MXPA04008536A - Controlled release dosage forms. - Google Patents

Abstract

A zero-order release pharmaceutical dosage form for oral administration to a patient comprising a core tablet sheathed in an annular body of compressed powder or granular material is provided. A preferred embodiment of the zero-order release pharmaceutical dosage form is a solid pharmaceutical dosage form which reduces contact of the active ingredient in solid form with the mucosa lining the gastrointestinal tract, which is particularly advantageous for delivering an ulcerative drug. A process for making the zero-order release pharmaceutical dosage form are also provided.

Description

METHOD OF DOSING CONTROLLED RELEASE FIELD OF THE INVENTION The present invention relates to oral pharmaceutical dosage forms and more particularly to controlled release forms and forms designed to mask the taste of the active ingredient BACKGROUND OF THE INVENTION Making the supply of a drug according to the needs of the therapy is an objective at present in the development of the drug delivery system. It may be desired that the delivery profile be one of immediate release within the oral cavity (known as "immediate dissolution" or "rapid dissolution" systems), immediate release in the stomach or intestine, controlled slow release of the drug in the gastrointestinal tract (GI), concomitant release of more than one drug in the same or different proportion and many combinations of the previous systems. There are systems that exist to provide drug delivery profiles that approximate the above requirements, but in each category there is room for improvement.

Immediate dissolution systems have been developed for the immediate delivery of drugs into the oral cavity by RP Scherer Corporation in the form of a lyophilized tablet that dissolves easily in the tongue, called Zydis® and by Cima labs, Inc. in the form of OraSolv® system. These systems dissolve rapidly in the mouth and are useful for cases where drug delivery is needed immediately and in cases where the patient has difficulty swallowing the tablets. These systems have the drawback of being relatively fragile and very sensitive to humidity. As a result, there are difficulties in manipulating the humidity of the fingers that damage the integrity of the delivery system ("it melts in the hands and not in the mouth" to paraphrase old advertising).

In the world of controlled-release delivery systems there have been certain axioms on which a large portion of development has been based. One of these axioms is that 'the flatter is better, that is, the flatter the delivery curve is as opposed to time, the better the system will behave. Accordingly, it is considered desirable to have supply systems that essentially provide a zero order release profile. The amount of drug released does not depend on the amount left in the delivery system and remains constant during the entire supply profile. Making the supply of the drug according to the needs of the therapy is another of the axioms of supply improvement. One can imagine that the therapies that need a sudden increase of drug after several hours of constant supply or a change in the proportion of the drug supply after several hours.

A size-increasing hydrogel tablet delivery system or an erosion tablet delivery system provides a drug supply that is reduced over time. In the erosion system, the surface that provides the drug supply decreases over time so the proportion drops proportionally. If the drug is delivered by diffusion through a non-eroding hydrogel, the proportion drops as the reduction in the drug changes the strength of the chemical gradient. These systems do not offer the opportunity to carefully tailor the release rates of the drug.

The zero-order supply with the osmotic pumps "Oros" has been achieved as documented in several patents belonging to Alza as any (for example, US Pat. No. 3,995,631 to Higuchi, T. et. Al., US Patent No. 3,977,404 to Theeuwes, F. and many other patents). The "Oros" system is based on the osmotic pressure expelled by the drug through an almost microscopic orifice. The zero order profile it is achieved due to the small and constant cross-section of the orifice which is the determining step of the release rate of the drug. The "Oros" system has been tested on several products but has its limitations. It is very useful for soluble drugs with insoluble drugs that have limited applicability. Manufacturing technology is somewhat complicated with the need for a laser-drilled hole in the semi-permeable coverage. The release of the drug through an almost microscopic hole can also have many obstacles. Obstruction of the hole can limit the release of the drug and fluid from the concentrated solution of drug from the delivery system to the intestinal lumen can damage the intestinal wall (see Laidler, P.; Maslin, S. C .; and Gihome, R. W. Pathol Res Pract 1985 180 (1) 74-76). The delay in the onset of drug release can be achieved through system coverage (as with enteric coverage) but the small orifice can be obstructed by coverage and provide erratic results in the opening (if it occurs). The "Oros" system is more appropriate for a simple zero-order supply profile. Complicated designs can be achieved with the "Pentacles" as described in U.S. Patent 5,156,850 to Wong, P. S. et. to the. and in PCT WO 9823263 to Hamel, L. G. et. to the. with concomitant complication of the manufacture and the system, and without solving the obstacles of the almost microscopic hole.

The profiles of order zero supply have been achieved with the brilliant manipulation of the geometric surface of the drug supply according to the realization of the "Geomatrix" supply systems. (U.S. Patent 4,839,177 to Colombo, P. et., And 5,422,123 to Conté, U. et al., And assigned to Jagotech AG and many other patents). These systems achieve a zero-order profile by placing the drug delivery layer between two layers that are impermeable. Only the drug delivery layer is eroded and the cross section of the erosion layer is constant. Again, in this situation, there are several obstacles. The manufacture of the system requires special equipment to produce tablets of two and three layers. The system does not lend itself easily to the change in the proportion of supply during the release profile. The amount of drug available in the tablet is somewhat limited since only one of the layers is used for drug delivery. The zero-order profile can not be followed up to 100% of the release of the drug because the tablet is broken once most of the core layer has been eroded.

In view of the foregoing, it would be desirable to have a solid and versatile dosage form that allows controlled release of an active ingredient that approaches zero order release. Accordingly, an object of the present invention is to provide a solid dosage form that can release a drug according to a predetermined release profile.

EXTRACT OF THE INVENTION The present invention provides controlled release dosage forms in which a core tablet is coated is coated in an annular body of compressed powder or granular material.

The drug layer can be embedded in the opening of the annular body on one or both sides. The layer of the drug is embedded from the surface in such a way that any contact, either with the hands or with the mucosa, will be with the walls of the annular body. The ring body is preferably made of non-ulcerative and non-sensitive pharmaceutical ingredients such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, starch, lactose, sugars, polyvinyl pyrrolidone, calcium phosphate and any other customary tablet excipient.

The controlled release dosage forms of the invention release the active ingredient from the core tablet into the environment of the dosage form in a proportion ranging from 3% per hour to 12% per hour.

The present invention further provides a pharmaceutical dosage form in which the pharmaceutical dosage form is adapted for release of the prolonged active drug material or zero deorion.

The present invention further provides a pharmaceutical dosage form in which the pharmaceutical dosage form is adapted for immediate release of the active drug material.

The present invention further provides a pharmaceutical dosage form in which the pharmaceutical dosage form is adapted for sublingual administration.

The present invention further provides a pharmaceutical dosage form in which the pharmaceutical dosage form is adapted in such a manner as to mask the taste. of the active material.

The present invention further provides a method for independently controlling the rate of release of coactive ingredients in a single dosage form.

The present invention further provides a pharmaceutical dosage form for the co-administration of coactive ingredients in a simple dosage form.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows the perspective, side and top views of a solid dosage form with a core active ingredient tablet embedded in an annular body of compressed powder or granular material according to the invention.

FIG. 2 is a perspective view of a press for single station tablets with the tool set installed.

FIG. 3 is a side sectional view of the column drill and the mounting of the drill.

FIGS. 4a-4e are the views in side section that describe the steps in a cycle of operation of the supply of powder or granular material for the ejection of a finished tablet in the tablet station equipped with a set of tools according to the invention.

FIG. 5 is a line of the average ratio of alendronate excression in the urine of humans who have taken a dosage form according to the present invention containing 70 mg monosodium alendronate and a 70 mg alendronate monosodium dosage form of the previous art FIG. 6 is a line of the oxybutynin release rate of a dosage form according to the invention, in which the release rate is maintained between 3% h-1 and 12% h-1 for seven hours or more.

FIG. 7 is a line of the "oxybutynin release" proportion of a dosage form according to the invention The proportion of hydrogel in the core tablet is increased relative to the dosage form produced in FIG. 6 which results in a decreased maximum release rate and a prolonged release between 3% and 12% per hour over twelve hours.

FIG. 8 is a line of the oxybutynin release rate of a dosage form according to the invention. The proportion of inhibition hydrogel of release in the annular body was increased in relation to the dosage form produced in FIG. 7. The maximum release rate was also reduced to less than 7% h-1.

FIG. 9 is a line of the carbidopa release ratio of the core tablet and levodopa of the annular body of a dosage form according to the present invention. The core tablet has a cylindrical and annular shape having a 2.5 irati diameter hole therethrough.

