|Publication number||US3247066 A|
|Publication date||Apr 19, 1966|
|Filing date||Sep 12, 1962|
|Priority date||Sep 12, 1962|
|Also published as||DE1617724A1|
|Publication number||US 3247066 A, US 3247066A, US-A-3247066, US3247066 A, US3247066A|
|Inventors||Milosovich Jr George|
|Original Assignee||Parke Davis & Co|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (10), Referenced by (79), Classifications (15)|
|External Links: USPTO, USPTO Assignment, Espacenet|
April 19, 1966 M osovm JR 3,247,066
CONTROLLED RELEASE DOSAGE FORM CONTAINING WATER-SWELLABLE BEADLET Filed Sept. 12, 1962 IN VEN TOR.
GIORGZ' 44/1 080 V/(Af JR.
ATTORNEY United States Patent Ofiice 3,247,066 CONTROLLED RELEASE DOSAGE FORM CON- TAINING WATER-SWELLABLE BEADLET George Milosovich, Jr., Ann Arbor, Mich, assignor to Parke, Davis & Company, Detroit, Mich, a corporation of Michigan Filed Sept. 12, 19-62, Ser. No. 223,093 Claims. (Cl. 1-67-82) This application is a continua'tion-in-part of my application Serial No. 81,277, filed January 9, 1961, now abandoned.
The present invention relates to novel forms and compositions of medicaments possessing advantages which are of value in the pharmaceutical field and other fields. More particularly, the invention relates to new controlled release dosage forms for the internal administration of medicaments.
The utilization of the principle of controlled release or timed released as exemplified by conventional sustained release, prolonged action, repeat action, or time delay types of-dosage forms has become increasingly more important in recent years. These dosage forms possess several advantages previously unattainable by conventional techniques. A single dose can provide a nearly constant blood level of medicament over an eight to twelve hour period of time eliminating the peak and valley type blood level picture previously obtained with single doses administered at more frequent time intervals. It has been found that patients respond far better to certain medication with reduced incidence of side effects when given in this manner. I addition to possible reduction in cost, it is also more convenient for the patient, especially when blood levels must be maintained throughout the twenty-four hour day.
Two basic drug release mechanisms, digestion and leaching, have been employed with varying modifications to attain the sustaining action of prior art products.
For the digestion mechanism of release, the medicament is either coated with or entrapped within a substance which is slowly digested or dispersed in the intestinal tract. As the digestive process progresses, the medicament is made availabie to the body fluids. The rate of availability is .a function of the rate of digestion of the slowly dispersible substance. Although products utilizing this mechanism have been formulated as compressed, coated, or multilayer tablets, and as encapsulated granules or pellets, the variety of the size and shape of the dosage forms does not circumvent the physiological variability of the patients receiving the drugs. These variations may be in gastric mobility, enzymatic activity, and hydrogen ion concentration. The variation in the ability of patients to digest insoluble substances is a well established fact and it follows that a dosage form which depends upon this variable must necessarily sufiier differences in effect. This lack of uniformity of release rate among patients is a serious limitation of dosage forms based on this mechanism. It is highly significant that digestion is primarily accomplished only in the upper intestine, whereas absorption may be realized throughout the intestinal tract.
The leaching mechanism of release is obtained by coating the drug with a film, part of which is soluble and dissolves leaving pores through which the drug may diffuse, or by entrap-ping the drug in an insoluble matrix from which it diffuses. While the leaching mechanism is not dependent upon digestive processes, it still has an inherent disadvantage. The rate of release is a function of the surface area exposed to the leaching fluid and the distance through which the medicament must diffuse in order to be available to the body fluids. As a result, the release of medicament is first order and the rate of release at any given time after ingestion will be dilferent 3,247,055 Patented Apr. 19, 1966 from the rate at any other time, and will be decreasing as time after ingestion increases. Thus, in order to provide medication at the necessary blood level over a period of eight to twelve hours, a large overdose must be present during the early stages after ingestion. Characteristically, dosage forms of this type do not completely release the drug in the prescribed eight to twelve hour period. Thus, the drug is either carried too far in the gastrointestinal tract to be physiologically available or there is the distinct hazard that the repeated administration of such products may result in a drug accumulation in the tissues and the occurrence of side effects. This hazard is recognized by the Federal Food and Drug authorities who designate such formulations as New Drugs even though the active principle in a smaller conventional dose is well known to be safe.
Controlled release medicaments may also be classified by product types. The two primary examples are controlled release tablets and capsules containing a multiplicity of small cores, pellets, or granules. Apart from the mechanism of action, products prepared from small cores or pellets are preferred because of the uniformity of the release pattern from their larger surface area and ease of maintaining quality control. In addition, a more uniform, reproducible movement of many small particles through the gastrointestinal tract can be attained than with a single large tablet.
The small particles likewise may be pictured as tWo distinct classes. One class consists of molded, cast, or peiletized particles in which the drug is entrapped in the solid matrix. Although this procedure has the advantage that a multiplicity of particles can be administered, prodnets of this type utilize either the digestion or leaching release mechanism and are particularly noted for rapidly releasing the drug initially or not completely releasing the drug over the eight to twelve hour prescribed period.
The second class comprises coated particles. Generally, they consist of nonpareil sugar seeds or cores coated first with the drug and subsequently coated with a partially water permeable film. Aside from the obvious high cost, this technique has many other disadvantages. When the drug is coated on small seeds the basic technological limitations of this procedure invariably result in seeds coated with varying quantities of drug. The coatings frequently are applied in layers alternating with the drug layers. Thus, because of dimensional restrictions, only small doses of drugs can be employed and, in addition, there is no positive release mechanism.
One object of the present invention is to provide a multiplicity of coated beads capable in dosage uni-t form of uniformly releasing medicament over an eight to twelve hour period of time at a rate sufficient to provide adequate blood levels for this period.
Another object of the invention is to provide a controlled release dosage form which operates independent of physiological variations encountered in individual patients.
Another object is to provide a dosage form affording complete release of medicament by means of internal pressure.
Still another object is to provide a medicament in dosage form which comprises a multiplicity of coated beads each containing a relatively high proportion of the medicarnent.
Yet another object is to provide coated beads containing medicament, each of which possesses the same ratio of drug content to bead weight thereby guaranteeing unexcelled uniformity.
A still further object is to provide a controlled release dosage form which can be adapted to medications having either relatively high or relatively low solubility in physiological fluids.
These and other objects and advantages will be apparent in the following description.
