JPH03363B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides for the use of one or more drugs, up to 80% by weight of therapeutically inert pharmaceutically acceptable adjuvant substances, up to 60% by weight of fatty substances having a specific gravity of less than 1, and when in contact with gastric fluids. , consisting of a homogeneous mixture of one or a mixture of hydrocolloids in an amount sufficient to produce a water-impermeable barrier at the surface of the homogeneous mixture, hydrodynamically balanced and thus bulky for the formulation when in contact with gastric fluids. For oral administration, the density is less than 1, so that it remains suspended in the gastric fluid until the formulation has released substantially all of the drug contained therein. Sustained release suitable for drugs in solid dosage form
release) regarding drug formulations. Furthermore, the present invention
a homogeneous mixture of one or more drugs, up to 80% by weight of therapeutically inert pharmaceutically acceptable auxiliary substances, up to 60% by weight of fatty substances with a specific gravity less than 1, and when in contact with gastric juices; A method for producing the above formulations comprises forming a homogeneous mixture of one or a mixture of hydrocolloids in an amount sufficient to produce a water-impermeable barrier on the surface of the hydrocolloid. The advantage of administering a single dose of a drug that releases the active ingredient over an extended period of time, as opposed to administering a large number of single doses at regular intervals, has been increasingly recognized in the pharmaceutical field. This has been recognized for a long time. Similarly, the benefits to patients and clinicians of maintaining constant blood levels of drugs over long periods of time are recognized. In most sustained release formulations known in the pharmaceutical art, the drug is coated at varying thicknesses with some type of relatively insoluble material or embedded in a rigid lattice of resinous material. In such formulations,
The purpose is to provide a continuous supply of drug for absorption into the blood stream so that the dosage form regains the amount consumed during its passage through the patient's gastrointestinal tract. The usual approach for the sustained release formulations outlined above is that the active ingredient is selected depending on its physiochemical properties and/or convenient site of absorption.
This can be a disadvantage in that it is not compatible with absorption during passage through the gastrointestinal tract. For example, the most acidic drugs are absorbed primarily through the stomach, while the most basic drugs are absorbed primarily through the intestines. Most drugs undergo varying degrees of change in solubility as they pass from the highly acidic conditions of the stomach to the neutral to alkaline conditions of the intestine. For example, ferrous salts are more soluble in the stomach than in the intestines. Finally, there are drugs such as antacids, which are intended to act in the stomach and therefore lose their most advantageous properties if they pass through the intestines. In view of the above, it is readily apparent that many drugs are not amenable to conventional sustained release formulations that are not retained in the stomach and release the drug slowly in the intestines. Similarly, it is clear that sustained release compositions that are retained in the stomach and release the drug there over an extended period of time are eminently suitable for such drugs. Such sustained release formulations are provided by the present invention. The sustained-release nature that characterizes the pharmaceutical formulations of the present invention is unique in the art, i.e., the formulations remain buoyant and free-floating in the gastric fluids for extended periods of time, during which time substantially All drug is released from the formulation. Although many mechanisms of sustained release are recognized in the art and the concept of floating formulations is recognized, the application of floating to sustained release as demonstrated by the present invention. is not known. For example, Davis US Pat. No. 3,418,999 shows tablets that are free-floating. However, the floating properties of this tablet are only disclosed as an aid for swallowing, and there is no suggestion that the floating properties be applied to sustained release. Also
Davis tablets must have an initial density of less than 1, whereas tablets of the present invention are not so limited. The concept of tablets that swell upon contact with gastric fluids is also recognized in the art. for example
US Pat. No. 3,574,820 to Johnson et al. shows tablets that swell upon contact with gastric fluids to such a size that they cannot even pass through the pylorus and are therefore retained in the stomach. It is readily apparent that such tablets are not buoyant. This is because if it is buoyant, its size is not important in terms of its ability to pass through the pylorus. It is also known in the art to incorporate swellable hydrocolloids into sustained release tablets.