FIG. 10 is a line of the carbidopa release rate of the core tablet and levodopa of the annular body of a dosage form according to the present invention. The core tablet of this dosage form has a 4.6 mm hole, larger than in the dosage form that FIG. 9, which results in a larger surface area and a faster rate of carbidopa release.

FIG. 11 is a line of the carbidopa release ratio of the core tablet and levodopa of the annular body of a dosage form according to the present invention. The dosage form that this figure produces had an oval core tablet with a 3 mm hole therethrough which resulted in a release similar to that of the 2.5 mm bore cylindrical core tablet (FIG 9).

DESCRIPTION OF PREFERRED EMBODIMENTS The present invention provides a novel solid dosage form, as well as tools and processes to produce the novel dosage form. Preferred embodiments of the invention are suitable for the controlled release of drugs, especially prolonged release that approaches zero order and to mask the taste of drugs that taste unpleasant.

The novel dosage form comprises a core tablet containing an active pharmaceutical ingredient covered with an annular body (also referred to herein as a coverage) comprising the compressed powder or the granular material. The core tablet has a first and a second opposing surface and a circumferential surface. "Covered" means that the annular body surrounds the core tablet and is in contact with the core tablet around the circumferential surface, but leaves the opposing surfaces of the core tablet substantially exposed. The core tablet contains at least one active pharmaceutical ingredient, apart from that its formulation is not fundamental for the invention. The core tablet can be formulated for any desirable release profile, such as immediate release, delayed release, sudden or rhythmic release, sustained release or zero order. The annular body can be formulated to achieve any desired effect, such as gastric retention, ease of swallowing, water taste and control of the release rate of the core tablet drug. The ring body may also contain or be covered with a co-active ingredient.

The terms "drug" and "active pharmaceutical ingredients" generally include any biologically, physiologically or pharmacologically active agent. The active pharmaceutical ingredients that can be administered in the compressed dosage form of the present invention include agonists and adrenergic receptor antagonists; muscarinic receptor agonists and antagonists; anticholinesterase agents; blocking neuromuscular agents; blocking ganglionic agents and stimulants; sympathomimetic drugs; serotonin receptor agonists and antagonists; active drugs of the central nervous system such as psychotropic drugs, antipsychotic drugs, antianxiety drugs, antidepressants, antimalarial drugs, anesthetics, hypnotics, sedatives, hallucinogenic drugs and anti-hucinogenic drugs; antiepileptic drugs; antimigraine drugs; drugs for the treatment of Parkinson's, Alzheimer's and Huntington's disease; analgesics; antitussive agents; antihistamine drugs; receptor antagonists ??, ¾, and ¾; antagonists of bradykinin receptors; antipyretic agents; anti-inflammatory agents; NSAIDS; diuretics; synport inhibitors of Na + -Cl ~; vasopressin receptor agonists and antagonists; ACE inhibitors; angiotensin II receptor antagonists; derenin inhibitors; calcium channel blockers; ß-adrenergic receptor antagonists; antiplatelet agents; anti-rhombic agents; antihypertensive agents; vasodilators; phosphodiesterase inhibitors; antiaritlúnicos drugs; HMG CoA reductase inhibitors; inhibitors of H +, K + -ATPase; analogs of prostaglandins and prostaglandin; laxatives; antidiarrheal agents; antiemetic agents; prokinetic agents; antiparasitic agents such as antimalarial agents, antibacterial agents, drugs for the treatment of protozoal infections and anthelminthic drugs; antimicrobial drugs such as sulfonamides, quinolones, ß-lactam antibiotics, aminoglycosides, tetracyclines, chloramphenicol and erythromycin; drugs for the treatment of tuberculosis, drugs for the treatment of leprosy; antifungal agents; antiviral agents; antineoplastic agents; immunomodulators; hematopoietic agents; growth factor; vitamins; minerals; anticoagulants; hormones and hormone antagonists such as antithyroid drugs, estrogens, progestins, androgens, adrenocortical spheroids and inhibitors of adrenocortical spheroids; insulin; hypoglycemic agents; calcium resorption inhibitors; glucocorticoids; retinoids and heavy metal antagonists.

The ring body can be formed of any pharmaceutically acceptable powder or granular excipient and can include a pharmaceutically active ingredient. In particular, it can be mentioned that diluents, binders, disintegrants, glidants, lubricants, flavors, colorants and the like can be included in the ring body. Powder and granulation with conventional excipients and techniques for forming compressed bodies thereof with defined characteristics in terms of friability, hardness and freedom to cover is well known to those skilled in the art of tablets.

Preferred excipients for forming the ring body include hydroxypropyl cellulose (e.g., Klucel ™), hydroxypropyl methylcellulose (e.g. Methocel ™), microcrystalline cellulose (e.g., Avicel ™), starch, lactose, sugars, polyvinylpyrrolidone (e.g., Kollidon) ™, Plasdone ™) and calcium phosphate.

In a particularly preferred compressed dosage form illustrated in FIG. 1, the core tablet 1 containing the active pharmaceutical ingredient is embedded in the ring body 2, which is composed of non-ulcerative pharmaceutical excipients. The "embedded" tablet is especially suitable for the oral delivery of ulcerative drugs. Reduce the incidence of the esophagitis of the pill and contact gastritis locating the ulcerative drug in a core tablet that is protected from contact with the mucosa that lines the gastrointestinal tract. The drug is protected because the core tablet is embedded. Embedding the core tablet does not significantly alter the release profile of the core tablet because a substantial portion of the surface of the core tablet is in fluid communication with the environment. Unlike coated or encapsulated dosage forms, the coverage or capsule must be broken through the gastric fluid before the drug is released. In the present inventionThe outer contour of the dosage form protects the mucosa that lines the gastrointestinal tract without interrupting the fluid communication between the core tablet and the environment.

By way of example, drugs that can be delivered with advantages using the preferred embedded dosage form of this invention are monosodium alendronate monohydrate, monosodium alendronate trihydrate, sodium etidronate, risedronate sodium, pamidronate, aspirin, ibuprofen, naproxen, fenoprofen, ketoprofen, oxaprozin, flubiprofen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, diclofenac, piroxicam, meloxicam, tenoxicam, phenylbutazone, oxy phenylbuzone, oxybutynin, alendronate, carbidopa, levodopa, tizanidine, sumatriptan, pharmaceutically acceptable salts, hydrates, isomers, esters and ethers thereof and mixtures thereof.

Any suitable form can be given to the core tablet and the annular body. The specific shapes can be achieved using specifically designed drills. Preferably, the core tablet and the annular body are cylindrical in shape. The core tablet and the ring body may have the same or different shape. The exposed surfaces of the core tablet may have any suitable shape. Preferably, the exposed surfaces of the core tablet are circular or oval.

Returning to FIG. 1, the core tablet 1 has the first and second opposing surfaces 3 and 4 and a circumferential outer surface extending between the opposing surfaces. The core tablet 1 is preferably cylindrical or disk-shaped to facilitate manufacture, but is not necessarily in that form. In a dosage form for administration to humans, the maximum distance between any of the opposing surfaces 3 or 4 is preferably from about 2 mm to 12 mu, more preferably from about 4 mm to 7 mm, even more preferably about 5 mm . The opposing surfaces 3 and 4 can be flat, concave or convex and are preferably flat to support the moderate axial compressive forces exerted by the flat pressing surfaces during the formation of the annular body around the core tablet.

In the outer contour, the annular body 2 is preferably cylindrical in shape, but may have any cut, such as oval, elliptical or oblong. The outer diameter is preferably from about 5 mm to 15 mm, more preferably from about 7 mm to 12 mm, even more preferably about 9 mm. The inner diameter can have any measurement up to 2 mm less than the outer diameter. A thin inner diameter of less than 2 mm can decrease the release of the drug if an excipient in the annular body swells upon contact with the gastric fluid. However, in some embodiments, a lower limit of 0.5 mm may also be useful. Preferably, the inner diameter is 3 mm or greater.

The annular body 2 has a first and second opposite annular face 6 and 7, a circumferential outer surface 8 extending between the annular faces from the outer edges and an inner circumferential surface 9 extending between the annular surfaces from the inner edges, defining a crown in this way.