In the accompanying drawing:
FIGURE 1 is an elevation of a coated medicament bead, cut away in part to show the interior of the bead;
FIGURE 2 is a perspective view of a ruptured coated medicament bead; and
FIGURE 3 is a plan view of a coated medicament bead following rupture.
Referring to FIGURE 1, the present invention in one of its embodiments includes a controlled release unit 1 which comprises a bead 2 speroidal in form, having a smooth surface, surrounded or enveloped by a contacting rupturable film coating 3 which is inert to body fluid (i.e. non-toxic, insoluble in body fluid and non-digestible) and permeable to diffusion of water. The bead or core 2, in turn, comprises a water-swellable, medicated colloid, i.e., colloid material containing one or more medicaments which are compatible with the colloid material. The medicament may be present in solution or, as shown in FIGURE 1, in the form of dispersed solid particles 4. Following ingestion and immediately upon entering the gastrointestinal tract, the unit 1 comes into contact with body fluid containing water which, with passage of time, diffuses gradually through the coating 3 into the central core 2. As indicated, the core contains a waterswellable colloid. The colloid, under influence of the water entering and coming into contact with the core, immediately begins to absorb the water and to swell. The process is a continuing one and the colloid progressively continues to swell as further amounts of water diffuse through the coating into the core. Finally, when the swelling pressure of the colloid builds up sufficiently and just exceeds the cohesive strength of the coating, the coating is ruptured at which time, and because of the extensive character of rupture ordinarily encountered, the medicament content of the core is substantially made completely available for immediate contact with the surrounding body fluid and tissue whereupon the absorption and uptake of the medicament proceed in normal physiological fashion, without further delay. FIGURE 2 represents a controlled release unit 1 after prolonged exposure to water as the result of which the coating 3 has undergone rupture, as described, to provide a gross opening defined in part by random edges 5 through which the bead 2 is visible. The representation is typical of the case where the fluid surrounding the coating 3 is in motion. FIGURE 3, on the other hand, is a representation of the rupture occurring when the fluid surrounding the coating is relatively static.
It is a significant feature of the invention that the bead 2 swells on the diffusion of water through the coating 3. Prior to rupture, trace amounts of the medicament may possibly diffuse through the coating, but it is only with rupture accomplished by swelling that essentially the total content of the drug is released. Thus, while the release of the medicament is substantially immediate (i.e., within several minutes after rupture), it is accomplished at a time which is considerably subsequent to the time of administration. Furthermore, the release of the medicament advantageously depends only on the presence of water and does not depend on enzyme action, pH, rate of digestion, mechanical attrition, etc. This feature is of great advantage since water is present in all individuals and its vapor pressure, a function of temperature, does not vary significantly among individuals.
Although various aspects of the coating 2 and the bead 3 will be described separately hereinafter, it is the cooperative combination of the swellable bead and the water permeable coating that provides controlled positive release results.
For inclusion in the bead 2, in accordance with the invention, various colloid materials are satisfactory. Gelatin is a particularly useful colloid for this purpose and although certain embodiments of the invention de scribed hereinafter are directed to dosage forms containing gelatin, it will be realized that other colloids or combinations of colloids can be used in place of or in addition to gelatin. Among other suitable colloids may be mentioned starch, starch phosphate, zein, gum arabic, agar, albumin, tragacanth and mixtures of colloids, such as gelatin-starch mixtures. The quantity or relative proportion of the colloid material of the bead is subject to considerable variation. In any case, a sufficient quantity of colloid material should be present to provide, on uptake of water, a swelling pressure in excess of the cohesive strength of the film coating. The choice of colloid is not critical, it being required merely that the colloid possess water absorption properties and undergo swelling with uptake of water. The colloid material may optionally contain plasticizing agents such as sorbitol, glycerin, and the like. The colloid material as used in the instant dosage forms is conveniently employed in dry form or in a form which has a substantial capacity for absorption of water. In the case of gelatin, for example, commercially available grades which ordinarily have a water content of about 11% are suitable for the present invention. In some instances, particularly where it is desired to achieve maximum stability with respect to medicament content, the water content of the gelatin should preferably be lower, i.e., less than 11% and downward to about 15%.
As indicated, the colloid material contains, in accordance with the invention, one or more compatible medicaments. The medicament may be present in the colloid material either in the liquid phase or solid phase, as desired. In one procedure, described in greater detail hereinafter, the medicament is dissolved or dispersed in warm liquid gelatin and the liquid is extruded through an orifice into a non-turbulent stream of liquid coolant so as to cause the gelatin to form into smooth, discrete, solid spheroidal beads containing medicament uniformly dissolved or dispersed therethrough, following which the beads are dried to render them hygroscopic. Thus, in a given lot, each head contains the same proportion of drug and in each the distribution of drug is homogeneous.
It is an advantageous feature of the invention that the beads may contain substantially more medicament on a Weight per dosage unit basis than conventional sustained release forms which comprise a multiplicity of individual delayed released granules or pellets. For example, the beads may contain as much as 50% or more by weight of medicament. In this connection, following formation of the beads, drying is accomplished at or below the tack point of the beads, i.e., the temperature at which the beads when subjected to cooling, cease to adhere to one another. The tack point varies inversely with the drug concentration. In a case where the beads contain a relatively high concentration of medicament, the tack point is ordinarily low and therefore drying must be carried out at relatively low temperatures, e.g., temperatures approaching 10- 15 C. or lower.
A wide variety of medicaments may be included in the present dosage forms and the concentration thereof is also subject to wide variation, as desired. In general, one may use any medicament which, in the concentration employed, is compatible with the colloid material, i.e., does not adversely affect the desired swelling properties of the colloid material. Illustrative examples of medicaments which may be included in the colloid material are analeptics such as pentylenetetrazol and ephedrine; central nervous stimulants such as amphetamine, bethanechol, neostigmine, Z-dimethylamino-ethanol tartrate, captodiamine and mepazine; anorectic agents such as phenmetrazine, diethylpropion and phenylbutylamine; antihistamines such as thonzylamine hydrochloride, diphenhydramine hydrochloride, bromodiphenhydramine hydrochloride and chlorpheniramine maleate; anti-inflammatory agents and analgesics such as acetylsalicylic acid, acetophenetidin and phenylbutazone; anticonvulsants such as diphenylhydrantoin sodium, trimethadione, phensuximide, pamidone, methsulximide and ethsuximide; antimicrobial agents such as antibiotics, sulfonarnides, etc.; antiparasitic agents such as amodiaquin hydrochloride, biallylamicol hydrochloride, quinacrine hydrochloride, chloroquine phosphate and pyrvinium pamoate; and central nervous depressants and tranquilizing agents such as chlorpromazine, meprobamate benactyzine, hydroxyzine, ethchlorvynol and ectylurea. Other types of medicaments may also be included.
