JP2005524670A - Controlled release dosage form - Google Patents

Abstract

There is provided a zero order release pharmaceutical dosage form for oral administration to a patient comprising a core tablet encased in a ring of compressed powdered or granular material. A preferred embodiment of a zero order release pharmaceutical dosage form is a solid dosage form that reduces contact between the active ingredient in solid form and the mucosal lining of the gastrointestinal tract, which is particularly advantageous for delivering ulcerative drugs. Zero order release pharmaceutical dosage forms are also provided.

Description

RELATED PATENT This application is a continuation-in-part of US application 29/1619 filed November 12, 2002, and is incorporated herein by reference, provisional application, December 24, 2001. Claims priority of 60 / 342,442 submitted; 60 / 361,182 filed March 4, 2002.

FIELD OF THE INVENTION This invention relates to oral pharmaceutical dosage forms, and in particular to controlled release forms and forms designed to mask the flavor of the active ingredient.

Background of the Invention Adapting drug delivery to therapeutic needs is a recent goal in drug delivery system development. Delivery profiles include immediate release in the oral cavity (so-called “immediate degradation” or “rapid degradation” system), immediate release in the stomach or intestine, controlled release of drugs in the gastrointestinal (GI) tract, the same for multiple drugs Or it may be desirable to have one of the simultaneous releases at different rates and many combinations of the above. There are systems that exist to provide drug delivery profiles close to the above requirements, but there is room for improvement in each field.

  An immediate disintegration system for immediate delivery of drugs in the oral cavity is the Clima by RPScherer Corporation in the form of a freeze-dried tablet that readily disintegrates on the tongue called Zidis® and in the form of the OrasolV® system Developed by labs, Inc. These systems break down rapidly in the mouth and are useful when drug delivery is needed immediately and when it is difficult for the patient to swallow the tablet. The problem is that both of these systems are relatively fragile and very sensitive to moisture. It is therefore difficult to handle with wet fingers and damages the integrity of the delivery system (in other words, “dissolution on the hands, not the mouth”).

  In the world of controlled release drug delivery systems, there are certain quotes that have led to much development. Such a maxim is “becomes better with flatter”, that is, the system will work better with a flatter delivery curve over time. Accordingly, it is considered desirable to have a delivery system that provides an essentially zero order release profile. The amount of drug released is independent of the amount exiting the delivery system and remains constant throughout the delivery profile. Adapting drug delivery to the needs of treatment is another adage for improved delivery. One skilled in the art can be aware of treatments that suddenly force the drug out several hours after steady delivery or require changes in the rate of drug delivery after several hours.

  Swelling of the hydrogel tablet delivery system or erosion of the tablet delivery system results in a drug delivery that tapers with time. In the corrosion system, the surface layer that is responsible for drug delivery shrinks so that the speed decreases in proportion to time. If the drug is delivered by diffusion through a non-erodible hydrogel, the rate decreases as the drug decreases and changes the force of the chemical gradient. These systems do not offer the opportunity to carefully tailor the drug release rate.

  Zero order delivery is as described in a number of patents maintained by Alza, such as Higuti, T et al. US Pat. No. 3,995,631, Theeuwevs, F US Pat. No. 3,977,404 and many other patents. This is achieved with the “Oros” osmotic pump. This “Oros” system is based on the osmotic pressure that pushes the drug out through an approximately microscopic orifice. The zero order profile is achieved by a constant, small cross-section of the orifice, which is the rate determining step in drug release. The “Oros” system has proven itself in several products but has limitations. It is most useful for soluble drugs and insoluble drugs with limited use. The manufacturing technique is somewhat complicated with the need to drill holes with a laser in the translucent coating. Drug release through nearly microscopic holes can also have several drawbacks. The clotting of the hole limits drug release and can cause damage to the intestinal wall by the flow of drug concentrate from the delivery system into the intestinal lumen (Laidler, P .; Maslin, SC; and Gihome, RWPathol Res Pract 1985 180 (vol. 1) pp. 74-76). Delay in the onset of drug release can be achieved by coating the system (eg enteric coating), but small orifices can become clogged by this coating, and unstable results at the opening (completely Can give. The “Oros” system is best suited for a simple zero order delivery profile. Complex molds involve the complexities of manufacturing and systems and do not solve the microscopic hole shortcomings, eg Wong, PS US Pat. No. 5,156,850 and Hamel, LG et al., PCT WO It can be achieved by “Oros” described in 9823263.