As best seen in the side view (FIG. IB), the inner circumferential surface 9 of annular body 2 consists of three longitudinal (axial) segments. The first and second segments 10 and 11 are terminal and are not in contact with the sides of the core tablet. They are separated by a third internal segment 12 which is in contact with the outer circumferential surface of the core tablet 1. Therefore, the opposing surfaces 3 and 4 of the core tablet are embedded between the annular faces 6 and 7 of the annular body. The opposing surfaces 3 and 4 are preferably embedded from about 0.5 mm to 4 mm, more preferably about 1.5 mm relative to the annular faces 6 and 7 of the annular body (said embedded distance corresponds to the corresponding terminal segment length). ). The depth of the incrustation of surfaces 3 and 4 may be the same or may be different.

Through the embedding of the drug containing the core tablet, any contact between the dosage form and the gastrointestinal mucosa occurs with an annular body surface formed of non-ulcerative excipients, and optionally one or more co-active non-ulcerative ingredients, in Instead of ulcerative solid active ingredients. However, one or both of the opposing surfaces 3 and 4 can be aligned with the annular faces 6 and 7 of the annular body without deleterious effects when the dosage form of the present invention is used to administer non-ulcerative drugs.

In order to better perceive the embodiment of the preferred embedded dosage form of the invention, it is useful to conceive the surface 3 of the core tablet and the first longitudinal segment 10 as defining a first vacuum 13. In the same manner, the surface 4 of the core tablet and the second longitudinal segment 11 define a second vacuum 14. The voids 13 and 14 are filled with gastric fluid when the dosage form is immersed in gastric fluid after reaching the stomach. The gastric fluid passes through the voids to contact the core tablet and the drug exits through the voids after it dissolves. The voids 13 and 14 are preferably from about 0.5 mm to 10 mm, more preferably from about 3 mm to 6 mm and even more preferably from about 4.5 mm in width (measured in parallel to the first and second opposite surfaces) . Therefore, the release of the drug does not occur by an osmotic mechanism as occurs with the perforated dosage forms made using the apparatus of U.S. Patent No. 5,071,607. Instead, in an even greater fluid environment, the drug concentration isotropically abruptly and exponentially reduced by diffusion. Unlike the osmotic release of the drug product that would produce a flowing stream and can cause high concentrations of drug and osmotic agents at a considerable distance from the tablet. Osmotic currents highly concentrated in an ulcerative drug are potentially irritating to the mucosa, such as the solid drug, particularly if the tablet is housed in a fold of the gastrointestinal wall.

The opposing surfaces 3 and 4 of the core tablet are preferably substantially exposed, ie they are not substantially covered by the annular body. "Substantially exposed" means that less than about 50% of each of the opposing surfaces is concealed or hidden from visual inspection by the annular body. A portion of the opposing surfaces 3 and 4 can be concealed by the annular body due to the differences between the diameter and shape of the core tablet and the diameter and shape of certain pressure portions of the tools used to compress the annular body , as will be evident after analyzing the description of the appearance of the tools of the invention. Said differences may result in the inner segment 12 compensating the terminal segments 10 and 11, which themselves may have different longitudinal cuts, for example they have different diameters, as described in FIG 1. Another possibility is that the cutting of the crown defined by the inner circumferential surface 9 may be uniform along the entire length. Even though a portion of the opposing surfaces 3 and 4 can be hidden by the annular body that is not necessarily the case.

In addition, the invention contemplates that the release rate of the drug is determined by the formulation and shape of the core tablet, not by diffusion of the drug through the annular body which contributes to the versatility of the dosage form for the different release profiles. .

In one embodiment, the pharmaceutical dosage form is a prolonged release dosage form. The active drug material is delivered through the exposed axial surfaces of the core tablet. The exposed axial surfaces retain a constant cut during the delivery of the active material, and thus produce a zero order release profile. For extended release applications, the core tablet can be formulated to have an erosive or diffuse nature.

A prolonged release core tablet preferably contains a hydrogel such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose and the like.

Optionally, the core tablet also contains a substance that dissolves more rapidly as compressible sucrose to open the pores in the hydrogel matrix and thereby modulate the hold of the hydrogel in the active ingredient. In a sustained-release zero-order dosage form in which the active ingredient is contained in the core tablet, the ring body will be formulated to be dissolving even more slowly than the core tablet such that the surface area of the core tablet The core tablet will remain constant. Mixtures of approximately 1 part of high molecular weight polyethylene glycol (PEG) and 3-5 parts of ethyl cellulose will maintain their shape and stiffness in the water for the time leading to more conventional erosion or swelling of hydrogel matrices. Release the drug completely. An especially preferred composition of the annular body of a sustained release dosage form according to this invention comprises about 15-25 parts of PEG 4000, about 70-80 parts of ethylcellulose and about 5 parts of polyvinylpyrrolidone. The release rate of the active material from the core tablet of sustained release dosage forms is less than about 15% by weight per hour. Preferably the release rate is from about 3% per hour to 12% by weight per hour. The sustained release dosage forms are adapted for release of active material or a period of at least about 4 hours, more preferably at least 7 hours, and even more preferably at least about 10 hours. The release rate of the active ingredient is measured in a United States Pharmacopeia standard apparatus II assay instrument in an aqueous solution with a barrier of 6.8 at 37 ° C with a stirring ratio of 50 revolutions per minute.

The dosage forms according to this invention are also adaptable for immediate release and have unique advantages when used for immediate release. The annular body or protective layer provides protection for the immediate release core tablet while being handled by the patient or the person providing care. The core drug layer is embedded from the surface such that any contact occurs with the walls of the annular body. While the core tablet may be fragile, the hands of people would only come into contact with the non-fragile ring body. The core tablet can be formulated to be of a "rapid dissolution" nature without the usual hurdles of "fast dissolution" systems. The drug can be released through the solution into the saliva as the "rapid dissolution" form is maintained in the mouth for a few minutes. The outer annular body can be formulated to dissolve also but to a lesser extent so that it is not so sensitive to moisture or can be swallowed (by people who can swallow a tablet) or expectorated. The release of the released drug is preferably carried out in less than about 5 minutes, more preferably in less than about 2 minutes. The dissolution rate of the active ingredient is measured in a unit of solution at 37 ° C of the apparatus III standard of United States Pharmacopeia or in a unit of dissolution at 37 ° C of the apparatus II standard of United States Pharmacopeia with agitation at 50 revolutions per minute. The dosage form can be formulated in such a way that it is suitable for rapid dissolution in the oral cavity without co-administration of liquid.

As a result of the protection achieved by the ring body, many ingredients Active ingredients can be used in greater proportion in the formulation of the core tablet than those used in conventional tablets. In this way a core tablet can contain a very high concentration of the active drug material without thereby producing a dosage form that is too delicate to handle. An immediate release core tablet preferably contains a superdisintegrant. Other preferred excipients for an immediate release formulation include sodium saccharin, microcrystalline cellulose, lactose and menthol.

An immediate release core tablet formulation which can be found to be well condensed in the tools of the invention contains 5 parts of active ingredient, 20 parts of crospovidone, 74 parts of MicrocelLac®, 1 part of lubricant and 0.4 part of menthol.

When the core tablet is formulated for immediate release, the ring body can be formulated differently than the ring body of an extended release formulation because it does not need to remain rigid for so long. However, the annular body will generally be formulated to dissolve slower than the core tablet. As illustrated in more detail in Example 3, an annular body can be made through the modification of the immediate release core formulation by reducing the superdisintegrating ratio, and optionally by replacing an excipient. that dissolves, but does not swell, like compressible sugar.

The immediate release dosage forms according to the invention are useful for administering active pharmaceutical ingredients which have unpleasant taste, such as sumatriptan succinate. One method for achieving taste concealment involves embedding the surface of the core tablet within the annular body, thereby avoiding contact between the tongue and the core tablet. The immediate release dosage forms according to the invention are also useful for sublingual and buccal administration of drugs. It is generally desirable that a sublingually administered drug be released from the dosage form as quickly as possible. Oral administration can also be through the immediate release dosage forms. To achieve rapid release, said dosage forms may be of a formulation with a high proportion of active ingredient. However, a high proportion of active ingredient will in many cases make the tablet fragile. As discussed previously in another context, the annular body protects fragile core tablets in the dosage forms of this invention, making them so that they are well adapted to sublingual and buccal administration of drugs. Preferred drugs for sublingual and buccal administration in the dosage forms of the present invention are tizanidine, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, vaccines, ergotamine and other anti-migraine compounds, lorazepam and other tranquilizers, vitamin B12 and acid folic acid and mixtures thereof. A dosage form of tizanidine is illustrated in more detail in Example 3.

