US 3148124 A
Description (OCR text may contain errors)
United States Patent C) 3 148 124 METHOD OF PREPAliIN SUSTAINED RELEASE PHARMACEUTICAL TABLETS William E. Gaunt, 280'Prospect Ave., Hackensack, NJ. No Drawing. Filed; June 12, 1962, Ser. No. 201,822
26 Claims. ((Jl. 167 82) This invention relates to pharmaceutical tablets and more specifically to orally administrable, controlled or sustained release tablets. Still more specifically, this invention relates to a method of preparing controlled release tablets from medicinal-coated insoluble particles. The insoluble particles form a lattice structure wherein the medicament or therapeutic material is dispersed uniformly.
The presently available sustained release, timed release, timed. disintegration, or delayed release preparations depend either upon some procedure of coating the therapeutic material in such a manner that it is protected from the direct action of alimentary fluids or upon some procedure of embedding the therapeutic material within a water insoluble matrix so as to achieve the same results. In the -former case, the coatings protecting the therapeutic materials or drugs are designed with the' purpose of having them disintegrate 'or dissolve in the alimentary fluids after being exposed thereto for certain periods of time, thus making the drugs available for dissolution in the alimentary fluids .and available for absorption and utilization by the patient. In the latter case, the matrix within which the drug is embedded is so designed that it will be dissolved, digested, or eroded slowly by the action of the alimentary fluids and the drug becomes available for dissolution in these alimentary fluids and subsequently is adsorbed and utilized by the patient.
The coating procedures, however, suffer the disadvantage of having the coatings lose their continuity or change their physical characteristics upon aging or exposure to mechanical shock. Such changes can defeat the objectives of using sustained or timed release tablets by permit ting the drug to be released immediately to the action of the alimentary fluids on inges-tition or, on the other hand, the change in physical characteristics of the coating may delay the process of dissolution or disintegration to the extent that the drug is released too slowly and does not become available to the patient in such quantity or at such a rate as to provide eflective therapy. For the most part, the matrix materials suffer from this same deflect of change in physical characteristics with time providing undesirable and unreliable release characteristics.
In addition, Where the medicamentis to act in the stomach, the coatings are required to be of different materials and thicknesses so that they are disintegrated by' the stomach fluids. Where, however, the medicament is to act in the intestinal tract, different types of protective or barrier coatings are required so that the medicament will released in the intestines. The reason for having to use different types of coatings is to control the rate of solubilizing the drugs in the alimentary fluids which difler from the acidity of the gastric juices to the alkalinity of the intestinal fluids. Thus, depending upon the absorp tion site, the coatings of the tablets are chosen to effect medication at the desired portion of the alimentary canal. For stomach absorption, the outer coatings are formulated to be dissolved by the acidic gastric fluids, whereas if the medicament is to be released in the intestines, a coating is used which is dissolved in the intestinal fluids but is unaffected by the fluids in the stomach.
To avoid these problems, it has been discovered that water-soluble therapeutic materials may be solubilized in a solvent which is used to coat water-insoluble particles that are compressed into the form of a tablet. The pharmaceutical-c'oat'ed insoluble particles are transformed,
. 3,148,124 Patented. ept. 8, .1964
by compression, into a lattice structure with a continuous interphase of the drug within the interstices. v
The lattice structure of these compressed tablets is such that it does not fall apart or disintegrate upon being exposed to alimentary fluids, which dissolve and; release 7 the therapeutic material, but the interstitial spaces formed by these Water-insoluble particles do provide a means of releasing the drug at the desired absorption site. It was unexpected to find that the lattice structure formed by compression of the coated particles would hold its shape as the drug is leached slowly from the lattice'by the alimentary fluids which progressively dissolve away the continuous interphase of drug. The rate at which the drug is released or leached can be modified in a variety of ways, such as, for example, by regulating-the size and shape of the lattice, or by regulating the relative proportion of the drug with respect to the lattice, or by dissolving in the solvent a Water-soluble or dispersible substance in combination with the therapeutic agent. If, however, it is desirable to decrease the rate of release in the system, a Water-insoluble substance can be'added to the solvent which is dispersed within the lattice of .the=compressed insoluble particles. Such materials may include-methyl cellulose, ethyl cellulose,- hydroxy ethyl cellulose,fatty acids, fatty alcohols, fatty esters, fatty oils, wax, etc. These water-resistant substances decrease the: rateat which the alimentary fluids penetrate the lattice structure and dissolve .away thewater-soluble drugs.