  Zero order delivery characteristics are specified in the “Geomatrix” delivery system (Colombo, P et al. US Pat. No. 4,839,177 and Conte, U et al. US Pat. No. 5,422,123 and other patents granted to Jagotech AG and others) As a result, the geometric surface layer of drug delivery has been achieved by more sophisticated operations. These systems achieve a zero order profile by sandwiching the drug delivery layer between two impermeable layers. Only the drug delivery layer is eroded and the cross section of the eroded layer is constant. Here again, it has some drawbacks. The production of this system requires special equipment to produce 2 and 3 layer tablets. The system itself does not change the rate of delivery during the release profile. The amount of drug that can be used in this tablet is somewhat limited because only one layer is used for drug delivery. The zero-order profile may not last until 100% drug release because the tablet ruptures at once and erodes most of the central layer.

  In view of the above, it is highly desirable to have a versatile solid dosage form that allows controlled release of the active ingredient approaching zero order release. Accordingly, it is an object of the present invention to provide a solid dosage form capable of releasing a drug according to a predetermined release profile.

SUMMARY OF THE INVENTION The present invention provides a controlled release pharmaceutical dosage form, wherein the core tablet is housed in an annular body of compressed powder or granular material.

  The drug layer may be recessed from the opening of the annular body on one or both sides. The drug layer is concave from the surface, so it is the wall of the toroid that contacts either the hand or the mucous membrane. The annulus is preferably a non-ulcer and insensitive pharmaceutical ingredient such as hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, starch, lactose, sugar, polyvinylpyrrolidone, calcium phosphate and other standard tablet shaping Made of agent.

  The controlled release pharmaceutical dosage form of the present invention releases the active ingredient from the core tablet into the dosage form environment at a rate of 3% per hour to 12% per hour.

  The present invention further provides a pharmaceutical dosage form wherein the pharmaceutical dosage form is adapted for long term or zero order release of the active drug material.

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

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

  The present invention further provides a pharmaceutical dosage form wherein the pharmaceutical dosage form is adapted to mask the flavor of the active material.

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

  The present invention further provides pharmaceutical dosage forms for co-administration of co-active ingredients in a single dosage form.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides novel solid dosage forms, as well as tools and methods for producing such novel dosage forms. Preferred embodiments of the present invention are very suitable for controlled release of drugs, especially for sustained release close to zero order release, as well as for masking unpleasant flavored drug flavors.

  The new dosage form comprises a core tablet containing the active pharmaceutical ingredient contained in an annular body (also called mantle in this disclosure) made of compressed powder or granular material. “Sheathed” means that the annular body surrounds the core tablet and is in contact with the core tablet and approximately its surrounding surface, while the other surface of the core tablet remains substantially exposed. Means that The core tablet contains one or more active pharmaceutical ingredients, but its formulation is not critical to the present invention. The core tablet may be formulated for any desired release profile, such as immediate release, delayed release, rupture or pulse release, sustained or zero order release. The annulus can be formulated to achieve any desired purpose, eg, holding in the stomach, facilitating swallowing, taste masking and controlling the rate of drug release from the core tablet. The annular body may contain or be covered by a co-active component.

The terms “drug” and “active pharmaceutical ingredient” generally mean any biologically, physiologically or pharmacologically active agent. Active pharmaceutical ingredients that may be administered in the compressed dosage forms of the present invention include: adrenergic receptor agonists and antagonists; muscarinic receptor agonists and antagonists; anticholinesterase agents; neuromuscular blockers; ganglion blockers and stimulants; Serotonin receptor agonists and antagonists; central nervous system active agents such as antipsychotics, anti-antipsychotics, anxiolytics, antidepressants, antidepressants, anesthetics, hypnotics, sedatives, hallucinogens and anti-illusions Drugs; antiepileptic drugs; anti-migraine drugs; drugs for treating Parkinson's disease, Alzheimer's disease and Huntington's disease; analgesics; cough medicines; antihistamines; H ₁ , H ₂ and H ₃ receptor antagonists; Antagonist; Antipyretic; Anti-inflammatory agent; NSAID; Diuretic Na ⁺ -Cl ^- co-transport inhibitors; vasopressin receptor agonists and antagonists; ACE inhibitors; angiotensin II receptor antagonists; renin inhibitors; calcium channel blocking material; beta-adrenergic receptor inhibitor; antiplatelet factors; antiarrhythmics; Antihypertensive agents; Vasodilators; Phosphodiesterase inhibitors; Arrhythmia drugs; HMG CoA reductase inhibitors; H ⁺ , K ⁺ -ATPase inhibitors; Prostaglandins and prostaglandin analogs; Laxatives; Antiemetics; exercise promotors; antiparasitic agents such as antimalarial agents, antibacterial agents, drugs and anti-helminths for the treatment of protozoal infections; antimicrobial agents such as sulfonamides, quinolenone, β-lactam antibiotics Substance, aminoglycoside, tetracycline, chloramphenico And erythromycin; drugs for the treatment of tuberculosis, drugs for the treatment of leprosy; antifungal agents; antiviral agents; anti-nepropytic agents; immunomodulators; hematopoietic agents; growth factors; vitamins; minerals; Hormones and hormone antagonists such as antithyroid drugs; estrogens, progestins, androgens, corticosteroids and corticosteroid inhibitors; insulin; hypoglycemic agents; calcium reabsorption inhibitors; glucocorticoids; retinoids and heavy metal antagonists .