The release rate of the active material of the immediate or sublingual core tablet dosage forms is well less than about 90% in 30 minutes. Preferably the release rate is greater than about 85% in 15 minutes. The release rate of active ingredient is measured in a standard apparatus III dissolution unit of United States Pharmacopeia at 37 ° C or a standard apparatus II dissolution unit of United States Pharmacopeia at 37 ° C with an agitation of 50 revolutions per minute.

The core tablet can also be a two-layer tablet in which each layer contains the same or different drugs and each layer releases the drug in the same or different proportions. One of the layers could be an immediate release layer and the other slow release layer, or both layers can be slow release. The inner tablet can be formulated to be a three layer tablet with the core layer which is a drug to be delivered after a delay. The two outer layers can be delay layers or drug delivery layers with the same or different drugs and with the same or different release profiles. The middle layer may in turn contain the same or different drugs compared to the outer layers and may be of a controlled release or immediate release nature. In that way, one can have the controlled release of two drugs each in its desired release rate and a delayed or delayed pulse release of a third drug. In this way the disclosed invention provides a wide range of drug delivery capabilities not treated by conventional dosage forms and improves the performance of other known delivery systems.

The dosage forms according to the invention can also be formulated to deliver two drugs by placing one of the drugs in the core tablet and the other in the ring body. Said organization allows the release rate of each active ingredient to be controlled independently through the formulation adjustments to the portion of the dosage form, i.e. the core tablet or annular ring, which contains the drug being released either very slowly or very quickly. In addition, the shape of one of the portions can be changed without adjusting the formulation. For example, the powder or granular material can be pressed around the core tablet in a body having an oval cut instead of a circular cut to achieve a faster release rate (resulting from the increased surface area). In addition, the core tablet may have a hole extending from one axial face to the other to increase the surface and thereby increase the release rate. In addition, the release rate can be controlled through changes in the diameter of the hole, as illustrated in more detail in Example 4.

Preferred combinations of drugs for use with the invention include levodopa / carbidopa, acetaminophen / caffeine, acetaminophen / codeine, acetaminophen / antihistamines, vitamin and mineral combinations, and combinations of antibiotics. The combination of levodopa / carbidopa is especially preferred. In Example 5, the especially preferred dosage forms of levodopa / carbidopa are illustrated in which levodopa is dispersed in a hydrogel matrix in the annular body and the carbidopa is directly compressed with a mixture of direct compression excipients and a superdisintegrant in the core tablet.

The release rate of levodopa material from the core tablet of a levodopa / carbidopa combination drug dosage forms is less than about 35% by weight per hour. Preferably the release rate is from about 3% per hour to 30% by weight per hour, more preferably from about 6% per hour to 30% per hour. The levodopa / carbidopa combination dosage forms are adapted from the release of active material for a period of at least about 2 hours, more preferably at least about 3 hours. The release rate of active ingredients is measured in a standard United States Pharmacopeia II apparatus II assay test instrument in 0.1 N HC1 at 37 ° C with a stirring ratio of 50 revolutions per minute.

Solid dosage forms with a drug containing a core tablet protected in a compressed annular body of non-ulcerative excipients can be produced using a novel tool set which constitutes a second aspect of the invention.

The tool set can be used in conjunction with conventional tablet presses such as rotary and reciprocating presses or presses that have been specially designed and manufactured. Examples of commercially available presses are the Manesty Express 25, the Kilian RUD or the RTS series and similar equipment. Examples of commercially available reciprocating presses are Manesty F3 and similar equipment manufactured by Stokes, Kilian and Key Industries.

The main elements of the tool assembly are a column drill and a drill assembly comprising an annular drilling machine having a crown (or gauge), a sliding core rod that engages within the crown of the annular drilling machine, in the Since the core rod is capable of moving between a retracted position and an extended position, the core rod is biased in the extended position. The column drill and the drill assembly are measured and shaped to fit the mold gauge of a rotating or reciprocating tablet machine.

The tool set is well suited for use with conventional single-station tablet presses in which the upper and lower opposing perforaters cooperatively comprise a powder or granular material within the mold. With reference to FIG. 2, simple station presses are provided with a horizontal mold table 15 having an opening for receiving a mold 16 and the associated grasping means for immobilizing the mold in position. The molds for said presses usually have opposite flat surfaces with a centrally located gauge 17 having a highly polished wall surface extending from surface to surface and a circumferential sealing groove 18 for engaging the grasping means. The gauge serves as a receptacle to receive dust or granular material that is compressed when the lower perforation is partially inserted. The edges of the gauge are usually ribbed to help guide the drills in the gauge. The cut of the gauge determines the size and shape of the finished tablets in the cut. The amount of material and the compression pressure determine the height of the tablet. The caliber can be cylindrical, but it can also have any other shape.

In operation, the gauge is filled with material and the upper drill is inserted into the gauge and pressed against the high pressure material, thereby compressing the powder or granulated material into a tablet between the pressure, or contact, of the surfaces of the drills.

Together, the gauge wall and the contact surfaces of the upper and lower drills define a mold that determines the contour of the size and surface of the final product. The final product may have any external contour by selection of the appropriate gauge shape and contour of the contact face.

After compression, the upper drill is removed and the lower drill is advanced to eject the tablet.

The upper and lower drills are advanced and removed by reciprocating upper and lower rams independently operated 19 and 20. Usually simple drilling presses are also provided with a stationary mounting point 21 below the mold table coaxial with the opening.

A set of tools of this invention adapted for use in a single station press comprises a column drill and the drill assembly comprising a clamp, core rod and annular drill.

Now with reference to FIG. 3, the column drill 22 can be of a conventional column shape and is provided with closure means, such as closing faces 23 for securing it to the upper reciprocating ram 19 of the tablet press.

The column drill 22 includes a contact face 24. the contact face 24 can have any desired contour, for example standard concave, deep concave, extra deep concave, modified or flat ball. Preferably, the contour of the contact face 24 is flat with beveled edges.

A column drill for use in the production of a dosage form of the present invention having an embedded core also has a protrusion 25 located centrally on the contact face 24, as illustrated. Preferably, the height of the protrusion 25 is from about 0.5 mm to 4 mm, more preferably about 1.5 mm. The shape of the protuberance in preferably cylindrical or cylindrical narrow but can also be oval, ellipsoidal, oblong or any other desired shape. The protrusion is preferably cylindrical and has a flat elevated surface 26. the protrusion 25 preferably has a diameter of about 3 mm to 7 mm, more preferably about 4.5 mm. In other embodiments, particularly suitable for use when non-ulcerative active pharmaceutical ingredients will be administered, this protrusion is absent.

The mounting of the punch 27 comprises the clamp 28, core rod 29 slidably engaged with the clamp 28 and annular punch 30 slidably engageable with the core rod 29.

Clamp 28 provides mounting means, such as external filaments 31 around its circumference for mounting at a stationary mounting point 21 located under the mold table. As illustrated at the distal end 32 of the bracket 28 relative to the mold table when installed, it has a grasping section (shown with the optional hex cut) for gripping with a wrench to mount at the mounting point stationary 21. At the proximal end 33 of the bracket 28 relative to the mold table when installed, the crown is dimensioned to receive and guide the core rod 29.

Away from the proximal end of the clamp, the diameter of the crown is substantially greater than that of the core rod to provide a housing 34 for a biasing means such as a spring 35. The spirals of the spring 35 surround the core rod. Although a spiral spring 35 is a preferred biasing means, polarization can be achieved by other means, such as a stack of Belleville washers or an elastic setting.

The spring 35 or other biasing means engage the retaining ring 36 coupled to the core rod 29. The retaining ring 36 can be coupled to the core rod through a clamping element with a circumferential groove 37 in the rod. The retaining ring can be a conventional clip C engaging the slot, or it can be a bracket or any other structure in which the biasing means can exert a biasing force and is contained in the movement relative to the core rod 29 in a direction parallel to the long axis of the core rod.

As illustrated, an annular clamping bolt 38 engages the internal filaments 39 at the distal end of the clamp 32. The caliper 40 through the clamping bolt 38 has the dimension to receive and, together with the crown in the proximal portion of the clamp. the clamp, retain the movement of the core rod 29 to axial movement. The clamping bolt 38 also retains and can compress the biasing means. The core rod 29 is biased in the direction of the mold table when the clamp is installed at a stationary mounting point 21 and is retained in a sliding gear with the clamp 28 by the retaining ring 36 and the clamping bolt 38. The tip height of the rod 41 is adjusted to advance or retract the clamp 28 relative to the stationary mounting point 21, for example by rotating the clamp engaged with the filaments with the stationary mounting point.