Playbair, US Pat. No. 3,147,187, teaches incorporating swollen rubber or proteinaceous materials into sustained release tablets to aid in disintegration of the tablet, thus exposing more surface to digestion. There is no indication that the disclosed tablets are intended to be floating. This is further evidenced by the fact that all ingredients are melted together, after which it is cooled and granulated. Therefore, the hydrocolloid is formulated in the manner of a conventional tabletting binder and, as in the practice of the present invention, is added to the formulation in dry, particulate form so that it promotes tablet flotation. It is the opposite of fulfilling a role. Finally, U.S. Pat. No. 3,065,143 to Christenson et al. uses hydrocolloids in sustained release tablets to
It is taught to create a water-impermeable barrier on the outer surface of the tablet that gradually erodes, thus releasing the drug over an extended period of time. however,
There is no suggestion that such a phenomenon can be exploited to achieve hydrodynamic equilibrium for tablets that remain suspended in gastric fluid for extended periods of time as in the present invention. The present invention provides for oral administration of hydrodynamically balanced fluids having a bulk density (specific gravity) of less than 1 when in contact with gastric fluids, and thus suspended in gastric fluids having a specific gravity of between 1.004 and 1.010. A solid sustained release dosage form pharmaceutical formulation is provided for. The sustained release formulations of the present invention consist of a homogeneous mixture of one or more drugs and one or more hydrophilic hydrocolloids which, upon contact with gastric fluids at body temperature, adhere to the surface of the mixture. A soft gelatinous mass is created, thus making it somewhat bulky and giving it a bulk density (specific gravity) of less than 1. The drug is gradually released from the surface of the gelatinous mass, which is suspended in the gastric fluid by virtue of its buoyancy. Eventually, after substantially all of the drug has been released, the gelatinous mass will disperse. The sustained release formulations of the invention are administered orally in the form of tablets or capsules, such as hard or soft gelatin capsules. Upon oral ingestion of solid pharmaceutical dosage forms prepared from the formulations of the present invention, the capsule shell or tablet film coating, if present, dissolves upon contact with gastric juices, leaving behind the contents. do. When in contact with gastric fluids, the outermost hydrophilic colloid hydrates to form an outer barrier which substantially retains the shape of the capsule or tablet and thus serves to prevent the mass from disintegrating. The hydrated layer then gradually dissolves and releases the drug. There is also a release of drug by a leaching effect at or near the surface of the mass. When the new surface is exposed to gastric fluids, it becomes hydrated, thus preserving the integrity of the barrier. This process is repeated continuously until the drug has been substantially leached out. Thereafter, the remaining matrix, which is also floating in the gastric juices, gradually dissolves and disappears. The mode of release and resulting blood levels achieved by the sustained release formulations of the present invention are found to have advantages over other sustained release mechanisms known in the art, particularly those contained therein. The drug is absorbed in the stomach or duodenum and exerts its therapeutic activity. Sustained release formulations made in accordance with the present invention unexpectedly produce optimal blood levels with certain agents, such as chlordiazepoxide. Results with chlordiazepoxide are superior to known sustained release formulations previously attempted, all of which previously failed to achieve sufficient blood levels. Additionally, the sustained release formulations of the present invention surprisingly provide an excellent method for administering antacids over extended periods of time. Hydrocolloids suitable for use in the sustained release formulations of the present invention include one or more of the following:
Partially or fully synthetic anionic or preferably nonionic hydrophilic gums, modified cellulosic or proteinaceous substances, such as: gum arabic, gum tragacanth,
Carob gum, guar gum, karaya gum, agar, pectin, carrageenan, soluble and insoluble alginate, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, carboxypropylmethylene (Carbopol-Cabot)
Corporation), gelatin, casein, zein,
Bentonite, Veegum RT
Vanderbilt Cr.) et al. A preferred hydrocolloid in the present invention is hydroxypropyl methylcellulose. The use of such substances in pharmaceutical preparations is recognized in the art. for example
US Pat. No. 3,555,151 to Kaplan et al. discloses the use of such hydrocolloids in sustained release antacid preparations. In order to carry out the invention advantageously, the hydrocolloids used must be hydrated in an acidic medium, for example gastric fluids with a PH value corresponding to 0.1N hydrochloric acid, ie a PH value of approximately 1.2. Furthermore, although the initial bulk density of the formulation of the present invention may initially be greater than 1, the formulation may have a
It is important to be hydrodynamically balanced to have a bulk density of less than 1 when in contact with gastric fluids. The rate of drug release from the sustained release formulations of the present invention can be adjusted in a number of ways. First, the selection of a particular hydrocolloid or mixture of hydrocolloids can influence the release rate, e.g. high viscosity hydrocolloids e.g. methylcellulose 60HG, 4000cps are compared with low viscosity hydrocolloids e.g. methylcellulose 60HG, 4000cps.