As a film coating for the above-described bead, a substance is employed which is inert to body fluid (i.e., nontoxic, insoluble and non-digestible) and permeable to diffusion of water. The term non-digestible as used herein refers to film-forming or coating substances which are completely non-digestible or are resistant to digestion, i.e., undergo substantially little, if any, digestion prior to the desired rupture and release of the medicament from the coated beads. Certain of the specific illustrative coating substances described hereinafter, although not completely non-digestible, are resistant to digestion and therefore when used as a coating substance should preferably be incorporated with at least one other more inert substance in a sufiicient quantity to provide controlled resistance to digestive attack. Similarly, some of these coating substances are better adapted to the formation of films than others so that in cases where improved film-forming properties are desired in a given coating substance, such improvement can be obtained by incorporating therewith a substance having enhanced filming properties. In general, the coating can be achieved with a substance that forms a relatively thin continuous rupturable cohesive film which is inert to leaching or digestion by body fluid.
In general, the substances which are employed for this purpose are the plastic film formers. Any one of a wide variety of plastic film formers can be employed, among which are the following types of plastic bases; cellulose ethers such as ethyl cellulose and ethyl hydroxyethyl cellulose; cellulose esters such as cellulose acetate, cellulose acetate ph-thalate, celluose acetate butyrate and celulose nitrate; fluorocarbon resins, particularly fluoroethylene resins such as tetrafluoroethylene and chlorotrifiuoroethy-lene resins; polyamide-epoxy resins; synthetic rubbers such as polychloroprenes and butadienestyrene, isoprene-styrene, polysulfide, polyacrylic, polybutadiene and polyurethane rubbers; vinyl chloride resins, vinyl chloride-acetate resins, vinyl chloride-vinylidene chloride copolymers and vinylidene chloride-acrylonitrile resins; acrylate and methacrylate bases; epichlorohydrin bisphenol resins; polyamide resins and polyamide-epoxy and polysulfide-epoxy resins; alkyd resins (phthalic anhydride-polyhydric alcohol-oil combinations); furan resins; silicone resins, silicone-alkyd resins, silicone phenolic and silicone rubber; coumarone resins; styrene resins and styrene-butadiene resins; hydrocarbon resins; terpene resins; and urethanes. Among the preferred plastic bases are ethyl cellulose, chlorotrifluoroethylene (CTFE) resin such as Kel+F800g tetrafluoroethylene (TFE) resin such as Teflon 30 and vinyl chloridevinylidene chloride copolymers such as Saran resin F-220 and Saran latex F-122A15. Curing or polymerization of the plastic bases, where necessary to provide the finished film coating, is accomplished by conventional means described hereinafter. The coating mixture may also contain a film modifying agent to provide the desired degree of water-permeability in the finished film coating. Among the many substances which can be employed as modifying agents, there may be mentioned petroleum waxes and vegetable and animal waxes; esters of higher (about C or higher) fatty acids and higher (about C or higher) fatty alcohols and their esters with such acids; fixed oils like castor oil; glyceryl esters of such acids; and acetylated monoglycerides.
The film coating material may be applied by any procedure which provides a continuous film of essentially uniform thickness. One method of film coating involves rotating a bed of uncoated beads in a conventional tablet coating pan and applying a solution or dispersion of the coating agent in a suitable solvent by pouring or spraying onto the moving beads, care being taken to uniformly coat each bead and to avoid incomplete film coating such as is caused by bead agglomeration, etc. Drying of the coated beads is accomplished by exposure to Warm, dry air. The coating procedure conveniently is continued until the desired film thickness is obtained. The resulting film coated beads are then cured if necessary with heat (air drying, baking or force drying), polished and finished as desired. Other coating procedures such as fluid bed coating, vertical spray coating, etc., can also be employed. A preferred procedure for coating is the vertical spray coating method described in US. Patents Nos. 2,648,669 and 2,799,241. According to this method, the beads to be coated are suspended in a column by means of a turbulent air stream, and an atomized solution or dispersion of the film coating agent is sprayed vertically upward into the column containing the suspended beads such that the beads become uniformly coated and dried. Curing of the coating where necessary can be accomplished in conjunction with the drying step or can be carried out subsequently. Various solvents and mixtures of solvents can be used to provide the coating agent solutions or dispersions. One may use any solvent which dissolves or disperses the coating agent and yet can be readily removed by evaporation or other conventional means. Preferably, the solvent should be relatively volatile and have a low viscosity. Some preferred solvents for this purpose by way of illustration, are water; halogen hydrocarbons such as =trichloroethylene, methylene chloride, carbon tetrachloride, and chloroform; alcohols such as absolute alcohol, isopropanol and methanol; low molecular esters such as ethyl acetate and amyl acetate; and ketones such as acetone, Z-butanone and the like. When carrying out the coating procedure, one can vary the strength of the coating film against rupture due to swelling pressure, as well as the permeability to water vapor, by the proper selection of the coating agent or agents and of the thickness of the coating. Hence, one can control, by suitable variation of the coating agent and the thickness of the coating film, the time at which the medicament will be released following administration of the dosage form. The relationship between the mentioned factors can be expressed mathematically by the following illustrative equation showing the release phenomenon as a two-step mechanism based on diffusion of water vapor and swelling of the colloid:
t=Kd +K' where t is time of exposure necessary for release,
is a constant dependent upon the coating substance, K is the time for the uncoated colloid to release the medicament, and d is the thickness of the coating film.
Thus, on the basis of constants for the coating substance and colloid material established by routine study, one can predict and control the release of internally administered medicaments for any given colloid material and coating substance by choosing the desired thickness of the coating film. The size of the bead or nucleus can also be varied, but variation thereof does not appreciably ar tect the release of the medicament.