  The annular body may be in the form of any powdered or granular pharmaceutically acceptable excipient and itself contains a pharmaceutically active ingredient. Specifically, it may include diluents, binders, degradation accelerators, glidants, lubricants, flavors, colorants and those that may be included in the ring. Techniques for forming compacts with forms that are characteristic in terms of powdering and granulating with conventional excipients and eliminating the need for hardness, friability and capping are known in the tableting industry. Known to those skilled in the art.

  Suitable excipients for forming the ring include hydroxypropylcellulose (eg, Klucel®), hydroxypropylmethylcellulose (eg, Methocel®), microcrystalline cellulose (eg, Avicel ( (Registered trademark)), starch, lactose, sugar, polyvinylpyrrolidone (for example, Kollidon (registered trademark), Plasdone (registered trademark)) and calcium phosphate.

  In a particularly preferred compressed dosage form illustrated in FIG. 1, a core tablet 1 containing an active pharmaceutical ingredient is embedded in an annular body 2 (consisting of a non-ulcer pharmaceutical excipient). “Embedded” tablets are particularly suitable for oral delivery of ulcerative drugs. Thereby, the occurrence of pill gastritis and contact gastritis is reduced by the localization of ulcerative drugs in the core tablets that are shielded from contact with the mucosa on the inner surface of the gastrointestinal tract. The drug is shielded because the core tablet is embedded. Embedding the core tablet does not significantly change the release profile of the core tablet because a substantial portion of the surface layer of the core tablet is in fluid communication with the environment. On the other hand, in coated or encapsulated dosage forms, the coating and capsule must be broken by gastrointestinal fluid before the drug is released. In the present invention, the outer contour of the dosage form protects the mucosal lining of the gastrointestinal tract without interfering with fluid communication between the core tablet and the environment.

  Examples of drugs that may be advantageously delivered using preferred implant dosage forms of the present invention include monosodium alendronate monohydrate, monosodium alendronate trihydrate, etidronate sodium, sodium risedronate, pamidronate, aspirin , Ibuprofen, naproxen, fenoprofen, ketoprofen, oxaprozin, flubiprofen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetine, ketorolac, diclofenac, piroxicam, meloxicam, tenoxicam, phenylbutazone, oxyphene Butazone, oxybutynin, alendronate, carbidopa, levodopa, tizanidine, sumatriptan, pharmaceutically acceptable salt Hydrates, isomers, their esters and ethers, and mixtures thereof.

  Both the core tablet and the annular body may be formed in any suitable shape. Specific shapes can be achieved through the use of specially designed punches. Preferably, the core tablet and the annular body have a cylindrical shape. The core tablet and the annular body may have the same or different shapes. The exposed surface layer of the core tablet may have any suitable shape. Preferably, the exposed surface of the core tablet is annular or oval.

  Returning to FIG. 1, the core tablet has opposing second and third surface layers 3 and 4 and an outer surrounding surface layer 5 (spread to the opposite surface layer). The core tablet 1 is preferably cylindrical or disc-shaped for ease of manufacture, but this need not be the case. In dosage forms for administration to humans, the maximum distance across the facing surfaces 3 and 4 is preferably about 2 mm to about 12 mm, more preferably about 4 to about 7 mm, and most preferably about 5 mm. The facing surfaces 3 and 4 can be flat, concave or convex and support the moderate axial compression force exerted by the flat pressing surface while forming the surrounding core tablet annulus. Is preferably flat for.

  At the outer contour, the annular body 2 is preferably cylindrical in shape, but it can have any cross section, for example oval, elliptical or oval. The outer diameter is preferably about 5 mm to about 15 mm, more preferably about 7 mm to about 12 mm, and most preferably about 9 mm. Its inner diameter is the largest, about 2 mm smaller than the outer diameter. A small inner diameter of less than 2 mm can slow the release of the drug if the excipients in the annulus are swallowed and contacted with gastrointestinal fluid. However, in certain embodiments, a lower limit of 0.5 mm may still be useful. Preferably, the inner diameter is 3 mm or more.