The core rod 29 can vary in diameter over its entire length. A preferred diameter of the tip of the rod 41 is about 0.5 mm to 10 m, more preferably about 4.5 mm. However, because of the stiffness, the core rod should be thicker, preferably from about 4 mm to 12 mm along its entire length, more preferably about 9 m. The rod may gradually narrow from a narrow diameter at the tip to a larger rod diameter or may change abruptly in a shoulder 42.

The core rod can be a two piece construction. For example, the tip of the core rod 41 could be adapted to be attached to the core rod through the provision of external filaments at its lower end and a plug with internal filaments at the upper end of the core rod, or vice versa. A two-piece construction allows the tip of the core rod to be replaced if a core rod tip is damaged or desired in a different way. The tip of the tip core rod can have any desired diameter or shape.

The mounting of the drill 27 further comprises an annular drill 30. The annular drill 30 is provided with the means for attaching to the reciprocating lower ram 20., as a flat closure face 43. The gauge 44 through the annular perforator 30 is dimensioned to receive and surround the core rod 29 while allowing the axial movement of the annular perforator 30 independently of the core rod. The caliper through annular perforator 30 can vary in diameter along the length of the perforator providing an annular flange 45 for meshing with the shoulder 42 of the core rod. Engaging the flange 45 with the shoulder 42 prevents the annular piercer 30 and bracket 28 from being contiguous with each other when handled and installed. The contact surface of the annular piercer 46 presses the powder or granular material during compression. The contact face 46 can have any desired contour, for example standard concave, deep concave, extra deep concave, modified or flat ball. Preferably, the contact face 46 is flat with a ribbed edge to facilitate ejection of the finished tablet.

The column driller, the annular driller, the core rod and the clamp are preferably made of metal, more preferably steel, even more preferably stainless steel.

In the final dosage form with the core tablet embedded, the depth of the first vacuum 13 (FIG.1) is determined by the height of the protrusion 25. The depth of the second vacuum 14 is determined by the depth of filling, the strength of the dollarization of the core rod, the compressibility of the material and the thickness of the core tablet. These parameters can be adjusted by routine tests to control the depth of the second vacuum 14, which is appropriately according to the depth of the first vacuum 13.

In a second embodiment of dosage form, either or both of the opposing surfaces 3 and 4 of the core tablet are in the same plane as the annular faces 6 and 7 of the annular body 2. This alternative embodiment can be produced using a core hole punch. column as previously described but does not have a protrusion 25. The surface 3 is generally placed at the same level as the annular face 6 if the column punch has a flat contact face. If the opposite surfaces 4 are placed at the same level as the annular face 7 will depend on the filling depth, the compressibility of the powder or granular material and thickness of the core tablet, these factors can be adjusted by routine tests to produce a form of dosage with the surface 4 embedded at the desired distance in relation to the annular face 7.

To illustrate the invention and operation of the toolkit in more detail, an operation cycle will now be described. The operating cycle is an embodiment of a process that constitutes a third aspect of the invention.

The operating cycle is illustrated first in a simple station press. The cycle begins with the first action that occurs after the ejection of the tablet formed in the previous cycle. Now with reference to FIG. 4a, the feed shoe 47 moves laterally towards the mold gauge while the annular drill 30 is in a forward position so that the contact surface 46 is substantially flush with the top surface of the mold. By doing this, the feed shoe pulls a finished tablet over the annular piercer into a hopper leading to a receptacle where the tablets are removed. The annular perforator 30 is retracted while the tip 41 of the core rod 29 is held at the same level as the surface of the mold (FIG 4b). The retraction of the annular perforator causes the formation of an annular cavity in which the particles of dust or granular material are fed from the supply shoe by gravity and / or differential pressure. Once the cavity is filled, the feed shoe changes direction with respect to the mold gauge.

The precompressed core tablet 1 is located above the core rod using any conventional apparatus for producing tablets with a compressed coverage like that of a Kilian RUD press (FIG 4c). The location means are not part of the invention and have been omitted for reasons of clarity.

The column drill 22 is advanced by the reciprocal top ram 19 (FIG 4d). As the column punch 22 approaches the gauge, the raised surface 26 of the protrusion 25 is pressed into the core tablet 1. As the column punch 22 enters the 17 gauge, the core tablet 1 is pushed towards the core. caliber by the protrusion against the dollarization force exerted on the core rod 29. The continuous movement of the column drill 22 in the mold gauge compresses the powder or granular material into an annular body around the core tablet. Intense compression forces can be exerted on the powder or granular material without breaking the core tablet because the core tablet is transported in the gauge before the powder or granular material is completely compressed.

Those skilled in the art can also appreciate that the protrusion 25 can be replaced with a core rod in the column drill that is biased to an extended position such that the tip of the rod would press the core tablet 1 during compression. Said core rod by the column drill is not necessarily attached to a stationary mounting point in the press. It could be polarized with greater force than the core rod 29 so that the pressure exerted by the column driller would push the core tablet in the gauge against the strength of the core rod.

After the powder or granular material is compressed, the column drill is removed. Either concurrently or subsequently, the annular piercer 30 is advanced by the lower reciprocating ram 20 to a position such that the contact face 46 is substantially at the same level as the upper surface of the mold to elevate the finished tablet above the mold. where it can be dragged from the mold table to the subsequent operating cycle (FIG 4e). Meanwhile, the core rod is biased back to its original position at the same level as the mold surface.

The tool set is well adapted for use in a rotary tablet press, the dimension and the cutting shape of the column drill, and the dimensions and shapes of the protrusion (if applicable) are the same as in a drilling machine adapted for use in a reciprocal tablet press. The other dimensions of the toolkit are generally dictated by the dimensions and scheme of a particular tablet press. These dimensions can be easily determined by those skilled in the art. The dimensions and cutting shapes of the annular perforator and the core rod are the same as in a drilling machine adapted for use in a reciprocating tablet press, again with other dimensions dictated by the dimensions and scheme of a tablet press particular. These dimensions can be easily determined by those skilled in the art. In addition, the drills include conventional bearing surfaces at the distal end toward the contact surfaces for engaging the cams and rollers that control their movement together with the mold gauge shaft, such as those shown in the patents that are incorporated for further reference. down.

In an annular punch for use in a rotating machine, the dollarization means of the core rod is preferably housed in the annular punch and includes a means for adjusting the extent of the core rod extension and / or polarization, such as a captive screw or a similar device.

Rotary presses of conventional tablets are known in the art. Some rotary presses and related improvements are described in U.S. Patent Nos. 5,462,427. 5,234,646. 5,256,046 and 5,635,223 which are incorporated herein by reference in their entirety. The rotary presses have a movable mold table that rotates around a vertical axis. Mounted above and below the mold table are the carriers of the upper and lower drill that rotate synchronously with the mold table. The carriers of the punch generally can be drum-shaped bodies of approximately the same diameter as the mold table or can have arms extending outwardly from a ring of smaller diameter. The carriers of the punch are provided with a plurality of vertical holes or grooves at regular intervals around their circumference or across the ends of the arms. When the press is in operation, the drills are inserted into each slot with the contact faces pointing towards the mold table. Each drill has a bearing means at the opposite end of the contact face. The bearing means engages the stationary cams and rollers that control the vertical movement of each punch during an operating cycle. The cams and rollers are arranged in such a way that in one operating cycle, a powder or granular material is fed into a mold while the lower perforator is introduced into the mold. Pressure is applied to the powder or granular material to produce a compressed body. After compression, one or more of the drills is removed from the mold and the dosage form is released. Rotary presses are especially suitable for high volume production because they typically contain numerous drills and sets of molds that operate simultaneously.