Although the invention contemplates a coated head of sufiicient size to provide by itself the complete medicament dosage required, a preferred embodiment of the invention is a plurality of small coated beads of a single type (.i.e., uniform bead size, film coating, film thickness, etc.) or a blend of different types, either in bulk form or contained in a pharmaceutical carrier such as a hard or soft shell capsule, suppository, non-aqueous syrup,
or other pharmaceutical carrier, together with excipients if desired. Each of such coated beads contains a partial dose and, as indicated, may be varied as desired with respect to one or more factors. The principal factors are the following: (a) The identity of the film coating (b) The film thickness The identity of medicament (d) The identity of the colloid material, and
(e) The size, and hence the total sunface area, of the coated bead Thus, where the dosage form includes a plurality of coated beads having individual variations with respect to medicament release, i.e., a plural dosage form, there is provided on administration a controlled release dosage form. In this case, a non-enteric gelatin capsule is administered orally containing a plurality of coated beads constituting a blend of beads having a uniformly graded variety of coatings or coating thicknesses, the capsule dissolves usually in about -30 minutes whereupon the individual coated beads become directly exposed to body fluid. In this condition, they each become separately ruptured in due course depending upon the film coating thickness and type of coating of each individual bead. In controlled fashion, some beads, i.e., ones having a thin coating or a relatively highly water-permeable coating, undergo rupture at an early stage to provide prompt medication, while others having thicker or less waterermeable coatings remain intact for prolonged periods and later undergo rupture individually and progressively from time to time depending on their respective coatings and thickness thereof, to provide continuing, uniform, sustained medication. Thus, where the water-permeability of the coatings in a given dosage form is varied in a uniformly progressive series over a predetermined range, the rupture of the coatings is gradual and uniform so that a sustained release of medicament is obtained. Such plural dosage forms can also include in admixture with the coated beads a number of uncoated beads which on administration operate to provide immediate medication.
The invention is further illustrated by the following specific examples:
PREPARATION OF UNCOATED COLLOID BEADS Example 1 (a) Pig skin gelatin, bloom 270 kg 10.0 Water, distilled l 34.0 Diphenhydramine hydrochloride kg 4.0 Glycerin l 0.5
Twenty-five liters of water are added to the gelatin with mixing and the wetted gelatin is allowed to hydrate overnight. The hydrated gelatin is heated to 70 C. and nine liters of hot water containing the diphenhydramine hydrochloride is added with stirring. The glycerine is heated to 70 C. and added with stirring. The resulting colloid mixture has a viscosity of 1300 cps. at 70 C. as determined by a Brookfield viscosimeter using a No. 2 spindle at 30 rpm. The mixture is then processed into solid beads by means of a bead-forming apparatus of an improved type. Briefly, this apparatus consists of a reservoir for the colloid material to be processed, conduit means connecting the reservoir with a manifold pipe having an integral bank of twenty parallel No. 22 gauge hypodermic needles for extrusion of the colloid, means for pumping the liquid colloid to the pipe at a desired rate, temperature and pressure, whereby the liquid colloid in the reservoir can be pumped to the manifold pipe and thence through the needles and out of the orifices thereof at a controlled rate. The apparatus also includes an inclined trough over which is flowed, by pump and refrigeration means, at a controlled rate, depth and temperature, a coolant liquid which is immiscible with the liquid colloid. The needles are arranged in a horizontal bank above and at right angles to the line of flow of the liquid coolant and are disposed vertically downward in a position such that the orifices thereof almost touch and are equidistant from the surface of the liquid coolant. In operation, the needles receive the liquid colloid (maintained at a temperature of C.) and direct it in a plurality of flowing streams or filaments into the body of the flowing liquid coolant. Petroleum ether maintained at a temperature of 10 C. is used as the liquid coolant; the flow thereof, as maintained, is laminar (i.e., non-turbulent) and the linear flow-rate is 50 cm. per second. The depth of the liquid coolant stream is about one-half centimeter, the width of the trough is 20 cm., and the angle of inclination with the horizontal is 20. The flow rate of the liquid colloid flowing from the needles is approximately 30 liters per hour. The velocity of the liquid colloid as it first enters the flowing liquid coolant is essentially zero with respect thereto, but it is immediately diverted in the body thereof and carried along in a stream with the coolant and at increasing velocity until the coolant and the colloid stream are moving at approximately the same velocity. At this point, the colloid stream becomes dynamically unstable and breaks up into uniform spheroids or beads which on further movement with the flowing coolant congeal and become hardened. The coolant containing the colloid beads is then collected in a receiver, and the beads are separated intact from the coolant and dried first at 10 C. to about 5% Water content and then at 45 C. to about 1% water content. The procedure provides about 11 kg. of dried colloid beads in the size range 590 to 840 microns (i.e., #20 to #30 mesh, U.S. series) containing about 28% by weight of uniformly distributed diphenhydramine hydrochloride. If desired, other methods of forming colloid beads can be employed in place of the foregoing procedure, such as dropping the liquid colloid into a vertical air column.
(b) For the preparation of similar colloid beads which differ only with respect to percentage of medicament content, the same procedure of Example 1( a) is followed except that the relative quantity of diphenyhdramine hydrochloride is varied as desired. For the incorporation of the latter in the colloid mixture, it will be understood that a sufficient amount of water is used to provide a solution of the diphenhydramine hydrochloride, the total amount of water used in the formulation of the colloid mixture being maintained substantially constant so as to insure the required viscosity of the mixture. For example, colloid beads containing 5% of diphenhydramine hydrochloride are provided by the procedure of Example 1(a) using the following starting materials:
Gelatin kg 6.0 Water, distilled l 22.0 Diphenhydramine hydrochloride kg 0.3 Sorbitol, 70% in water l 1.0
In a specific procedure, four batches of these starting materials when processed batch-wise to the wet beads, then pooled and dried, provide beads having the following mesh size distribution:
Mesh size (U.S.): Weight percent In a similar manner, colloid beads containing a higher percentage of medicament are provided, using the following materials:
Gelatin, SO -free, grade F kg 1.0 Diphenhydramine hydrochloride kg 1.5 Glycerin kg 0.25 Water l 3.0
The gelatin is hydrated in two liters of water, the third liter being used to dissolve the diphenhydramine. The yield is 2.35 kg. of dry (1%) beads assaying 52.3% diphenhydramine.
Example 2 Gelatin kg 0.9 3 sulfanilamido 6 methoxypyridazine (micronized) kg 0.45 Sorbitol, 70% in water kg 0.1 Water l 2.4
The gelatin is prehydrated with 900 cc. of water at room temperature for three hours. The hydrated mass is then heated to provide a melt and 1000 cc. of water containing the pyridazine in slurry form is added. The melt is held at 70 C. and thoroughly mixed to assure complete dispersion. The sorbitol is dissolved in 500 cc. of water and the solution blended into the melt suspension. The resulting blend is then converted into small, dry, solid beads or spheroids by the bead-forming procedure described in Example 1(a). Each bead contains approximately 29% by weight of the pyridazine. This example illustrates the preparation of colloid beads which contain a water-insoluble medicament in the form of a suspension in the colloid. Other water-insoluble medicaments or mixtures thereof, particularly relatively highmelting medicaments (e.g., chloramphenicol, diphenhydramine salicylate, sulfaguanidine, dimenhydrinate, and the like) can be used in place of the above-mentioned pyridazine to provide similar suspensions.