Hydrates gradually over 10cps and holds soft mass for a long time. further adding to the formulation an edible, pharmaceutically inert fatty substance having a specific gravity of less than 1;
The hydrophilic character of the formulation can be reduced and thus the buoyancy can be increased. Examples of such substances include: refined beeswax; fatty acids: long chain fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol, glycerides such as glyceryl esters of fatty acids or hydrogenated fatty acids; For example, glyceryl monostearate, glyceryl distearate, hydrogenated glyceryl ester of castor oil, etc.; oils, such as mineral oil. Additionally, edible, non-toxic ingredients recognized in the field of pharmaceutical formulations, such as excipients, preservatives, stabilizers, tablet lubricants, etc., can be incorporated into the sustained release formulations of the present invention. . The selection of such materials and the amounts utilized are considered to be within the knowledge of those skilled in the art. However, it should be noted that common pharmaceutical adjuvants that can adversely affect the hydrodynamic balance of the sustained release formulations of the invention are not suitable for use. The amount of active agent or mixture thereof in the sustained release formulations of the present invention can range over a wide range, i.e. from about 0.1% by weight to about
It can be varied within a range of 90% by weight. The amount of active substance present is usually between about 5% and 50% by weight. Factors governing the amount of active substance present in the sustained release formulations of the invention include, for example, the amount required to give the complete therapeutic dosage, its bulk density, its hydrophilic or hydrophobic properties, its stability. Gender, etc. These properties are known or readily ascertainable to those skilled in the art and are necessary to incorporate any therapeutically active substance into the sustained release formulation of the present invention. The preparation of such materials is considered to be within the skill of the art. Additionally, the amount of hydrocolloid component present in the sustained release formulations of the present invention can vary over a wide range, ie, from about 5% to about 99.9% by weight. The amount of hydrocolloid component used will also vary in relation to the amount and nature of the active ingredient and inert formulation adjuvants used. Generally the amount of hydrocolloid present will be between about 20% and about 75% by weight. If one or a mixture of fatty substances is present in the sustained release formulations of the present invention, such substances may comprise up to about 60% by weight of the total composition. Generally, if the formulation contains fatty materials, such materials will be present at about 5% to about 30% by weight. The amount of fatty material used is governed by the amount and physical properties of both the active ingredient and the hydrocolloid, with the aim of producing a hydrodynamically balanced formulation, i.e. a bulk density (specific gravity) of less than 1 in gastric fluids. The goal is to create a formulation that provides Also, the amount of edible inert pharmaceutical adjuvant material that may be present in the sustained release formulations of the present invention will vary according to the amounts and physical characteristics of the other ingredients. Such substances which themselves have a bulk density of less than 1 will increase the buoyancy of the formulation. More importantly, the selection of inert pharmaceutical adjuvant substances can be used to alter the release rate of the formulation. For example, soluble excipients, such as lactose, mannitol, etc., will increase the release rate, whereas insoluble excipients, such as dicalcium phosphate, terra alba, etc., will decrease solubility. When such pharmaceutical adjuvant substances are included in the formulations of the invention, they may be present in amounts up to 80% by weight of the final formulation. Generally such pharmaceutical adjuvants are present at about 5% to about 60% by weight of the formulation. The inclusion and selection of such materials is also considered to be within the skill of the art utilizing the principles of the present invention. The hydrodynamically balanced sustained release dosage formulations of the present invention are manufactured by methods well established in the art. When the formulations of the present invention are administered in the form of capsules, it is necessary to mix and mill or crush all the ingredients to produce a homogeneous mixture of particles of relatively fine size. However, sometimes conventional formulation methods of sludging, wet granulation or extrusion are required to achieve a suitable fill weight in the capsule. The resulting mixture is then filled into suitable pharmaceutical capsules. Hard gelatin capsules are preferred. Capsules should be completely filled. The preparation of the necessary formulations to achieve this objective is within the knowledge of those skilled in the art. When the formulation of the invention is administered in tablet form,