An operating cycle using the tool set of this invention adapted to use the rotating press will now be described. As the mold table rotates, one of the molds passes under a filling or force feeder shoe. While the mold goes underneath the shoe or feeder, the annular drill is removed by the cam. The core rod is maintained in an extended position, up to the face of the upper mold. The annular space left by the removal of the ring drill is filled with powder or granules. In the next station, a core tablet is inserted into the tip of the core rod by conventional means, such as those used in "press coverage" machines such as the Kilian RUD. The core tablet can be located above the core rod by any method. In additional turns, the mold reaches the compression station when the column drill with or without its protrusion moves downward and pushes the core tablet into the bed of powder or granular material. The strength of the column drill retracts the core rod against polarization and the powder or granular material is compressed in an annular form around the core tablet. In the product of the dosage form, an inlay is defined by the height of the protrusion and the other incrustation is defined by a combination of the factors such as the strength of the polarization, the depth of the filling, the compactness of the powder or granular material and the thickness of the core tablet. Then the powder is compressed, the mold also rotates to where the column drill is removed from the mold. Either concurrently or subsequently, the annular piercer rises to the face of the mold. The core rod rises concurrently towards the face of the mold due to polarization. The tablet is dragged from the mold by an ejection element and removed.

While reference has been made to the "upper" and "lower" elements in the description of the tool set and process for making the solid dosage form according to the invention, the spatial relationships of the elements are determined by the design and construction of the press in which they are used. The use of the terms "superior" and "inferior" are not to limit the invention to vertical arrangements of the elements.

After describing the present invention with reference to certain preferred embodiments, the invention will be illustrated in more detail by the following example.

EXAMPLES Example 1 Immediate release monosodium alendronate tablets This example summarizes a study designed to determine the proportion and level of absorption of alendronate sodium in humans subjected to the administration of a solid pharmaceutical dosage form of the present invention ("protected tablet").

Materials and Methods Protected tablets were made as follows.

Core tablet: 85.4 g of alendronate trihydrate (TEVA Assia Ltd.) and 2.6 g of xylitol (Danisco S eeteners OY) were granulated with 20 g of water in a Diosna granulator (model Pl / 6) for 3 min . The pellet was dried at 40 ° C for one hour in a fluidized bed dryer and ground through a 0.8-inch screen. The granulate was mixed with 11 g crospovidone NF (BASF Pharma) for five minutes. One gram of magnesium stearate NF / EP (Mallinkrodt Inc.) was added and then the granulate was mixed for an additional 0.5 minutes. The mixture was compressed using a simple Manesty F3 punching tablet machine embedded with a 5 mm flat beveled punch. The weight of the tablet was 94.9 mg ± 1.0% RSD. The hardness of the core tablets was 3-6 kP.

Protected tablets: a mixture of 94 grams of compressible sucrose (Nu-Tab ™, DMV International) and 5 grams of microcrystalline cellulose (Avicel ™ pH102, FMC International) were mixed for five minutes. One gram of magnesium stearate (NF / EP, Mallinkrodt Inc.) was added and the mixture was mixed for another half minute.

A Manesty f3 simple drilling tablet machine was possible with a polarized spring column drilling rig and the drilling rig assembly was constructed in accordance with the present invention. The core rod was designed for a 5 mm round core tablet and the mold and punches for the outer tablet were designed to produce a round, solid, bevelled and flat 9 mm diameter pharmaceutical dosage form. The upper drill had a protrusion of diameter 4.5 mm and 1.2 mm in height. The press of the tablet was operated and the protected tablets were produced. The weight of the tablet was 474 mg ± 0.62% RSD and the hardness of the protected tablets was 12-15 kP. The content of alendronate trihydrate, expressed as alendronic acid was 66.8 mg ± 1.38% RSD (82.4 mg alendronate trihydrate equivalent to 70 mg alendronic acid).

The inner tablet containing the drug was embedded from the surface of the annular body by approximately 1 mm.

Pharmacokinetic study A clinical trial involving twelve (12) human volunteers was conducted to demonstrate the pharmacokinetics of a solid dosage form of the present invention containing 70 mg alendronate. Its pharmacokinetics was compared with that of the 70 mg Fosalan ™ commercial tablet of the prior art (Merck, Sharpe &Dohme).

Method The study was a randomized, open label, 2-treatment, 2-period, 2-sequence, fasting trial design. Twelve (12) healthy adult male volunteers, aged 18 to 55 years old, underwent the study.

The study was divided into first and second periods of study, each of 36 hours duration, with a period of "washing" on day 14 between study periods. All subjects who completed the study periods were included in the analysis. Two groups were randomly assigned to the subjects. It was administered to an alendronate group through protected tablets in the first period and Fosalan was administered as control in the second period. The order of administration to the second group was reversed.

In both periods, alendronate was administered in a fasting state. A normal meal was provided 4 hours after administration. Refreshments were provided according to a standardized schedule that was the same for all subjects in both study periods. Water was provided ad libitum. In addition, subjects were encouraged to drink at least 200 ml of water at regular intervals during each study period.

The bioavailablity of alendronate was determined by measuring the cumulative levels of alendronate excreted in the urine over a period of 36 hours after oral ingestion of the test and control tablets (hereinafter referred to as "Ae0_36"). An initial urine sample (t = 0) was taken immediately after administration. Urine samples were taken at 11 regularly scheduled time points in a 36-hour trial period. All urine samples were analyzed for alendronate using a valid HPLC-FLR assay.

Results The main pharmacokinetic parameters obtained from the urinalysis samples were collected in Table 1.

Table 1: Pharmacokinetic parameters A comparison of the pharmacokinetic parameters of the dosage form according to this invention with the pharmacokinetic parameters of the dosage form of the prior art is provided in Table 2.

Table 2. Pharmacokinetic Comparison of the Protected Tablet with the Prior Art By reference to Tables 1 and 2, and FIG. 5, it can be seen that alendronate administered through the solid dosage form of the present invention provides essentially the same pharmacokinetic results as administration through Fosalan. The total amount of alendronate excreted in the urine in 36 hours is essentially the same for both treatments with the maximum excretion rates (parallel to Cmax in a pharmacokinetic study of plasma levels of the drug) also closed.

The excretion profile in the urine was similar for all subjects and both treatments. Most subjects had their maximum excretion ratio (Rmax) between one and two hours. For five of the subjects, the Rmax occurred within 1 hour after the administration when they took Fosalan. Four of the subjects suffered an Rmax in less than an hour when they took the protected tablet. One of the subjects had an Rmax in the third hour when he took Fosalan while two of the subjects had a Rraax in the third hour when they took the protected tablet.

The total amount of excreted alendronate ranging from 36, 9] ig to 158.6 pg when Fosalan was minimized and from 30, lpg to 284, 4 pg when the solid oral dosage form of the present invention was administered. In only two subjects there was a difference two times greater in the total excreted amount of alendronate between the two treatments. Another subject excreted a very low amount of alendronate regardless of how the alendronate was administered.

The bioavailability of alendronate administered through the novel solid dosage form of the present invention is equivalent to that of alendronate administered by dosage forms of the prior art. However, the dosage form of the prior art does not provide any protection against the contact of alendronate with the mucous membranes of the esophagus and the stomach while the novel bioequivalent dosage form of the present invention has such protection.

Drug release profile The solution was voided in a dissolution unit of apparatus III USP (Hanson B-3) at 37 ° C. The alendronate content of samples taken at 5, 10, 15 and 30 minutes was determined by HPLC on an anion column using the refractive index detection. The results of the dissolution are reported in Table 3.

Table 3 The outdoor coverage took more than an hour to dissolve.

Tablets were tested in a pharmacokinetic study of humans and proved to be bioequivalent to commercially available alendronate (70 mg).

Example 2 Oxybutynin Tablets (Zero Order Release) Extended Release Tablets The ring-covered tablet is only suitable for prolonged controlled release, particularly when it is necessary to approach the zero-order release over a prolonged period of time. The drug is delivered through the exposed axial faces of the delivery system. These faces retain a constant cut during drug delivery, and thereby assist in achieving a constant rate of drug release.

A. Interior tablet Oxybutynin (50 g) was mixed with anhydrous lactose (50 g) in a Zanchetta Rotolab ™ granulator. The granulation solution, 5% / w hydroxypropylcellulose (Klucel ™ LF, 21 ml), was added with stirring at 500 rpm until mixing was achieved. The granulate was dried from a granulator at 45-50 ° C with suppressing gas for a period of about 20 minutes. The granulate was milled on a Quadro ComilTM grinding machine using a screen size of 1143 μp ?.

The granulated oxybutynin (27.6 g) was mixed with hydroxypropylmethylcellulose, (HPMC, Methocel ™ K15M, 19 g), and compressible sucrose (Nu-Tab ™, 52.4 g). Magnesium stearate, 1 g, was added with the mixture. The mixture was compressed into the tablets in a simple Manesty f3 punching tablet machine using 6 mm flat beveled punches to produce tablets weighing approximately 110 mg and having a hardness of 4 Kp.

