged period of time;

as an in vivo depot for delivering an orally effective dose of a drug to and effecting treatment in the gastrointestinal tract, the body comprising:

(2) a pharmaceutically acceptable non-toxic cellulose gum having the ability to retain fluid within its cellulose gum structure, absorb fluid from the gastrointestinal tract, swell and increase in volume by at least 2 times, so as to retain the device in the stomach for an extended period of time;

(3) micro-pills distributed within the body, the micro-pills comprising:

(a) an orally effective dose of the drug;

(b) a wall comprised of a controlled drug release composition comprising a polyamide surrounding an administered dose of drug;

(4) when the device is in the fluid environment of the gastrointestinal tract, and the treatment is performed, the device has effective effects by the following modes:

(c) the micro pills release the medicine in the stomach, and the medicine is absorbed by the stomach and the intestinal tract when reaching the intestine;

(d) the micro-pills release the drug for a long time after entering the intestinal tract.

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