Such tablets are manufactured in conventional manner. In most cases, it is necessary to use wet granulation followed by compression into tablets. However, tablets can be made by direct compression of a homogeneous mixture of the ingredients if the physical properties of the ingredients permit. Such tablets contain conventional tablet lubricants and may also contain other pharmaceutical adjuvant substances according to the criteria set out above. It is noted that many of the hydrocolloids used in the practice of this invention are commonly used in pharmaceutical formulations as tablet binders and as such, and are incorporated into tablet formulations in the form of solutions or dispersions in suitable solvents. Should. However, in practicing the present invention, the hydrocolloid component is introduced into the formulation in dry form;
Therefore, the use of hydrocolloid components is avoided when using wet granulation methods. However, small percentages of the hydrocolloid component can be used as formulation binders in accordance with conventional methods. Hydrocolloids as described herein are commonly used as tablet binders;
When incorporated into a formulation in the presence of a solvent,
Such hydrocolloids do not have the function of promoting the floating properties of these manufactured tablets. Tablets made according to the invention can be made on conventional tablet making equipment. however,
It is important that the tablets are not compressed to such a degree of hardness that a bulk density of less than 1 is not achieved on contact with gastric fluids. According to the invention, tablets with an initial density greater than 1 will be buoyant in gastric juices. This buoyancy is due to an increase in the bulk volume of the tablet due to hydration and swelling of the hydrocolloid particles on the tablet surface when the tablet comes into contact with gastric juices, as well as an increase in the bulk volume of the tablet due to the hydration and swelling of the hydrocolloid particles on the tablet surface, as well as the center of the tablet remaining dry due to the barrier created by the hydrocolloid particles. This is caused by the combination of internal spaces in .
It is therefore important that the tablets are not compressed to such a degree of hardness that porosity is substantially reduced, and that the hydrocolloid particles on the surface of the tablets are so hard and dense as to retard rapid hydration. It will be clear that the maximum hardness that can be compressed into a tablet having an initial density greater than 1 will vary depending on both the initial density of the tablet and the size of the tablet. The hardness for all tablets is the highest hardness that a buoyant tablet can be made in accordance with this specification and the minimum hardness required for a tablet to meet basic pharmaceutical testing for stability during transportation, etc. It's between. This hardness range can be easily determined by standard drug hardness measurements combined with buoyancy testing of tablet samples of different hardness in gastric fluid.
Such a determination is considered to be within the knowledge of one of ordinary skill in the art. Drugs or drug combinations amenable to sustained release therapy using the novel formulations of the present invention include all those suitable for oral administration where sustained release therapy is medically contemplated. It is also to be understood that this invention should not be construed as limited to any particular agent or class of agents. Moreover, the sustained release formulations of the present invention are not limited to drugs that are primarily absorbed from the stomach;