In addition to the water-soluble or dispersible substances and: the water-insoluble wor water-resistant substances, the solution of: medicament or drug also-may contain a non-reactive or inert carrier, which facilitates the dispersion of the drugs over the surfaces of the Waterand solvent-insoluble particles. These inert carriers are highlyWater-soluble and non-reactivematerials which serve to disperse the drug throughout the lattice and pro-' vide a continuous interstitial film,*particularly in instances Where only a small amount of the drug is used in the tablets. The medicament or drug-together with any one or more of these modifying agents, or mixtures thereof, are put into solution and mixed uniformly with the waterinsoluble particles; This agglomerated mixture iscompressed into tablets which are characterized by having the drug dispersed within their interstitial spaces.
It is obvious, then, that in order-to obtain a satisfactory release medicament according to the principles of thisinvention, it is essential that the lattice structure be water insoluble in both acid and basic media, and also insoluble in the solvent used to prepare the solution of medicaments and modifying agents.
Accordingly, then, it is an object of this inventidn'to provide a method of preparing a sustained release medicament.
It is another object of this invention to provide a method of preparing a sustained release tablet comprising a pharmaceutical material uniformly dispersed within the interstitial spaces of a Water-insoluble material.
It is another object of this invention to provide a method of preparing a sustained release tablet comprising a watersoluble drug uniformly dispersed within the lattice structure of a water-insoluble material.
It is still another object of this invention to provide a a method of preparing sustained or timed release tablets comprising a water-soluble medicament, together with one or more modifying agents, uniformly dispersed within the lattice structure of a water-insoluble material; the
1 v 3 water-insoluble material further characterized by being substantially insoluble in either acid or basic media and completely insoluble in the solution which contains the medicament and modifying agents.
It is a still further object of this invention to provide a method-of preparing timed or sustained release tablets from water-insoluble particles having a uniform coating of the medicament or drug.
It is a still further object of this invention to provide a method of preparing sustained release medicaments by compressing small particles of water-insoluble materials having uniformly dispersed thereon an effective amount of medicament.
It is a still further object of this invention to provide a sustained-release medicament from medicinal coated, water-insoluble particles which are compressed into a lattice structure that does not disintegrate or dissolve upon being exposed to alimentary fluids.
It is a still further object of this invention to provide sustained release tablets from a uniform mixture of watersoluble drugs and water-insoluble particles, said tablets being further characterized by having the drug dispersed uniformly within the lattice structure of the waterinsoluble material.
These and other objects of the invention will become apparent from a further and more detailed description as follows:
It has been discovered that unique controlled or sustained release characteristics can be obtained from (1) a solution of a water-soluble drug and (2) a water-insoluble material which is also insoluble in the solvent used in preparing the solution of the drug. More specifically, it has been discovered, unexpectedly, that unique controlled release characteristics can be obtained from medicinalcoated Waiter-insoluble particles by compressing these coated particles with suflicient pressure so as to obtain a lattice structure wherein the medicament is dispersed. These tablets are obtained by coating the water-insoluble particles uniformly with a solution of the medicament. The solution also may contain other modifying agents which may increase or decrease the solubility rate of the medicament in the alimentary canal.
It has been found that the unique sustained or controlled release tablet can be prepared by forming a solution of the drug or medicament which is added to the particles of the water-insoluble material until a homogeneous mixture is obtained. The solvent then is removed, e.g. evaporated, and the substantially dry or dry agglomerated mixture is compressed at conventional tableting pressures into a lattice structure. Where it is desirable, modifying agents, such as water-solubilizing agents or surfactants, either alone or in combination with inert or non-reactive carriers, water-repelling agents, and gastric or intestinal fluid solubilizing materials, may be added to the medicinal solution which is then mixed with the waterand solventinsoluble particles. Depending upon the characteristics required of a particular controlled release medicament, any one or more of the modifying agents, or mixtures thereof, may be used in preparing the tablets.