Example 3 Gelatin kg 0.45 N-methyl a-methyl a-phenylsuccinimide crystalline kg 0.45 Sorbitol, 70% in water kg 0.05 Water l 0.9
The gelatin is prehydrated in 450 cc. of water at room temperature for three hours. The hydrated mass is then heated to provide a melt and the succinimide is added. The resulting mixture is vigorously agitated while hot (75 C.) to provide a finely divided emulsion of the molten succinimide. A solution of the sor-bitol in 450 cc. of Water is mixed in and the resulting emulsion is converted into small, dry, solid beads or spheres by the bead-forming procedure described in Example 1(a). Each bead contains approximately 45% by weight of the succinimide. This example illustrates the preparation of colloid beads which contain a water-insoluble medicament in the form of an emulsion in the colloid. Other water insoluble medicaments (e.g., liquid medicaments or lowmelting medicaments such as phensuximide and ethsuximide) or mixtures thereof can be used in place of the above-mentioned succinimide to provide similar emulsions. 1
Example 4 Gelatin kg 2.0 2 diethylamino 2 methylpropiophenone, ni-
trate kg 1.0 Glycerin kg 0.1 Water l 8.0
The gelatin is prehydrated with 4 liters of water at room temperature for three hours. The hydrated gelatin is then heated to 70 C. The Z-diethylamino-2-methylpropriophenone nitrate is dissolved in one liter of hot water and added to the above hot gelatin mixture with stirring. The glycerin and an additional 3 liters of hot water are added While the temperature is maintained at about 70 C. The resulting colloid mixture is converted into dry solid beads or spheres by the bead forming procedure described in Example 1(a) The dried beads assey 27% by Weight of the nitrate salt. This example illustrates the preparation of colloid beads which contain a water-soluble medicament. Other water-soluble medicaments or mixtures thereof can be used in place of the above-mentioned nitrate salt to provide similar forms. As an illustration of water soluble substances which may be used in place of the salt, there may be mentioned thiamine hydrochloride, chloroquin disphosphate, soluble acetylsalicylic acid compounds and the like.
Example 5 Gelatin kg 6.0 Methylene blue kg 0.1 Sorbitol, 70% in water kg 1 Water l 27 The gelatin is prehydrated overnight at room temperature in 15 liters of water. The hydrated mass is heated to 70 C. and the methylene blue is added in the form of an aqueous solution (100 g. methylene blue in two liters of water). The sorbitol solution and 10 liters of Water are added with stirring and heating to maintain the temperature at 70 C. The resulting colloid solution is converted into small, dry, solid colloid beads by the beadforming procedure described in Example 1(a). Each of the resulting beads contains about 1.5% by weight of methylene blue.
PREPARATEONS OF COATED COLLOID BEADS Example 6 Two kilograms of dried gelatin beads ranging in size from 16 to 20 mesh (U.S.) containing 5% by weight of diphenhydramine hydrochloride, prepared in accordance with Example 1(b), are placed in the coating chamber of a Wurster coating apparatus of the type described in U.S. Patent No. 2,648,609 and are suspended or fluidized in the chamber by means of turbulent air flowing at the rate of 68 cubic feet per minute. The air inlet temperaature is maintained at F. and the outlet temperature at 66 F. To the chamber is added, under an atomizing air pressure of 70 p.s.i., a coating solution consisting of 500 grams of ethyl cellulose (10 cps.) dissolved in five liters of equal parts of chloroform and anhydrous ethanol. The total volume of the solution is 5400 cc. and the viscosity l-2 cps. at 70 F. The solution is added at a constant rate of about 33 cc. per minute. The total time required for coating and drying is 2 hours and 45 minutes following which the finished coated beads (approximately 2950 grams) are recovered from the chamber. Similar beads coated with a thinner coating of the same composition are prepared in the same manner. A controlled release product designed to have an in vivo uniform release pattern of eight to twelve hours is provided by blending and encapsulating batches of such coated beads, each batch having a dilferent coating film thickness.
This same procedure may be used for the production of beads having other types of film coating, as desired, employing other coating solutions in place of the abovedescribed solution. As illustrations of other coating solutions and of the corresponding delayed release of the medicament from the coated beads produced, one may use the following solutions in the above procedure:
Based on coated bead sample having 20% (weight) coating. 3 Based on coated bead sample having 10% (weight) coating. 4 Vinyl chloride-vinylidcnc chloride eopolymer F-122A15.
1 1 Example 7 Two kilograms of dried gelatin beads, 12-20 mesh containing 27.0% by weight of 2-diethylamino-2 methyl propiophenone nitrate, prepared in accordance with Example -4, are placed in the coating chamber of a Wurster air suspension apparatus of the type referred to above, and are fluidized in the chamber by turbulent air flowing at the rate of 60 cubic feet per minute. The air inlet temperature is maintained at 125 F. and the outlet temperature at 88 F. To the chamber is added, under an atomizing air pressure of 60 p.s.i., a coating solution consisting of 300 g. of ethyl cellulose (10 cps.), 60 g. of hydrogenated castor oil and 3 g. of castor oil dissolved in four liters of equal parts of chloroform and alcohol. The solution is added at a constant rate of about 44 ml. per minute. For purpose of analysis, 50 gm. samples of beads are removed from the coating chamber after each 2.5% weight increment of coating (relative to the weight of the uncoated bead) has been applied. Samples are collected following application of 2.5%, 5.0%, 7.5% and 10% coating increments. The coating procedure is continued until all of the coating solution has been applied and the coating has dried. Total time required for coating and drying is 95 minutes.
Example 8 Two kilograms of dried gelatin beads, 16-20 mesh, containing 1.5% by weight of methylene blue, prepared in accordance with Example 5, are placed in the coating chamber of a Wurster coating apparatus of the type referred to above, and are fluidized in the chamber by turbulent air flow. The air flow and inlet and outlet temperatures are maintained at substantially the same values given in Example 6. To the chamber is added, in atomized form under a presure of 70 p.s.i., 6.4 liters of a solution of by weight of ethyl cellulose (10 cps.) in equal parts by volume of absolute ethanol and chloroform. The solution is added at a constant rate of about cc. per minute. For purposes of analysis, samples of the beads are periodically taken from the chamber as they are being coated, the first sample being taken when the first 2% weight increment of coating (relative to the weight of the uncoated bead) has been applied and successive samples being taken following application of succeeding 2% coating increments, specifically, 4% through 16% increments. The coating procedure is continued until all of the coating solution has been applied and the coating has dried. The coated beads are then recovered from the chamber; yield, exclusive of samples, about 2.2 kg. of free flowing, coated beads. The film coating of the beads is, relatively speaking, extremely thin. For example, 20-mesh (i.e., 840-micron) beads, processed by the procedure to a 16% coating, have an average film thickness of about 28 microns.