This is because it has been found to be as effective as drugs absorbed from the intestine, such as chlorphenylamine maleate. The sustained release dosage formulations of the present invention obviously cannot be used with acid-sensitive drugs. Among the various drugs that are advantageously administered by sustained release dosage forms are, for example, antibiotics such as penicillins, cephalosporins and telacyclines; catecholamines such as epinephrine and amphetamine; analgesics such as aspirin; sedatives such as barbiturates. These include acid salts, antispasmodics, antiemetics, muscle relaxants, antihypertensives, and vitamins. It has been reported in the literature that gastric irritation caused by aspirin is the result of contact of this highly acidic substance with the stomach wall. It will therefore be clear that the formulations of the invention are particularly advantageous for the administration of aspirin, since they are suspended in the gastric juices. The types of drugs for which the sustained release formulations of the present invention are actually used are benzodiazepines, such as chlordiazepoxide, diazepam, oxazepam, bromazepam, and the like. It is noteworthy that excellent results were obtained with chlordiazepoxide using the formulations of the present invention, after many sustained release mechanisms known in the art have proven unsuccessful. Should. For benzodiazepines, the formulations according to the invention are preferably in the form of capsules. The sustained release formulations of the invention may also be used to treat drugs that are absorbed only from the stomach or upper intestine, such as ferrous salts such as ferrous fumarate, or drugs that have a therapeutic effect on the stomach, such as magnesium oxidation. It is particularly useful in the administration of antacids such as compounds, hydroxides and carbonates, aluminum hydride, magnesium trisilicate. If such substances generate carbon dioxide,
Air bubbles are trapped in the hydrated outer layer, thus increasing the buoyancy of the formulation. Also, an amount of carbon dioxide generating base can be used in the non-antacid composition to increase buoyancy. Additionally, it is within the scope of the present invention to administer the hydrodynamically balanced formulations of the present invention as one layer of a bilayer tablet. The remaining layers contain the drug as a conventional formulation without sustained release components. This unique tablet, when ingested, has an immediate release layer of drug and a floating layer that continues to release drug over a period of time while being retained in the stomach. Such unique bilayer tablets are particularly advantageous for the administration of antacid substances. It has been found that the sustained release formulations of the invention remain suspended in gastric fluids despite the presence of surfactants or food. It has been found that the efficacy of drugs administered using sustained release formulations of the present invention is not affected by the site of absorption of the particular drug. Using dogs administered capsules containing barium sulfate in the formulation of the present invention, it can be demonstrated using X-rays that the composition floats in the gastric fluid and does not adhere to the stomach wall. Ta. The following examples further illustrate the invention. Example 1 Sustained release capsules containing chlordiazepoxide were prepared as follows: Ingredient mg/capsule Chlordiazepoxide 30.6 Hydroxypropyl methyl cellulose,
4000cps 100.4 Lactose Anhydrous 30.0 Sterotex K ^* 58.0 Talc 50.0 Magnesium Stearate 6.0 Total 275.0 *Hydrogenated Cottonseed Oil, Capital City
Manufactured by Products, Columbus, Ohio. The chlordiazepoxide, methylcellulose and lactose were evenly blended in a suitable blender, and then the mixture was passed through a grinder at high speed using an advancing knife and a No. 2B sieve. The Sterotex K, talc and magnesium stearate were then added to the mixture and the whole was blended for an additional 5 minutes. The mixture was passed through the mill at high speed using the No. 0 plate of the advancing knife. After repeated blending and grinding, the mixture was filled into No. 2 pink opaque capsules. The capsules thus prepared were tested for in vitro release rate by the rotating bottle method in simulated gastric fluid. The results of this test are shown in Table 1. Table % of active ingredient released in hours (hours) gastric juice (PH 1.2) 0 0 1 39 2 61 3.5 86 5 94 7 100 In both amber and polyethylene bis with silica stoppers, in a light chamber at 55°C and 37°C Chemical stability testing at °C/85% relative humidity showed that the capsules had acceptable stability. Samples of the above capsules were compared with three commercially available capsules each containing 10 mg of chlordiazepoxide for in vivo testing in humans, administered at 0.4 and 8 hours. The results are shown in Table 1.