B. Exterior coverage that does not dissolve on cylindrical surfaces Polyethylene glycol (PEG 4000) was ground and passed through a 500 gm screen. The ground PEG 4000 (24 g) was mixed with polyvinyl pyrrolidone (Povidone ™, PVP K-30, g), and ethyl cellulose (Ethocel ™ 7 cps, 71 g), for 3 minutes. Magnesium stearate (1 g) was added and the mixture was mixed by others.,5 minutes. The inner cores, which were previously produced, were pressed into the outer shell using this mixture and a 9 mm core rod loaded with an outer cylinder spring equipped as described above. The diameter core rod was 4.5 mm. The upper drill had a 5 mm diameter protrusion that tapers to 4.5 mm on the upper surface with a height of 1.2 mm. The final product, a tablet with annular ring coverage with exposed incrusted axial faces, had an outside diameter of 9 mm, a total weight of 350 mg and containing 15 mg of oxybutynin (Formulation A).

C. Drug release profile The release profile of the oxybutynin drug from the delivery system of Example 1 was tested in a USP II apparatus dissolution test instrument using 900 ml of phosphate barrier pH = 6.8 at 37 ° C, 50 rpm. The oxybutynin content of the sample is determined by an HPLC method with UV detection. The results are reported in Table 4, below, and graphically represented in FIG. 6 Table 4 Time (h) Release of cumulative percentage 1 1,7 2 4,9 4 20, 0 6 41,8 8 58, 3 10 75, 1 14 79, 0 16 79, 1 18 79, 5 D. Release control for changes in the Formulation Tablet Interior The above procedure for the preparation of the inner tablet was repeated using 30 g of Methocel ™ K15M and 41.4 g of Nu-Tab ™, thereby increasing the gel forming the HPMC and decreasing the sucrose that dissolves (Formulation B) ). The results of the dissolution experiment are reported in Table 5, below, and are described in FIG. 7 Table 5 Time (h) Release of cumulative percentage 1 0.8 2 3.4 4 11.8 6 29, 1 8 47.5 10 59, 8 12 68, 8 14 76.2 16 79, 8 18 82.0 A significant decrease in drug release was observed in the first ten hours.

E. Release Control for Changes in the Formulation of Lime Coverage Foreign The procedure for the preparation of Formulation B was repeated, with the outer covering containing 14 g of PEG 4000 and 81 g of Ethocel ™ (Formulation C). The results of the dissolution experiment are shown in Table 6, below, and are described graphically in FIG. 8 Table 6 Time (h) Release of cumulative percentage 1 0, 6 2 1,2 4 7, 6 6 20, 5 8 30, 5 10 39, 6 12 46, 1 14 51.5 16 55, 5 18 58, 0 Again, significant changes were observed in the rate of drug release, which shows that changes in the formulation of the inner core tablet or the outer ring body can determine the release rate of active drug material.

Example 3 Fast-dissolving Tizanidine Tablets for Sublingual Delivery Sublingual tablets were formed in the inner core of a rapidly disintegrating formulation containing tizanidine (2 mg) and an outer annular ring of protective excipients.

A. Interior Tablet The inner nuclei were made by mixing tizanidine hydrochloride (4.5 parts) and crospovidone (20 parts), for 2 minutes. Sodium saccharin (0.5 parts), MicrocelLacl OOTM (73.6 parts), and menthol (0.4 parts) were added and the mixture was continued for 3 more minutes. Magnesium stearate (1 part) was added and continued mixing for half a minute. The mixture was compressed in a Manesty f3 tablet press equipped with a 5 mm flat beveled punch. The tablets formed were 5mm in diameter, weighed 45 mg each, were approximately 2mm thick and had a hardness of 1 - 3.5 Kp.

B. Dissolvable outer cover The outer annular ring was made by mixing Nu-Tab ™ (48.5 parts), MicrocelLaclOOTM (a 25:75 mixture of microcrystalline cellulose and lactose commercially available for direct compression, 45 parts), sodium saccharin (0.5 parts) and of crospovidone (5 parts) for 5 minutes. Magnesium stearate (1 part) was added and continued mixing for half a minute. The mixture was compressed in a Manesty f3 tablet press equipped with the spring loaded core rod manufactured as described above. The total weight of the tablet was 290 mg, the outer diameter was 9 mm, the height of the tablet was approximately 4.5 mm and the hardness was 5-9 Kp.

C. Drug release profile The tablets were tested to determine the total disintegration of the inner tablet in 3 ml of water within 4 minutes and at least 85% of the tizanidine solution in 450 ml of water at 37 ° C and 50 rpm in a solution of II USP device in 15 minutes. The outer covering dissolves after approximately 15 minutes.

Example 4 Release of two Drugs in different proportions The ring body and the core tablet can be formulated to contain different drugs and to release the drugs with completely different release profiles. The release rates can be controlled by the formulation of the core tablet and the annular ring and by the geometry. In this case, we formulated carbidopa immediate release profile in the core tablet with controlled release of levodopa from the ring body while using an oval tablet as the annular ring around a cylindrical tablet or an oval interior tablet. The inner cores, either cylindrical or oval, are emptied with a cylindrical hole in each of them.

A. Interior Tablets The Carbidopa (160 g) was mixed with pre-sieved xylitol (500 gm screen) (40 g) in a Diosna granulator pl / 6. Water (45 ml) was added according to the granulation solution. The mixture was granulated for 5 minutes at 500 rpm and then kneaded at 800 rpm for 1.5 minutes.

The granulate was air dried at room temperature overnight and then milled, while still wet, through a 1.6 mm screen. The ground granulate was dried in a fluidized bed for 30 minutes at 40 ° C and then milled on a 0.8 mm screen. This granulate, 56.3 g, was mixed with crospovidone (10 g) and MicrocelLaclOO ™ (32.7 g) for three minutes. Magnesium stearate (1 g) was added to the mixture which was then mixed for 0.5 minutes. The mixture was compressed in a simple Manesty f3 tablet punching machine using three different core drilling rods to make hollow cylinders of the following dimensions: Formulation D: outer cylindrical diameter 7.5 mm inner diameter 2.5 mm Formulation E: outer cylindrical diameter 7.0 mm inner diameter 4.6 mm Formulation F: Oval outer diameters 12 x 6 mm, internal diameter 3 mm.

Each tablet contained 54 mg of carbidopa.

B. Drug that contains non-dissolvable and oval outer cover Levodopa (150 g) was mixed with xylitol (75 g) and hydroxypropyl cellulose (Klucel ™ LF, 25 g) at 500 rpm per minute. Ethanol (50 ml) was added slowly and the granulate formed at 500 rpm in 1.5 minutes. The granulate was air dried overnight at room temperature and ground through a 0.8 mm screen.

The levodopa granulate (44.4 g) was mixed with ethyl cellulose (Ethocel ™ 7 cps, 30 g) and Cellactose 80 ™ (25:75 powder cellulose: lactose mixture for direct compression, 24.6 g) for three minutes. Magnesium stearate (1 g) was added and the mixture was mixed for another 0.5 minutes.

The previously formed inner tablets, Formulations D, E and F were compressed in an oval-shaped cover core on the radial surfaces using a core rod drill loaded with an oval shaped spring as described above, with dimensions 17.6 x 8.8 mm with an inner core rod of 5 mm in diameter and an upper hole with a 5 mm diameter protrusion that narrows to 4.5 mm at the height of 1.8 mm. The total weight of each tablet is 750 mg and each contained 200 mg of levodopa.

C. Drug release profile The solution was carried out in 0.1N HC1 (900 ml) at 37 ° C in a USP apparatus II dissolution test instrument at 50 rpm and the levodopa and carbidopa concentrations of each sample was determined by HPLC. The results of the dissolution experiments are given in Tables 7, 8 and 9 and are described in FIGS. 9, 10, and 11.

Table 7 Dissolution results for Formulation D Table 8 Results of the Dissolution for the Formulation E Release of the cumulative percentage Time (h) Levodopa (%) Carbidopa (%) 0. 5 27 102 1 43 2 63 3 76 4 85 6 94 8 101 Table 9 Dissolution results for Formulation F Release of cumulative percentage Time (h) Le odopa (%) Carbidopa (%) 0.5 26 72 1 40 95 2 61 103 3 72 4 88 6 93 8 99 Thus, two drugs with totally different release profiles can be delivered with independent control of the release rate of each drug. It should be noted that this control can be achieved through the shape and size of the core tablet, for example by means of the proportion of a hole of predetermined size or shape, without the need for a change in the formulation.