The sustained or controlled release tablets of this invention comprise approximately 20 to 65 percent, preferably 40 to 65 percent by weight of the water-soluble medicament, and about 35 to 70 percent, preferably 40 to 50 percent by weight, of the water-insoluble particles. Alternatively, a combination of the medicament and the water-soluble inert carrier may comprise approximately 20 to 65 percent, preferably 40 to 65 percent by weight of the tablet. In addition, the tablets may contain one or more modifiers comprising to 65 percent by weight of an inert or non-reactive water-soluble carrier, 0 to percent by weight of a water-resisting agent, 0 to 10 percent by weight of a water-dispersible agent, or surfactant, and 0 to percent by weight of an antacid or intestinalfluid solubilizing agent, which can be added to the solution of medicament.
In preparing the sustained release tablets, the thera- 4 peutic material, either alone or with one or more of the modifying agents, is dissolved in the solvent, which is selected carefully to provide a solution of the drugs and modifying agents without affecting the insoluble particles. The drug solution is mixed thoroughly with the insoluble particles, which are in finely divided form, until a substantially smooth, creamlike composition is obtained. The mixture is agitated until all of the insoluble particles are coated uniformly with the solution of medicament, and then the solvent is removed. Normally, the solvent is removed by evaporation, with continuous mixing either with or without. the application of heat. Once the solvent is removed, the agglomerated mixture is compressed by tableting pressures to a lattice structure having a continuous interphase of the medicament within the inter stices. The tableting pressures used are those to be found in conventional tableting machines and may range as high as 6,000 p.s.i.
In order to insure uniform dispersion of the medica ment within the lattice structure of the insoluble particles, it is important that the therapeutic material have a high degree of solubility in the solvent. Preferably, the solvent should be one which can be removed at low temperatures by evaporation. Since the solvent acts as a carrier in dispersing the medicament over the surface of the insoluble particles, it is obvious that it is essential to have the insoluble particles completely insoluble in the solvent, and likewise it is essential that the lattice structure formed by compressing these particles be highly insoluble in both acidic and alkaline media which are found in the stomach and intestinal tract. After the solvent is removed and before the agglomerated mixture is compressed into tablets, it is usually a practice to add to the dry mixture a lubricant which facilitates tableting.
-As an alternative to the simple mixing of the solution of the medicament with the insoluble particles, it is pos sible also to spray the therapeutic solution, with one or more of the modifying agents, onto the surface of the water-insoluble particles; the particles being suitably agitated so as to insure their uniform coating. By following this procedure, the solvent is removed continuously, by evaporation, as the solution of the medicament is sprayed over the insoluble particles. The sprayed particles may be dried further, if required, then lubricated with talc, and compressed into tablets of the appropriate size and shape in a conventional manner.
In preparing the solutions of the drum or medicament, a wide variety of solvents obviously can be employed. Both polar and non-polar, or mixtures thereof, can be used. Such solvents include, for example, water; the lower molecular weight alcohols, i.e. methyl or ethyl alcohol; acetone; methyl ethyl ketone; the halogenated hydrocarbons; aliphatic or aromatic hydrocarbons; or any other volatile liquid, with the limitation that it is a solvent for the medicament and modifying agents but not for the water-insoluble particles which form the structure that holds the medicament.
Drugs or therapeutic materials which may be used in the practice of this invention include, for example, the antihistamines, sedatives such as phenobarbital, tranquilizers, antibiotics, analgesics, including narcotics, steroids, hormones, vitamins, anorexics such as phenmetrazine, phendimetrazine, e-tc., anti-infective agents such as sulfonamides, anti-spasmodics such as atropine, scopolamine hydrobromide, and mixtures of one or more of these drugs which are soluble inwater.
The water and solvent-insoluble materials or particles. which form the lattice structure include the water-insoluble salts of higher fatty acids, saturated or unsatu-- rated, containing from 6 to 22 carbon atoms per molecule. More specifically, the alkaline earth metal salts of these fatty acids, e.g., calcium stearate, are preferred. In addition to the fatty acid salts, other water-insoluble lattice-forming materials include the clays, such as bentonite, aluminum oxide (A1 0 hydrated aluminum oxide, silica gel, barium sulfate, or mixtures thereof.