Table 1 From the above data it is clear that sustained release capsules are very compatible with single dose capsule therapy. Example 2 An anti-anemic sustained release capsule was prepared as follows: Ingredients mg/capsule Ferrous fumarate 150 Hydroxypropyl methyl cellulose;
4000 cps 100 Lactose 100 Talc 40 Magnesium Stearate 10 Total 400 The ferrous fumarate, hydroxypropyl methylcellulose and lactose were mixed evenly and passed through a grinder at medium speed with a No. 0 plate with advancing knives. A portion of this mixture was mixed with talc and magnesium stearate, passed through a 60 mesh sieve, and added to the remainder of the initial powder mixture. The composition was then mixed for an additional 15 minutes and filled into No. 1 capsules. The dissolution rate of the capsules was determined in gastric fluid by a modified NF method using a bottle rotating at 40 rpm. The results are shown in Table 1. Table 1 : % of active ingredient released in hours Gastric juice (PH 1.2) 0 0 1 45 2 85.7 3 98.6 The capsules remained floating during the test. The release of ferrous fumarate from capsules tested in media of varying PH values was very low due to the low solubility of ferrous fumarate in relatively high PH media. The results of this study demonstrate the effectiveness of ferrous fumarate in a conventional sustained release formulation that is not retained in the stomach. Example 3 Sustained release antacid capsules were prepared as follows: Ingredients mg/capsule FMA-11 ^* 254.7 Magnesium oxide, light 127.0 Lactose, hydrated 20.3 Hydroxypropyl methyl cellulose,
4000cps 63.0 Karayagom, Stein Hall
31.0 Talc, tablet grade 24.0 Magnesium stearate 5.0 Total 525.0 *Aluminum hydroxide-magnesium carbonate coprecipitate: Reheis Co., Berkley Heights, New
Jersey. The FMA-11, light magnesium oxide, lactose and magnesium stearate were blended in a suitable mixer for 10 minutes and then passed through the mill at medium speed using the No. 1 plate of the advancing knife. This mixture is made into a sludge on a suitable press using a 3/4″ FF punch, and this sludge is passed through the advancing knife.
Grind with a grinder at medium speed using a No. 1 plate. The resulting granules were thoroughly mixed with the remaining ingredients and filled into No. 0 capsules using a conventional capsule filling machine. Although the Federal Register does not provide a specific method for testing sustained release antacid preparations, the capsules were tested in the following manner. The capsules were placed in 300 ml of 0.1N hydrochloric acid in a stoppered flask that was rotated at 40 rpm. A 50 ml sample is taken at a given time and titrated with 0.1N NaOH to a pH value of 3.5, which is the neutralization point indicated by the acid neutralization capacity in the Federal register. The amount of acid consumed was calculated from the sample. The results are shown in Table 1. The capsules were floating during the test. Table Time (hours) Antacid release 1 42.1% 2 96.7% 3 104% Example 4 Extended release aspirin capsules were prepared as follows: Ingredients mg/capsule Acetyl salicylic acid, fine powder 400 Dicalcium phosphate, anhydride 20 Hydroxypropyl cellulose 40 Tragacanth 100 total 560 Thoroughly mix all ingredients except tragacanth.
Passed through the grinder using the No. 00 plate of the advancing knife. This mixture was granulated with absolute ethanol,
Dried and ground. Tragacanth was then blended with this mixture and filled into No. 0 capsules. This capsule was found to be suspended in gastric fluid. Example 5 Sustained release capsules containing riboflavin were prepared as follows: Ingredients mg/capsule Riboflavin, type S ^* 15 Hydroxypropyl methylcellulose 110 Lactose 120 Talc 30 Magnesium stearate 5 total 280 *Riboflavin phosphate A type of riboflavin that is characterized by being less soluble and more crystalline. All ingredients were thoroughly mixed and filled into No. 2 gelatin capsules. Release rate in gastric fluid at 40 rpm
It was measured by a modified NF method. The results are shown in Table 1. Table 1 % of active ingredient released over time (hours) 1/2 34 1 45.3 2 62.6 3 1/2 84.7 5 92.6 The capsules remained floating during the experiment. Example 6 The following sustained release capsules containing riboflavin were prepared as follows: Ingredients mg/capsule Riboflavin, Type S 15 Guar Gum 100 Mannitol Powder 75 Corn Starch 60 Tragacanth 30 Total 280 All Ingredients Except Tragacanth were combined and mixed in a suitable mixer. The resulting mixture was granulated with a mixture of equal parts water and ethyl alcohol. The wet granules were passed through the mill using the No. 3 plate of the advancing knife. The granules were then dried at 110° and again passed through the Fitzpatrich mill using the No. 0 plate of the advancing knife. Dry tragacanth was added to the granules, the whole was thoroughly mixed, and the mixture was filled into No. 2 gelatin capsules. The release rate of this capsule is NF at 40rpm.