Example 5 Tablet with annular cover to hide the taste A. Interior Tablets The surnatriptan succinate (70 parts) is granulated in water (20 parts) with microcrystalline cellulose (Avicel ™ PH 101, 80 parts). The granulate is dried in a fluidized bed dryer for 30 minutes at 40-50 ° C and then ground through a 0.8 mm screen. The granulate (75 parts) was mixed with anhydrous lactose (9 parts), microcrystalline cellulose (Avicel ™ PH101, 10 parts) and croscarmellose sodium (AODI-SOL ™, 5 parts) for 3 minutes. Magnesium stearate (1 g) was added and the mixture was mixed for another 0.5 minutes. The tablets were pressed into a simple Manesty f3 tablet punched machine using a 6 mm flat bevel perforation. The weight of the tablet is 100 mg and contains the equivalent of 25 mg sumatriptan.

B. Dissolvable outer cover A mescal of compressible sucrose (Nu-Tab, 94 g), microcrystalline cellulose (AviceP ™ PH102, g) and menthol (1 g) was mixed for five minutes. Magnesium stearate (1 g) was added and the mixture was mixed for another half minute.

The tablets were formed using the inner cores described in Example 4, above, and core rod tool loaded with an outer cylinder spring 9 mm described above. The obtained tablets are cylindrical tablets of 9 mm outside diameter with axial faces without coverage and embedded from the surface. The tablet weighs a total of 475 mg.

C. Drug release profile The release profile of the tablets is measured in a USP apparatus II dissolution test instrument in 900 ml of water at 37 ° C and 50 rpm. The tablets are expected to provide a drug release greater than 80% in 30 minutes.

After thus describing the invention with reference to certain preferred embodiments, other embodiments will be apparent from this description to those skilled in the art to which the invention pertains. It is assumed that the memory should be considered only for the purposes of exemplification, with the scope and spirit of the invention indicated by the following claims.

Claims (39)

CLAIMS It is claimed:

1. A pharmaceutical dosage form for oral administration to a patient comprising a core tablet containing an active ingredient covered in an annular body of compressed powder or granular material, that releases the active ingredient from the core tablet at a rate ranging from 3% per hour at 12% per hour for a period of seven hours or more.

2. The pharmaceutical dosage form of claim 1 in which active pharmaceutical ingredient is selected from the group consisting of oxybutynin, alendronate, carbidopa, levodopa, tizanidine, sumatriptan and pharmaceutically acceptable salts and solvates thereof.

3. The pharmaceutical dosage form of claim 2 wherein the active pharmaceutical ingredient is oxybutynin.

4. The pharmaceutical dosage form of claim 1 wherein the core tablet further contains hydroxypropylmethylcellulose and compressible sugar.

5. The pharmaceutical dosage form of claim 1 wherein the ring body contains solid polyethylene glycol, polyvinyl pyrrolidone and ethyl cellulose.

6. The pharmaceutical dosage form of claim 5 wherein the polyethylene glycol is polyethylene glycol 4000.

7. The pharmaceutical dosage form of claim 1 in which the proportion of oxybutynin release from the core tablet is measured in United States Pharmacopeia standard apparatus II solution test instrument in an aqueous solution with a barrier of 6.8 to 37 ° C with a stirring ratio of 50 revolutions per minute.

8. The pharmaceutical dosage form of claim 1 wherein the active ingredient is released from the core tablet at a rate ranging from 3% per hour to 12% per hour for a period of ten hours or more.

9. A pharmaceutical dosage form for oral administration to a patient comprising a core tablet containing an active ingredient covered in an annular body of compressed powder or granular material, which releases approximately 90% or more of active ingredient from the core tablet within approximately 30 minutes.

10. The dosage form of claim 9 wherein the release rate is measured in a unit III dissolution unit standard of United States Pharmacopeia at 37 ° C.

11. The dosage form of claim 9 wherein the active ingredient is monosodium alendronate.

12. The dosage form of claim 11 wherein about 85% of the monosodium alendronate is released within about 15 minutes.

13. The dosage form of monosodium alendronate of claim 11 wherein the core tablet further contains xylitol and crospovidone.

14. The dosage form of monosodium alendronate of claim 11 wherein the annular body contains compressible sucrose and microcrystalline cellulose.

15. A pharmaceutical dosage form for oral administration to a patient comprising a core tablet containing an active ingredient covered in an annular body of compressed powder or granular material, which is suitable for sublingual delivery.

16. The pharmaceutical dosage form of claim 15 wherein about 90% or more of the active ingredient is released from the core tablet within about 15 minutes.

17. The dosage form of claim 16 wherein the active ingredient is tizanidine and wherein about 85% or more of the tizanidine of the core tablet is released within about 15 minutes.

18. The tizanidine dosage form of claim 17 wherein the core tablet further contains crospovidone, sodium saccharin, microcrystalline cellulose and menthol.

19. The dosage form of the tizanidine of claim 17 wherein the ring body contains microcrystalline cellulose, sodium saccharin and crospovidone.

20. The dosage form of claim 16 wherein the release rate is measured in a standard apparatus II dissolution system of United States Pharmacopeia at 37 ° C with an agitation of 50 revolutions per minute.

21. A pharmaceutical dosage form for oral administration to a patient comprising a core tablet containing a protected active ingredient in an annular body of compressed powder or granular material, which is suitable for dissolution of the active ingredient within the oral cavity at approximately 5 minutes or less.

22. The dosage form of claim 21 wherein the release rate is measured in a standard solution system of apparatus II of United States Pharmacopeia at 37 ° C with an agitation of 50 revolutions per minute.

23. A method for independently controlling the release rate of coactive ingredients in a simple dosage form comprising the formulation of an active ingredient in the core tablet of a dosage comprising a core tablet protected in a compressed ring body of pharmaceutical excipients and formulating a second active ingredient in the compressed ring body.

24. A pharmaceutical dosage form for the co-administration of two active pharmaceutical ingredients to a patient comprising a core tablet containing a first active pharmaceutical ingredient protected in an annular body of compressed powder or granular material and containing a second active pharmaceutical ingredient.

25. The pharmaceutical dosage form of claim 24 wherein the first active pharmaceutical ingredient is carbidopa and the second active pharmaceutical ingredient is levodopa.

26. The pharmaceutical dosage form claiming that levodopa releases from the body voids ratio ranging from 3% per hour to 30% for a period of time of three hours or more.

27. The pharmaceutical dosage form of claim 26 which releases levodopa from the ring body at a rate ranging from 6% per hour to 30% per hour in a period of time of three hours or more.

28. The pharmaceutical dosage form of claim 26 wherein the period of three hours or more begins between one and two hours after contacting the dosage form with water, this period is preceded by a faster initial release of carbidopa.

29. The pharmaceutical dosage form of claim 25 wherein the carbidopa is released completely within about three hours after the dosage form comes into contact with water.

30. The pharmaceutical dosage form of claim 29 wherein the carbidopa is released completely within about one hour after the dosage form comes into contact with water.

31. The pharmaceutical dosage form of claim 26 wherein the release rate is measured in 0.1 N HC1 at 37 ° C in a United States Pharmacopeia apparatus II dissolution test instrument with an agitation of 50 revolutions per minute.

32. The pharmaceutical dosage form of claim 24 wherein the core tablet further contains xylitol, crospovidone, microcrystalline cellulose and lactose.

33. The pharmaceutical dosage form of claim 24 wherein the ring body further contains ethyl cellulose, cellulose powder and lactose.

34. A pharmaceutical dosage form for oral administration to a patient comprising a core tablet containing a protected active ingredient in an annular body of compressed powder or granular material, which is suitable to mask the taste of the active ingredient.

35. The dosage form of claim 34, wherein the active ingredient is sumatriptan succinate.

36. The dosage form of claim 35 wherein the core tablet releases approximately 80% of the sumatriptan succinate of the core tablet in about thirty minutes or less.

37. The solid dosage form of sumatriptan succinate of claim 35 in which the core tablet further contains microcrystalline cellulose, lactose and croscarmellose sodium.

38. The solid dosage form of the sumatriptan succinate of claim 35 in which the ring body contains sucrose, microcrystalline cellulose and menthol.

39. The solid dosage form of sumatriptan succinate of claim 35 which hides the taste of sumatriptan succinate when the dosage form is kept in the mouth.