Example 9 Employing the same primary bead formula and coating procedure referred to in Example 8, but utilizing a coating solution consisting of 300 g. of ethyl cellulose (10 cps.), 30 g. of hydrogenated castor oil and 3 g. of castor oil dissolved in four liters of equal parts of chloroform and alcohol, the following controlled release patterns are obtained:
CUMULATIVE PERCENTAGE OF MEDICAMENT This demonstrates the concise controlled release pattern that is obtainable. It also shows that any desired release pattern can be obtained by proper selection of coated beads having the same film coating or a blend of coated beads having a variety of coatings.
PREPARATION OF CONTROLLED RELEASE DOS- AGE FORMS Example 10 To provide a sustained release plural dosage form, in bulk, containing methylene blue as a medicament, equal weights (2 g.) of samples 4% through 16% of Example 8 are blended. The resulting blend can be administered orally, either in bulk form or other form. A No. 0 hard shell capsule contains about 0.4 gram of the blended beads.
When assayed for release of medicament in vitro, a sample of the blended product gives sustained action, up to eight hours, in water and in two types of simulated body fluid, as follows:
Cumulative Percentage of Medicament Released Time (Hours) Water Gastric Intestinal Fluid 1 Fluid 2 1 U.S. Pharmacopcia, Volume 16, page 1072.
2 11.8. Pharmacopcia, Volume 16, page 1073. Although extraction studies were terminated after eight hours, data collected on subsequent studies indicated eventual complete release.
It is notable that the release of the medicament is substantially the same for all three media used throughout the period represented, even though these media differ fundamentally in their chemical makeup and pH (water being neutral, gastric fluid strongly acidic and intestinal fluid mildly alkaline). Further, the release in each case is gradual and uniform throughout the period.
It is to be understood that the invention is not limited to the specific embodiments described and illustrated hereinabove inasmuch as various modifications and equivalents thereof, all within the spirit of the invention, will become apparent to those skilled in the art. Therefore, the invention is limited only by the scope of the following claims.
What is claimed is:
1. A controlled release dosage form for internal administration, comprising a solid bead and contacting and surrounding the bead a rupturable plastic, non-toxic, insoluble, non-digestible film coating which is inert to gastrointestinal fluid and permeable to diffusion of water, the bead consisting essentially of a uniform dispersion of medicament in a water-swellable colloid, the thickness of the coating and the swellability of the bead being such that on prolonged exposure to gastrointestinal fluid diffusion of water takes place through the coating into the bead causing the bead to swell and build up pressure exceeding the cohesive strength of the coating thereby resulting in outward rupture of the coating and substantially immediate and total release of the medicament from the head into the gastrointestinal fluid.
2. A controlled release dosage form in accordance with claim 1 in which the colloid is gelatin.
3. A controlled release dosage form in accordance with claim 1 in which the coating is ethyl cellulose.
4. A controlled release dosage form for internal administration comprising a plurality of solid beads and a rupturable plastic, non-toxic, insoluble, non-digestible film coating for each of the beads which is inert to gastrointestinal fluid and permeable to diiiusion of Water, the beads each consisting essentially of a uniform dispersion of medicament in a Water-swellable colloid, the thickness of the individual coatings and the swellability of the individual beads being such that on prolonged eX- posure to gastrointestinal fluid diffusion of water takes place through the individual coatings into the respective beads causing each bead to swell and build up pressure exceeding the cohesive strength of its coating thereby resulting in outward rupture of the respective coatings and substantially immediate and total release of medicament from each bead into the gastrointestinal fluid.
5. A controlled release dosage form in accordance With claim 4 in which the beads each contain the same proportion of medicament.
6. A controlled release dosage form in accordance with claim 4 in which the beads are contained in a pharmaceutical carrier adapted for internal administration.
7. A controlled release dosage form in accordance with claim 6 in which the carrier is a gelatin capsule.
8. A sustained release dosage form for internal administration comprising a plurality of solid beads and rupturable plastic, non-toxic, insoluble, non-digestible film coating for each of the beads, the beads each consisting essentially of Water-swellable colloid containing medicament uniformly distributed through the colloid, the individual coatings being inert to gastrointestinal fluid and Water-permeable, the water-permeability of said coatings being selected in a progressive series over a predetermined range, such that on prolonged exposure to gastrointestinal fluid diffusion of water takes place inward through the individual coatings at selected varying rates into the respective beads causing each bead to swell at a rate corresponding to the inward Water diffusion and to build up pressure exceeding the cohesive strength of its coating thereby resulting in serial outward rupture of the several coatings and substantially immediate and total release of medicament from each bead.
9. A sustained release dosage form in accordance with claim 8 in which the beads are contained in a pharmaceutical carrier adapted for internal administration.
10. A sustained release dosage form in accordance with claim 9 in which the carrier is a gelatin capsule.
References Cited by the Examiner UNITED STATES PATENTS 2,853,421 9/1958 Adams et al. 167-82 2,887,440 5/1959 Greminger 16782 2,921,883 1/1960 Reese et al. 167-82 2,928,770 3/1960 Bardani 16782 3,028,308 4/1962 Zambito et al. 16782 3,043,782 7/1962 Jensen l67-82 3,065,143 11/1962 Christenson et al 167-82 3,081,233 3/1963 Enz et al. 16782 3,087,860 4/1963 Endicott 16782 3,092,553 6/1963 Fisher et al l67-82 JULIAN S. LEVITT, Primary Examiner.