  The annular body 2 has first and second annular surfaces 6 and 7 facing each other, an outer peripheral surface layer 8 (spreading from their outer edge to the annular surface), and an inner peripheral surface layer 9 (annular from their inner edge) Spread between the surface layers), thereby defining an annulus.

  As best seen in the side view (FIG. 1B), the surrounding surface layer 9 inside the annular body 2 consists of three longitudinal (axial) segments. The first and second segments 10 and 11 are terminal and do not contact the side of the core tablet. They are separated by an inner third segment 12 (in contact with the outer surrounding surface layer 5 of the core tablet 1). The facing surface layers 3 and 4 of the core tablet are preferably about 0.5 mm to about 4 mm, more preferably about 1.5 mm, recessed with respect to the annular surface layers 6 and 7 of the annular body (the recessed distance is corresponding). Corresponds to the length of the end segment). The depths of the recesses in the surface layers 3 and 4 may be the same or different.

  By implanting the drug-containing core tablet, any contact between the dosage form and the gastrointestinal mucosa is not a solid ulcerative active ingredient, but an ulcerative excipient, and optionally one or more non-ulcerative It occurs in the surface layer of the annular body formed by the co-active component. However, when the dosage form of the present invention is used to administer a non-ulcer drug, both or one or both of the facing surfaces 3 and 4 together with the annular surface layers 6 and 7 have no adverse effect. And you can be leveled.

  To better understand the preferred implant dosage form of the present invention, it is useful to imagine the core tablet surface layer 3 and first longitudinal segment 10 (defined as first space 13). Similarly, the surface layer 4 and the second longitudinal segment 11 of the core tablet define a second space 14. Spaces 13 and 14 are filled with gastrointestinal fluid if the dosage form is immersed in gastrointestinal fluid after reaching the gastrointestinal tract. Gastrointestinal fluid passes through this space and contacts the core tablet, and the drug is released from the space after it has dissolved. The spaces 13 and 14 are preferably about 0.5 mm to about 10 mm, more preferably about 3 mm to about 6 mm, and most preferably about 4.5 mm wide (measured parallel to the opposing first and second surface layers). And). Thus, drug release is not caused by an osmotic mechanism such as occurs with penetrating dosage forms made using the device of US Pat. No. 5,071,607. Correctly, in a high volume of static fluid environment, drug concentration drops roughly unidirectionally and exponentially by diffusion. In contrast, osmotic release of drugs will create a streaming flow that can produce high local concentrations of drug and osmotic agent at a distance very far from the tablet. Highly concentrated osmotic flow in ulcerative drugs can potentially irritate the mucous membrane if the tablets wrap around the gastrointestinal tract wall, like solid drugs.

  The opposing surface layers 3 and 4 of the core tablet are preferably substantially exposed, i.e. not substantially covered by the annulus. By “substantially exposed” is meant that less than about 50% of each facing surface is visually concealed or hidden. The facing surface portions 3 and 4 may be concealed by an annulus, because the diameter and shape of the core tablet and the diameter and shape of a given compression part of the tool used to compress the annulus. This will become clear from considering the description of the tool aspect of the present invention. Such a difference results in an internal segment 12 that is offset from the internal segments 10 and 11 (which themselves may have different longitudinal cut planes, eg, different diameters as shown in FIG. 1). Instead, the cut surface of the annular body defined in the inner peripheral surface layer 9 is uniform throughout its entire length. The parts of the facing surface layers 3 and 4 may be hidden by an annular body, but that is not an essential case.

  Furthermore, the present invention determines the rate of sustained release of the drug not by diffusion of the drug through the annulus, which contributes to the versatility of the dosage form for various release profiles, but by the formulation and core tablet shape. Think about it.

  In one embodiment, the pharmaceutical dosage form is a sustained release form. The active drug substance is delivered through the exposed axial surface of the core tablet. The exposed axial surface layer maintains a constant cross-section during active substance delivery, thus producing a zero order release profile. For sustained release applications, the core tablet may be formulated to be erodible or dispersible.