Measured by a modified method. The results are shown in Table 1. Table 1. Time (hours) % of active ingredient released 1/2 54.5 1 59.5 2 65.6 3 1/2 78.5 5 88.8 The above capsules remained buoyant during the experiment. Example 7 Riboflavin tablets were prepared from the following composition: mg ingredient /tablet riboflavin-5'-phosphate sodium ^*
21.4 Methylcellulose, 4000cps 70.0 Mannitol 250 Sodium carboxymethylcellulose High viscosity, degree of substitution 0.38-0.48 110.0 Hydroxypropylmethylcellulose,
4000 cps 60.0 Polyvinylpyrrolidone 20.0 Ethylcellulose 80.6 Talc 10.0 Magnesium stearate 3.0 Total 400.0 *Contained in excess of 2% by weight Riboflavin and sodium carboxymethylcellulose were thoroughly mixed and granulated with polyvinylpyrrolidone as a 10% by weight solution in alcohol. Except for the talc and magnesium stearate, the remaining ingredients were mixed thoroughly and passed through a mill using a #1 sieve with advancing knives.
This mixture and granules were combined and mixed thoroughly. Then add talc and magnesium stearate,
The entire mixture was evenly blended and compressed into tablets using a standard concave punch. The tablets were compressed to a hardness of 4-6 s.cu and the hardness was determined not to exceed 10 s.cu. It was found that the 4s.cu tablets immediately floated in the simulated gastric fluid, while the 6s.cu tablets temporarily sank before the surface lifted. 10s.cu tablets did not float. For control purposes, gelatin capsules were filled with the following composition: mg ingredient /capsule riboflavin-5'-phosphate sodium.
21.4 Corn starch 73.6 Lactose, hydrate 150.0 Talc 30.0 Magnesium stearate 5.0 Total 280.0 In vitro release studies were carried out in gastric fluid using a modified NF method at 40 rpm only. The results are shown in the following table. TABLE % TIME OF ACTIVE INGREDIENTS RELEASED (HOURS) AVERAGE RANGE 1/2 32 27-40 1 49 39-59 2 76 55-87 3 1/2 91 89-95 5 104 95-108 IN CONTROL CAPSULES Contains 100% Riboflavin
% released within 30%. In vivo testing was performed on 5 volunteers.
Doses were administered approximately 1 1/2 hours after breakfast. Urine samples were analyzed periodically for recovery of riboflavin, an index of absorption. The results are shown in the following table.

【table】

[Table] % of administered dose
The results of this experiment clearly show that SR tablets containing riboflavin are retained in the stomach because absorption of riboflavin occurs only from the proximal end of the small intestine. This result clearly shows that riboflavin is continuously obtained from the SR tablets at the appropriate absorption site for a long period of time. The second significant peak of riboflavin with tablets is due to the enterohepatic circulation, which according to the literature can be attributed to the concentration related to the processing of riboflavin by the liver. Example 8 Extended release aspirin tablets containing 7.5 aspirin tablets were prepared from the following ingredients: Granules A mg acetylsalicylic acid 500 hydroxypropyl methylcellulose, 400 cps
125 Hydroxypropyl Methyl Cellulose, 15cps
3 total 628 granules B mg Calcium carbonate, precipitated 65 Magnesium carbonate 20 Mannitol 10 Carboxymethyl cellulose 2 Total 97 The above two types of particles were mixed evenly with 5 mg of talc,
It was compressed to a hardness of 5-6 s.cu using a capsule forming punch. Hardness is necessary for tablets to maintain their buoyancy.
Should not exceed 11s.cu. Example 9 A sustained release bilayer antacid tablet was prepared as follows: Layer A - Immediate Release Ingredient mg/tablet FMA-11 ^* 160.0 Methylcellulose 5.8 Magnesium Oxide 80.0 Primojel ^** 10.0 Magnesium stearate 2.5 Total 258.3 *Aluminum hydroxide-magnesium carbonate coprecipitate: Reheis Co. **Sodium carboxymethyl starch: E.