30 FRANK CACCIAPAGLIA, JR., Examiner.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US2853421 *||Oct 4, 1956||Sep 23, 1958||Merck & Co Inc||Gelatin pan coating|
|US2887440 *||Aug 12, 1957||May 19, 1959||Dow Chemical Co||Enteric coating|
|US2921883 *||May 3, 1957||Jan 19, 1960||Smith Kline French Lab||Novel coating material for medicaments|
|US2928770 *||Nov 28, 1958||Mar 15, 1960||Bardani Frank M||Sustained action pill|
|US3028308 *||Oct 1, 1959||Apr 3, 1962||Merck & Co Inc||Dry pharmaceutical vehicle of copolymer of hydrolyzed gelatin and glyoxal, and its production|
|US3043782 *||Dec 22, 1958||Jul 10, 1962||Upjohn Co||Process for preparing a more impermeable coating by liquid-liquid phase separation|
|US3065143 *||Apr 19, 1960||Nov 20, 1962||Richardson Merrell Inc||Sustained release tablet|
|US3081233 *||Aug 8, 1960||Mar 12, 1963||Upjohn Co||Enteric-coated pilules|
|US3087860 *||Dec 19, 1958||Apr 30, 1963||Abbott Lab||Method of prolonging release of drug from a precompressed solid carrier|
|US3092553 *||Apr 11, 1960||Jun 4, 1963||Jr Carl E Fisher||Pharmaceutical preparations and method and apparatus for making same|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US3340152 *||Dec 6, 1963||Sep 5, 1967||Ciba Geigy Corp||Compressed oral drug tablet granulations containing admixed therein about 1% to 15% of polyfluorocarbon type polymer lubricant powders in about 1 to 150 micron particle size|
|US3361632 *||May 7, 1965||Jan 2, 1968||Hoechst Ag||Medicinal preparations having a protracted activity and method of making them|
|US3390050 *||Jun 8, 1965||Jun 25, 1968||Ciba Geigy Corp||Stable pharmaceutical beads conaining medicament incorporated in synthetic copolymerby bead polymerization|
|US3492397 *||Apr 7, 1967||Jan 27, 1970||Warner Lambert Pharmaceutical||Sustained release dosage in the pellet form and process thereof|
|US3538214 *||Apr 22, 1969||Nov 3, 1970||Merck & Co Inc||Controlled release medicinal tablets|
|US3732865 *||Jan 13, 1971||May 15, 1973||Alza Corp||Osmotic dispenser|
|US3835221 *||Mar 4, 1971||Sep 10, 1974||Hoechst Ag||Orally administrable drug dosage form having delayed action|
|US3844285 *||Dec 14, 1972||Oct 29, 1974||Commw Scient Ind Res Org||Device for administration to ruminants|
|US3896806 *||Dec 21, 1971||Jul 29, 1975||Ceskoslovenska Akademie Ved||Implant for directed infusion of biologically active substances|
|US3906086 *||Jan 22, 1974||Sep 16, 1975||Powers Richard G||Timed-release aspirin|
|US3917813 *||Mar 20, 1974||Nov 4, 1975||Benzon As Alfred||Oral drug preparations|
|US3938515 *||Oct 19, 1973||Feb 17, 1976||Alza Corporation||Novel drug permeable wall|
|US3952741 *||Jan 9, 1975||Apr 27, 1976||Bend Research Inc.||Controlled release delivery system by an osmotic bursting mechanism|
|US3954959 *||Aug 27, 1975||May 4, 1976||A/S Alfred Benzon||Oral drug preparations|
|US4016880 *||Mar 4, 1976||Apr 12, 1977||Alza Corporation||Osmotically driven active agent dispenser|
|US4083949 *||Jul 8, 1974||Apr 11, 1978||Byk Gulden Lomberg Chemische Fabrik Gmbh||New oral form of medicament and a method for producing it|
|US4111201 *||Nov 22, 1976||Sep 5, 1978||Alza Corporation||Osmotic system for delivering selected beneficial agents having varying degrees of solubility|
|US4111202 *||Nov 22, 1976||Sep 5, 1978||Alza Corporation||Osmotic system for the controlled and delivery of agent over time|
|US4111203 *||Nov 22, 1976||Sep 5, 1978||Alza Corporation||Osmotic system with means for improving delivery kinetics of system|
|US4138475 *||Sep 14, 1977||Feb 6, 1979||Imperial Chemical Industries Limited||Sustained release pharmaceutical composition|
|US4153677 *||May 18, 1978||May 8, 1979||Sterling Drug Inc.||Controlled-release composition|
|US4155993 *||Jan 13, 1978||May 22, 1979||Lipha, Lyonnaise Industrielle Pharmaceutique||Prolonged-release pharmaceutical compositions for oral administration, their methods of making and use|
|US4173626 *||Dec 11, 1978||Nov 6, 1979||Merck & Co., Inc.||Sustained release indomethacin|
|US4190642 *||May 11, 1979||Feb 26, 1980||Alza Corporation||Ocular therapeutic system for dispensing a medication formulation|
|US4207890 *||Sep 21, 1978||Jun 17, 1980||Mcneilab, Inc.||Drug-dispensing device and method|
|US4229428 *||Apr 5, 1979||Oct 21, 1980||Cherqui Jean S||Galenical form of administration of betahistine and its derivatives|
|US4252786 *||Nov 16, 1979||Feb 24, 1981||E. R. Squibb & Sons, Inc.||Controlled release tablet|
|US4261971 *||Dec 17, 1979||Apr 14, 1981||Aktiebolaget Hassle||Pharmaceutically preparation comprising a cardiac glycoside in combination with a polymer|
|US4263273 *||Dec 17, 1979||Apr 21, 1981||Aktiebolaget Astra||Pharmaceutical preparation comprising a cardiac glycoside with a polymer coating|
|US4277364 *||Oct 19, 1976||Jul 7, 1981||The United States Of America As Represented By The Secretary Of Agriculture||Encapsulation by entrapment|
|US4344857 *||May 16, 1980||Aug 17, 1982||The United States Of America As Represented By The Secretary Of Agriculture||Encapsulation by entrapment|
|US4361546 *||Jun 15, 1981||Nov 30, 1982||Boehringer Ingelheim Gmbh||Retard form of pharmaceuticals with insoluble porous diffusion coatings|
|US4367217 *||Dec 31, 1980||Jan 4, 1983||Boehringer Ingelheim Gmbh||Dipyricamole sustained release forms comprising lacquer-coated particles and the preparation thereof|
|US4415547 *||Jun 14, 1982||Nov 15, 1983||Sterling Drug Inc.||Sustained-release pharmaceutical tablet and process for preparation thereof|
|US4459279 *||Aug 18, 1982||Jul 10, 1984||Boehringer Ingelheim Gmbh||Retard form of pharmaceuticals with insoluble porous diffusion coatings|