More than one therapeutic material may be used in the same lattice and be released from the interstitial spaces at substantially the same time. The therapeutics or drugs are solubilized in the appropriate solvent and coated over the water-insoluble lattice-forming materials or particles by mixing the solution thoroughly with the insoluble particles until a cream-like consistency is obtained[ To insure uniform dispersion of the drugs and to provide suflicient Water soluble, interstitial film, 6 to-60 percent by weight of the'table'ts may consis-t of a highly water soluble non-reactive carrier, such as' urea, glycine, water-soluble glycol, polyvinyl pyrrolidone, polyvinyl alcohol, and any mixtures thereof. These carriers are inert or non-reactive with the drugs and provide a continuous interstitial film of the drug within the lattice structure and are particularly useful when the medicament is used in low dosages.
Where it is desirable to increase the rate at which the alimentary fluids penetrate the lattice structure and dissolve th e water-soluble interstitial substances, a watersoluble surfactant is added to the solution of drugs. These may include, for example, polysorbates, e.g. polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monooleate, bis-2-ethylhexyl sodium sulfosuccinate, sodium lauryl sulfate, lecithin, fatty acid esters of polyhydric alcohols, such as ethylene glycol, diand triethylene glycols, and the polyethylene glycols, fatty alcohols, Watersoluble waxes, and glycerol stearates. However, where it is desirable to decrease or slow down the rate at which the alimentary fluids penetrate the lattice and dissolve the water-soluble interstitial substances, it may be advisable to add water-insoluble or water-resistant substances, such as methyl, hydroxy ethyl, or ethyl cellulose, fatty acids, fatty alcohols, fatty esters, waxes, and the like. 1 Since the rate at which the medicament or drugs are solubilized in the alimentary fluids depends on the basicity or acidity of these fluids, it may be desirable in some instances to use in combination with the medicament and other modifying agents, a material which is acidresistant, alkali-susceptible, and which will decrease the rate of penetration of the insoluble lattice by the gastric fluids but increase the rate of penetration by the intestinalfluids, so that the medicament will be released largely in the intestines. These alkali-susceptible materials include, for example, the cellulose acetate phthalate, starch acetate phthal-ate, polyvinyl acetate phthalate, and the polyacrylic acid derivatives of phthalic acid, or any mixtures thereof.
The methods used in preparing the controlled or sustained release tablets according to the principles of this invention are illustrated by the following examples:
EXAMPLE I Approximately 75 grams of phenmetrazine hydrochloride were dissolved in 260 ml. of methanol. This solution was added with mixing to 70 grams of calcium stearate USP, with continuous agitation until a smooth homogeneous creamlike mixture was obtained. The methanol was evaporated from the mixture with continued agitation until the resultant product broke up into discrete particles. After approximately all of the solvent had been removed the product was passed through a 20 mesh screen. To this screened mixture approximately 6.0 grams of talc and 1.5 grams of magnesium stearate was added and intimately dispersed through the product. The resulting dry product was compressed, i.e. 4,000 pounds p.s.i., into tablets which contained approximately 75 mg. of phenmetrazine hydrochloride.
Upon exposing these tablets to alimentary fluids, the phenmetrazine hydrochloride was released slowly to the extracting solutions until nothing=remained but the lattice 6 structure of the calcium stearate. The remaining insoluble:lattice had its interstitial spaces filled with the extracting fluids.
- EXAMPLE H A mixture of two grams chlorpheniramine maleate, ten grams of methapyrilene hydrochloride, and 37.5 grams of phenylpropanolamine, together with 50 grams of urea and 30'grams of polyvinylpyrrolidone, was dissolved in 420 ml. of .methanol. This solutionwas addedgto grams of calcium stearatejand mixed to a uniform; smooth creamy paste. evaporation in a current of warm air with continued mixing and the remaining solvent removed by drying in an oven at 45 C. The resulting dry product was passed through a 20 mesh screen, thoroughly mixed with 10 grams of silica gel and 2.5 grams of magnesium stearate, and compressed into tablets containing a total of 49.5 mg. of medicament. The tablets of Example II can be modified further by replacing part of the polyvinylpyrrolidone with ethyl, methyl, or hydroxy ethyl cellulose to decrease the rate of release of the drug.