Mendel & Co., Carmel, New York. FMA-11 and magnesium oxide were mixed in a suitable mixer. The resulting mixture was granulated using a 2.5% by weight solution of methylcellulose in a mixture of equal parts water and ethyl alcohol. The granules were dried at 60°C overnight. The dried granules were then ground and the brimodiel and magnesium stearate were combined and mixed for 5 minutes. The resulting homogeneous mixture was then compressed on a conventional two-layer tablet press. Layer B - Sustained Release Ingredients mg/tablet FMA-11 170 Magnesium Oxide 85 Methylcellulose, 4000cps (dry) 90 Methylcellulose, 4000cps (wet) 6 Ethylcellulose 90 Direct Compression Grade Starch 35 Syloid ^* 30 Stearic Acid Magnesium 23 total 529 *Purified silicon dioxide: WR Grace & Co.,
Baltimore, Maryland. FMS-11 and magnesium oxide were mixed in a suitable mixer. The resulting mixture was granulated with a solution of methylcellulose (wet) in a mixture of equal parts water and ethyl alcohol, and the granules were dried at 60°C overnight. The resulting granules were combined with methylcellulose (dry), ethylcellulose, direct compression grade starch, and siloids and thoroughly mixed for about 10 minutes.
Magnesium stearate was added and the mixture was mixed for an additional 5 minutes. This mixture is then compressed with layer A in a conventional bilayer tablet machine and 3/
It was made into a standard concave capsule shape of 4″ x 5/16″. The permissible hardness of this tablet is between 12 and 14 s.cu; the hardness is
I found that it should not exceed 16s.cu. A sample of the resulting two-layer antacid tablet was placed in a beaker containing gastric juice and a magnetic stirrer rotating at low speed was placed. It was observed that the immediate release layer separated and settled in fine particles at the bottom of the beaker. The sustained release layer was suspended for 2 hours while gradually releasing the drug.

Claims (1)

[Scope of Claims] 1 (a) one or more drugs; (b) 5 to 60% by weight of a therapeutically inert pharmaceutically acceptable excipient substance; (c) a specific gravity of less than 1; Fatty substances with 0-60
% by weight, and (d) 20 to 75% by weight of a hydrocolloid or mixture in the dry state which provides a water-impermeable barrier to the surface of the homogeneous mixture when in contact with gastric fluids, mechanically applied in the substantially solid state. A homogeneous mixture is prepared by mixing by a mixing method [wherein the above weight percentages are based on the mixture], and each component of the mixture is adjusted to a bulk density that causes the mixture to float on contact with gastric juices. A method for producing a sustained release drug formulation suitable for formulation in a solid dosage form for oral administration, characterized in that: 2. A method according to claim 1, in which the formulation is formed into tablets. 3. The method of claim 1, wherein the formulation is in the form of capsules. 4. A method according to any one of claims 1 to 3, using about 5% to about 30% by weight of said fatty substance. 5 Methyl cellulose as the hydrocolloid,
Claim 1 using hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, sodium carboxymethylcellulose or a mixture thereof
3. The method according to any one of items 3 to 3. 6. The method according to claim 5, wherein hydroxypropylmethylcellulose is used as the hydrocolloid. 7. The method according to any one of claims 1 to 3, wherein a benzodiazepine is used as the drug. 8. The method according to claim 7, wherein chlordiazepoxide, diazepam, oxiazepam or bromazepam is used as the benzodiazepine. 9. The method according to claim 8, wherein chlordiazepoxide is used as the benzodiazepine. 10. The method of claim 2, wherein the drug in the tablet is one or more antacids. 11. A first layer comprising a therapeutically inert pharmaceutically acceptable adjuvant substance free of one or more drugs and sustained release ingredients; and Claim 2
A method according to claim 1 for producing a bilayer tablet comprising a second layer made of a tablet produced according to the method described in claim 1. 12. The method according to claim 11, wherein an antacid substance is used as the drug. 13. The method according to claim 3, wherein a benzodiazepine is used as the drug in the capsule. 14. The method according to claim 13, wherein chlordiazepoxide, diazepam, oxiazepam or bromazepam is used as the benzodiazepine. 15. The method according to claim 14, wherein chlordiazepoxide is used as the benzodiazepine.