|US4508702 *||Feb 3, 1984||Apr 2, 1985||Key Pharmaceuticals, Inc.||Sustained release aspirin|
|US4555399 *||Mar 8, 1984||Nov 26, 1985||Key Pharmaceuticals, Inc.||Aspirin tablet|
|US4557925 *||Sep 5, 1984||Dec 10, 1985||Ab Ferrosan||Membrane-coated sustained-release tablets and method|
|US4587118 *||Dec 12, 1984||May 6, 1986||Key Pharmaceuticals, Inc.||Dry sustained release theophylline oral formulation|
|US4629619 *||Sep 19, 1985||Dec 16, 1986||Ab Ferrosan||Membrane-coated sustained-release tablets and method|
|US4629620 *||Sep 19, 1985||Dec 16, 1986||Ab Ferrosan||Membrane-coated sustained-release tablets and method|
|US4634587 *||Aug 16, 1984||Jan 6, 1987||Key Pharmaceuticals, Inc.||Sustained release quinidine dosage form|
|US4752470 *||Nov 24, 1986||Jun 21, 1988||Mehta Atul M||Controlled release indomethacin|
|US4800084 *||Aug 13, 1987||Jan 24, 1989||Horst Zerbe||Pharmaceutical product in the form of a pellet with continuous, delayed medicament substance emission|
|US4820521 *||Jan 16, 1987||Apr 11, 1989||Eland Corporation P.L.C.||Sustained absorption pharmaceutical composition|
|US4871542 *||Apr 30, 1987||Oct 3, 1989||Ferring Service Center, N.V.||Method and apparatus useful for delivering medicinal compositions into the bladder and urinary tract|
|US5051262 *||Nov 18, 1986||Sep 24, 1991||Elan Corp., P.L.C.||Processes for the preparation of delayed action and programmed release pharmaceutical forms and medicaments obtained thereby|
|US5051305 *||Dec 30, 1988||Sep 24, 1991||Arcade, Inc.||Stabilized perfume-containing microcapsules and method of preparing the same|
|US5130171 *||Dec 21, 1989||Jul 14, 1992||Rhone-Poulenc Sante||Process for encapsulating particles with a silicone|
|US5219572 *||Jul 25, 1991||Jun 15, 1993||Pitman-Moore, Inc.||Controlled release delivery device for macromolecular proteins|
|US5275819 *||Apr 26, 1991||Jan 4, 1994||Amer Particle Technologies Inc.||Drug loaded pollen grains with an outer coating for pulsed delivery|
|US5358502 *||Feb 25, 1993||Oct 25, 1994||Pfizer Inc||PH-triggered osmotic bursting delivery devices|
|US5431921 *||Jul 22, 1991||Jul 11, 1995||Pfizer Inc||Dispensing device containing a hydrophobic medium|
|US5576022 *||Apr 12, 1995||Nov 19, 1996||Warner Lambert Company||Controlled release tacrine drug delivery systems and methods for preparing same|
|US5609590 *||Oct 19, 1994||Mar 11, 1997||Pfizer Inc.||PH-triggered osmotic bursting delivery devices|
|US5798119 *||Jun 13, 1995||Aug 25, 1998||S. C. Johnson & Son, Inc.||Osmotic-delivery devices having vapor-permeable coatings|
|US7964216||Jan 11, 2002||Jun 21, 2011||Sun Pharma Advanced Research Company Limited||Spaced drug delivery system|
|US8029822||May 21, 2004||Oct 4, 2011||Osmotica Kereskedelmi és Seolgáltató KFT||Rupturing controlled release device having a preformed passageway|
|US8637080||Jun 25, 2008||Jan 28, 2014||Osmotica Kereskedelmi és Szolgáltató, KFT||Rupturing controlled release device comprising a subcoat|
|US20040156900 *||Apr 9, 2002||Aug 12, 2004||Shanghvi Dilip Shantilal||Time pulsed release composition|
|US20040265381 *||Oct 8, 2002||Dec 30, 2004||Shanghvi Dilip S.||Anti-asthmatic drug (asmakure) from indigenous herbs to cure the disease asthma|
|US20050008702 *||May 21, 2004||Jan 13, 2005||Joaquina Faour||Rupturing controlled release device having a preformed passageway|
|US20050031688 *||Aug 4, 2003||Feb 10, 2005||Ayala William J.||Positive wakeup pharmaceutical sleep system with compatible pre-bedtime administration|
|US20050265955 *||May 28, 2004||Dec 1, 2005||Mallinckrodt Inc.||Sustained release preparations|
|DE2051580A1 *||Oct 21, 1970||May 6, 1971||Title not available|
|EP0052917A2 *||Jul 22, 1981||Jun 2, 1982||Alza Corporation||Osmotic device with hydrogel driving member|
|EP0077956A1 *||Oct 8, 1982||May 4, 1983||Tanabe Seiyaku Co., Ltd.||Enteric microcapsules and process for the preparation thereof|
|EP0250374A1 *||Jun 15, 1987||Dec 23, 1987||RECORDATI INDUSTRIA CHIMICA E FARMACEUTICA S.p.a.||Therapeutic system for controlled release of drugs|
|EP0467975A1 *||Apr 10, 1990||Jan 29, 1992||Depomed Systems Inc||Sustained-release oral drug dosage form.|
|EP0670718A1 *||Nov 2, 1993||Sep 13, 1995||Andrx Pharmaceuticals, Inc.||Pulsatile particles drug delivery system|
|EP0701437A1 *||Jun 3, 1993||Mar 20, 1996||Andrx Pharmaceuticals, Inc.||Multiparticulate pulsatile drug delivery system|
|EP1738751A2||Jan 11, 2002||Jan 3, 2007||Sun Pharmaceutical Industries Limited||Spaced drug delivery system|
|EP2586429A1 *||Oct 26, 2011||May 1, 2013||Freund Pharmatec Ltd.||Multi-unit drug delivery device for pulsatile or sustained release|
|WO1983000284A1 *||Jul 8, 1982||Feb 3, 1983||Key Pharma||Sustained release theophylline|
|WO1984000004A1 *||Jun 14, 1983||Jan 5, 1984||Key Pharma||Sustained release aspirin|
|WO1984000295A1 *||Jul 8, 1983||Feb 2, 1984||Key Pharma||Sustained release quinidine dosage form|
|WO1996017598A1 *||Dec 1, 1995||Jun 13, 1996||Bernard Charles Sherman||Diltiazem hydrochloride formulation|
|WO2011039686A1||Sep 24, 2010||Apr 7, 2011||Pfizer Inc.||Latrepirdine oral sustained release dosage forms|
|WO2012151343A1||May 3, 2012||Nov 8, 2012||Balance Therapeutics, Inc.||Pentylenetetrazole derivatives|
|U.S. Classification||424/495, 604/368, 424/490|
|International Classification||A61K9/50, A61K9/22, A61K9/16|
|Cooperative Classification||A61K9/1623, A61K9/5047, A61K9/1658, A61K9/5042, A61K9/5084|
|European Classification||A61K9/50H6F2, A61K9/16H6H, A61K9/50H6F2B, A61K9/16H4B|