EXAMPLE III A methanol acetone solution containing approximately 4 grams of chlorpromazine hydrochloride, 2 grams of cellulose acetate phthalate, and 2 grams of urea was sprayed uniformly over the surface of approximately 8 grams of finely-divided particles of calcium oleate until a smooth creamlike mixture was obtained. The alcohol was removed by evaporation and the dried product was passed through a 20 mesh screen. The screened particles were compressed at pressures up to 5,000 psi. to tablets having the cellulose acetate phthalate and medicament uniformly dispersed within the lattice structure of the insoluble calcium oleate.
EXAMPLE IV A tablet containing a small dosage of drug comprises 5 grams dexamethazone, 50 grams urea, and 45 grams of polyvinyl pyrrolidone dissolved in 300 ml. of methanol, Which was added to 100 grams of calcium stearate and mixed until a uniform, smooth cream was obtained. The
solvent then was removed by evaporation in a current of EXAMPLE V Seventy-five grams of phendimetrazine hydrochloride was dissolved in ml. of a mixture of 80 parts of methylene chloride and 20 parts methanol and added to 150 grams of dried precipitated aluminum oxide. The mixture was stirred to a smooth cream and the solvent then removed by evaporation. The resultant dry product was reduced to 20 mesh granules, lubricated with talc and magnesium stearate and compressed into tablets containing 75 mg; phendimetrazine hydrochloride. On exposing these tablets to alimentary fluids, the aluminum oxide Was observed to have formed a lattice structure resistant to gastric and intestinal fluids, but releasing phendimetrazine from its intersititial surfaces to the extracting solutions.
EXAMPLE VI 49.5 grams of polyvinyl pyrrolidone and 0.5 gram of cyanocobalamine (crystalline vitamin B was dissolved in 200 ml. of methanol. This solution was added to 50 grams of calcium stearate and the mixture stirred to a homogeneous cream. The solvent is removed by evaporation in a current of warm air, with the last traces being. removed in'the oven at 45 C. The resultant dry product was reduced to a 20 mesh granule, lubricated with talc and magnesium stearate and compresed into tablets.
On exposing these tablets to intestinal fluids, the B is leached slowly out of the pink colored tablets, and the The solvent waspartially removed by- E 7 l 1 surface of the tablets becomes the white color of the calcium stearate lattice. On breaking these tablets in half, after progressive increments of time, it is observed that the amount of white lattice free from the red colored vitamin B .becomes progressively greater and that the central part of the tablet, still containing B in the interstices of the lattice, becomes progressively smaller and thinner. Data obtained on the release rate of B from tablets of identical proportionate composition but of different thicknesses, indicates that the rate of leaching or the rate of penetration of the interstices of the lattice, is the same with each tablet, with the thicker tablets still retaining an inner portion of the full lattice structure when the thinner tablets have the lattice structures completely exhausted of the interstitial film of medicament and inert carrier. This is illustrated in the following table where the data was obtained from tablets having the same diameter but a different thickness.
Table I.- Milligrams of Vitamin B in Tablets Average Thickness of Tablets Within the limits of experimental error, the amount of B leached out of each set of tablets was the same at each time interval, the thinner tablets starting initially with the lower B content and continuing with a lower content throughout the leaching process.
EXAMPLE VII 100 grams of ascorbic acid was dissolved in 400 cc. of aqueous ethanol containing 2 grams of polyoxyethylene sorbitan monooleate and the solution was then added to 80 grams of calcium stearate. The mixture was stirred to give a uniform, smooth cream. The solvent was removed in a vacuum and the dried mass screened to 20 mesh granules. The granules was lubricated with talc and magnesium stearate and compressed into tablets containing 150 mg. of ascorbic aci In instances where a particular drug is sensitive to the solvent, the drug is mixed with the water-insoluble particles after they have been coated with a solution of the water-soluble inert carriers, e.g., an alcohol solution of urea, polyvinyl pyrrolidone, or glycine, with or without the other modifiers. Here the drug, in the form of finelydivided powder, is mixed with dry particles of the insoluble material which have been coated previously with one or more modifying agents, to obtain an intimate mixture. This mixture then is compressed at tablet-forming pressures, to form a lattice structure of the insoluble particles with the interstitial spaces containing the drug and modifying agents. The addition of medicaments or drugs to the dry coated particles of insoluble material is applicable particularly in the preparation of tablets containing enzymes and some vitamins which are highly sensitive to water and organic solvents.
A typical method of preparing tablets containing sensitive materials, e.g., enzymes, comprises preparing a solution containing about to 60 percent by weight of the tablet of a water soluble inert carrier, i.e., a mixture of urea and polyvinyl pyrrolidone, dissolved in a solvent,
such as a lower molecular weight alcohol. This solution, which also may contain 0 to 15 percent by weight of a water-resisting agent, 0 to 10 percent of a water dispersible agent or surfactant, and '0 to 20 percent by weight of an antacid or intestinal fluid solubilizing agent, is thoroughly mixed with approximately 40 to 60 percent by weight of a water and solvent insoluble lattice forming material, such as calcium stearate, until a smooth creamlike mixture is obtained. The solvent is removed and the dry mixture is passed through a 20 mesh screen. To the screened product is added approximately 10 to 45 percent by weight of an enzyme, and a small amount of lubricant comprising a mixture of talc or silica and magnesium stearate. This mixture is agitated thoroughly until a uniform product is obtained. The dry product then is compressed into tablets containing an effective amount of the enzyme.
EXAMPLE VIII A mixture consisting of approximately 32 grams of urea and 16 grams of polyvinyl pyrrolidone was dissolved in 300 ml. of methanol. This solution was mixed thoroughly with approximately 96 grams of calcium stearate until a smooth creamlike mixture was obtained. The solvent was removed by evaporation and the dry product was passed through a 20 mesh screen. To the screened product was added 48 grams of bromclin, 8 grams of talc, and 2.5 grams of magnesium stearate. This blend was mixed thoroughly until a uniform product was obtained which then was compressed into a tablet containing 1 20 mg. grams of brornelin.
EXAMPLE 1x To 23 liters of methanol containing 1,146 grams of calcium chloride di ydrate was added 6,600 grams of phendimetrazine bitartrate with stirring. After the therapeutic material had dissolved, 5,850 grams of calcium stearate were added. Stirring was continued until a smooth homogeneous mixture was obtained. The greater part of the methanol was removed in a stream of air with continued stirring. The remaining solvent was re.- moved by drying at 100- F.
The dry product was milled to a granular powder, lubricated with talc and magnesium stearate and compressed into tablets containing mg. of phendimetrazine bitartrate. Some tablets were compressed at diameter and others at 7 diameter.
On exposing these tablets to artificial gastric juice and artificial intestinal fluids at 37 C., the following data on the release of phendimetrazine was obtained.
Table II.Release Rate of Phendimetrazine Bitartratc The data in Table II illustrates the influence of the tablets size and shape on the release characteristics of the lattice systems after a total exposure of seven hours. Furthermore, when the proportion of phendimetrazine bitartrate to calcium stearate is changed from the 1.25/1 ratio of the above example to a 1.0/1 ratio, the release rate of phendimetrazine is lowered from 90.5 percent to 75.5 percent. Tablets of such composition, containing 110 mg. of phendimetrazine bitartrate and compressed to diameter, gave the following release data:
Table IIIRelease Rate of Phendimetrazine Bitartrate As illustrated in Tables II and III, the rate of release of the drug can be lowered by decreasing the ratio of drug and calcium stearate. When the ratio of 1.25/1 was lowered to 1.0/1, the rate of release was lowered from 90.5 to 75.5 percent.
Medicaments or drugs with widely ranging solubility characteristics can be used in the practice of this invention, with the less soluble medicaments being combined with highly soluble inert carriers. These water-soluble carriers enhance the solubility of the medicaments and permit progressively deeper entry of the alimentary fluids into the tablet, thus affecting the rate at which medicaments are released. The rate at which the drug is released also depends on other factors, for example, the size of the tablet, the thickness, the relative proportion of the insoluble lattice structure to the dose of drug, and in addition on the use of other solubilizing agents, such as the surface active agents.
In preparing the controlled or sustained release tablets according to this invention, it is essential that the medicament and any one or more of the modifying. agents used therewith be highly soluble in the solvent selected such that it can be used to coat the surface of the small particles of the insoluble material. The solution is added to the insoluble particles until a creamlike consistency is obtained and, upon removing the solvent, the remaining particles agglomerate. These agglomerated particles are granulated, if need be, and passed through a screen, i.e,. 20 mesh, to provide uniform particle sizes. The particular mesh size of the particles depends in part on the size of the tablet to be prepared. Thus, the larger tablets can be prepared from larger particle sizes. For example, a 1 diameter tablet is pressed from particles passed through a 20 mesh screen, which has a 0.034" opening and a 0.016" wire diameter. Preferably, about 80 percent of the screened particles should be 20 mesh before they are compressed in a conventional tablet making machine. ticles are compressed so as to form a tablet in diameter having a lattice structure wherein the medicament is dispersed uniformly and released readily upon coming into contact with the gastric or intestinal fluids. The hardness and size of the lattice structure or interstitial spaces between the particles of the insoluble material will depend upon the mesh size of the particles and the amount of pressure used to compress them into a tablet. The finished tablets have a hardness which can be expressed in terms of kilograms of pressure. Normally, the tablets have a hardness of about 10-12 kilos which means that they can withstand these pressures before breaking.
To prevent binding of the particles to the die, it is a practice to use lubricating agents, such as talc, stearic acid, magnesium stearate, or the like, which have little or no effect on the above characteristics of the tablets.
For purposes of description, certain specific examples have been employed, but these are meant to be illustrative only. Numerous variations may be made with respect to the particular materials employed, the amounts utilized, etc., without departing from the spirit of the Agglomerates of the finely-divided coated par-' invention. It is desired, therefore, to be limited only by the scope of the appended claims. 4 i
The invention claimed is:
1. In the method of preparing oral dosage formulations comprising water-soluble medicaments and waterinsoluble materials, the improvement which consists essentially of (1) completely solubilizing a dosage quantity of at least one water-soluble medicament in a solvent to form a solution,
(2) mixing said solution with at least one waterinsoluble lattice forming material, said material being insoluble in the solvent and selected from the group consisting of alkaline earth metal saltsof the higher molecular weightfatty acids, aluminum oxidesa-nd silica gels, i 1
(3) removing said solvent to obtain asubstantially dry mixture; and r p (4) compressing said mixture into tablets having a lattice structure with a continuous interphase of the medicament within the interstices. I
2. The method of claim 1 further characterized in that said solvent is selected from the group consisting of water, the lower molecular weight alcohols, acetone, methyl ethyl ketone, the halogenated hydrocarbons, and the aliphatic and aromatic hydrocarbons;
3. The method of claim 1 further characterized in that a water-resisting agent is added to the solvent, said waterresisting agent being selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxy ethyl cellulose, fatty acids, fatty alcohols, fatty esters, and waxes.
4. The method of claim 3 further characterized in that the water-resisting agent is a fatty acid.
5. The method of claim 3 further characterized in that up to about 15 percent by: weight of the tablet of a waterresisting agent is added to the solvent.
6. The method of claim 1 further characterized in that at least one non-reactive water-soluble carrier is added to the solvent, said carrier being selected from the group consisting of urea, glycine, water-soluble glycol, polyvinyl pyrrolidone, and polyvinyl alcohol, and mixtures thereof. l f
7. The method of claim 6 further characterized in that up to about 65 percent by weight of the tablet of said non-reactive water-soluble carrier is added to the solvent.
8. The method of claim 6 further characterized in that the combination of the water-soluble medicament and the water-soluble carrier range from 20 to 65 percent by weight of the tablet.
9. The method of claim 6 further characterized in that a water-soluble surfactant is added to the solvent, said surfactant being selected from the group consisting of polyoxyethlene sorbitan monolaurate, polyoxyethlene sorbitan monopalitate, polyoxyethylene sorbitan mono-oleate, bis-2-ethylhexyl sodium sulfosuccinate, sodium lauryl sulfate, and lecithin.
10. The method of claim 9 further characterized in that a water-soluble surfactant is added to the solvent in an amount ranging up to about 10 percent by weight of the tablet.
11. The method of claim 1 further characterized in that the solvent contains an intestinal fluid solubilizing material which decreases the rate of penetration of gastric fluids and increases the rate of penetration of intestinal fluids into the lattice structure of the tablets; said material being selected from the group consisting of cellulose acetate phthalate, starch acetate phthalate, polyvinyl acetate phthalate, and mixtures thereof.
12. The method of claim 11 further characterized in that the intestinal-fluid solubilizing material ranges up to 20% by weight of the tablets.
13. The method of claim 1 further characterized in that the water-insoluble lattice-forming material is an aluminum oxide.
14. The method of claim 1 further characterized in 1 1 that the water-insoluble lattice-forming material is an alkaline earth metal salt of a higher molecular weight fatty acid.
15. The method of claim 1 further characterized in that the solvent is a mixture of water and a lower molecular weight alcohol.
16. The method of claim 1 further characterized in that the water soluble medicament is selected from the group consisting of antihistamines, sedatives, tranquilizers, antibiotics, analgesics, steroids, hormones, vitamins, anorexics, anti-infective agents and anti-spasmodics, and mixtures thereof.
17. The method of claim 1 further characterized in that the medicament is an anorexic.
18. The method of claim 6 further characterized in that the water-soluble carrier is a mixture of urea and polyvinyl pyrrolidone.
19. The method of claim 12 further characterized in that the intestinal-fluid solubilizing material is cellulose acetate phthalate.
20. The method of claim 1 further characterized in that the solution of medicament is mixed with the waterinsoluble lattice-forming material by spraying said solution over the lattice forming materials to obtain a uniform coating of the medicament thereon.
21. The method of claim 14 further characterized in that the salt of the higher fatty acid is calcium stearate.
22. The method of claim 14 further characterized in that the salt of the higher fatty acid is calcium oleate.
23. The method of claim 9 further characterized in that the surfactant is polyoxyethylene sorbitan monooleate.
24. In the method of preparing oral dosage formulations consisting of water-soluble medicaments and Water-insoluble materials, the improvement which consists essentially of (1) completely solubilizing a non-reactive water-soluble carrier in a solvent to form a solution,
(2) mixing said solution with at least one waterinsoluble lattice-forming material, said material being insoluble in the solvent and selected from the group consisting of alkaline earth metal salts of higher molecular weight fatty acids, aluminum oxides and silica gels,
(3) removing said solvent to obtain a substantially dry mixture and adding to the dry mixture a dosage quantity of an enzyme, and
(4) compressing the rmxture into tablets having a lattice structure with a continuous interphase of the enzyme Within the interstices.
25. The method of claim 24 further characterized in that the enzyme is bromelin.
26. The method of obtaining controlled in vivo release of water-soluble medicaments which consists of admin- Etering to a subject an oral dosage formulation prepared (1) completely solubilizing a dosage quantity of at least one water-soluble medicament in a solvent to form a solution,
(2) mixing said solution with at least one water-insoluble lattice-forming material, said material being insoluble in the solvent and selected from the group consisting of alkaline earth metal salts of the higher molecular weight fatty acids, aluminum oxides and silica gels,
(3) removing said solvent to obtain a substantially dry mixture, and
(4) compressing said mixture into tablets having a lattice structure with a continuous interphase of the medicament within the interstices.
References Cited in the file of this patent UNITED STATES PATENTS 2,918,411 Hill Dec. 22, 1959 2,957,804 Shuyler Oct. 25, 1960 3,102,845 Fennell Sept. 3, 1963 OTHER REFERENCES Chapman et al.: Physiological Availability of Drugs in Tablets, Canad. Med. Assn. 1., vol. 76, pp. 102-106, Jan'. 15,1957.
Dragstedt: Oral Medication With Preparations for Prolonged Action, J.A.M.A., vol. 168, No. 12. pp. 1652- 1655,Nov. 22, 1958.
Lazarus et al.: Oral Prolonged Action Medicaments: Their Pharmaceutical Control and Therapeutic Aspects, J. Pharm. and Pharmacol'., vol. 11, No. 5, pp. 257-290 (pp. 266-271, 277-279, and 285-288 are especially pertinent to in vivi tablet availability of drugs), May 1959.
Campbell et al.: Oral Prolonged Action Medication, Practitioner, vol. 183, pp. 758-765, December 1959. I