  The sustained release core tablet suitably comprises a hydrogel such as hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose and the like. Optionally, the core tablet contains a more rapidly dispersing material, such as compressible scrose, to perforate in the hydrogel matrix, thereby adjusting the hydrogel grip to the active ingredient. Including. In the zero order sustained release dosage form in which the active ingredient is contained in the core tablet, the annular body is formulated to degrade even more slowly than the core tablet so that the surface area of the core tablet remains constant. right. A mixture of about 1 part high molecular weight polyethylene glycol (PEG) and 3-5 parts ethyl cellulose maintains their shape and stiffness in water over the time that most commonly used eroded or swollen hydrogel matrices completely release the drug. . A particularly preferred composition of the cyclic form of sustained release dosage form according to the present invention comprises about 15-25 parts PEG 4000, about 70-80 parts ethylcellulose and about 5 parts polyvinylpyrrolidone. The rate of release of the active substance from the core tablet of this sustained release dosage form is less than about 15% by weight per hour. A suitable release rate is about 3% by weight per hour to about 12% by weight per hour. Sustained release dosage forms are adapted to release the active ingredient over about 4 hours or more, more preferably about 7 hours or more, and most preferably about 10 hours or more. The rate of release of the active ingredient was measured in a United States Pharmacopeia standard apparatus II solution tester in a 37 ° C. aqueous solution buffered to 6.8 with stirring at a rate of 50 rpm.

  The dosage forms of the present invention are also adapted to provide immediate release and have unique advantages when used for immediate release. The annular body or storage layer provides protection of the immediate release core tablet while being handled by the patient or caregiver. The core drug layer is recessed from the surface layer, so all contacts become the walls of the toroid. The core tablet is fragile, but the hand will only come into contact with the hard-to-break annular body. Core tablets may be formulated to be “rapidly disintegrating” in nature without the disadvantages of current “rapid disintegrating” systems. Drugs can be broken down into saliva in a few minutes while the “rapidly degrading” form is retained in the mouth. The outer annulus is not too slow to disintegrate, but may be formulated to be insensitive to moisture or to be swallowed (by someone who can swallow the tablet) or be squeezed out. Degradation of the released drug is preferably performed in less than about 5 minutes, more preferably in less than about 2 minutes. The rate of degradation of the active ingredient was measured at 37 ° C. in the United States Pharmacopeia Standard Unit III cracking unit or in the United States Pharmacopeia Standard Unit II cracking unit with stirring at 50 rpm until 37 ° C. The dosage form may be prepared to be suitable for rapid degradation in the oral cavity without administering the liquid together.

  As a result of the protection provided by the annulus, many active ingredients can be used in the core tablet formulation in a greater proportion than can be used with conventional tablets. Thus, the core tablet can contain a very high concentration of the active drug substance, thus avoiding producing dosage forms that are too delicate to handle. The immediate release core tablet preferably comprises a superdegradation promoting substance. Other suitable excipients for immediate release formulations include sodium saccharin, microcrystalline cellulose, lactose and menthol.

  One immediate release core tablet formulation that has been found to be well compressed in the tools of the present invention is 5 parts active ingredient, 20 parts crospovidone, 74 parts MicrocelLac®, 1 part lubricant. And 0.4 parts menthol.

  If the core tablet is formulated for immediate release, the annulus can be formulated differently than the annulus of the sustained release formulation because it does not need to remain rigid over time. However, annular bodies will generally be formulated to degrade more slowly than core tablets. As further illustrated in Example 3, the cyclic product is an immediate release core formulation by reducing the proportion of superdegradation-promoting substance and optionally replacing excipients that degrade but do not swell, such as compressible sugars. It may be produced by modifying.

  The immediate release dosage forms of the present invention are suitable for administering active pharmaceutical ingredients having an unpleasant flavor, such as sumatriptan succinate. One way to achieve flavor masking is to embed the surface layer of the core tablet in the annulus, thus avoiding contact between the tongue and the core tablet. The immediate release dosage forms of the present invention are also suitable for sublingual and buccal administration of drugs. Often it is preferred that the sublingually administered drug is released from the dosage form as quickly as possible. Buccal administration may be administered via an immediate release dosage form. In order to achieve rapid release, such dosage forms may be formulations with a high percentage of active ingredient. However, a high proportion of active ingredient often makes the tablet fragile. As discussed previously in other backgrounds, the annular bodies in the dosage form of the present invention will protect the fragile core tablets and make them compatible with sublingual and buccal administration of drugs. Suitable drugs for sublingual and buccal administration in the dosage forms of the present invention include tizanidine, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, vaccines, ergotamine and other anti-migraine compounds, lorazapan and other sedatives, Vitamin B12 and folic acid, and mixtures thereof. The dosage form of tizanidine is further described in Example 3.

  The rate of release of the active substance from the core tablet in immediate release or sublingual dosage form is greater than 90% in 30 minutes. Preferably, the release rate is greater than about 85% in 15 minutes. The rate of degradation of the active ingredient was measured in a United States Pharmacopeia Standard Unit III cracking unit machine at 37 ° C. or in a United States Pharmacopeia Standard Unit III cracking unit with stirring at 37 ° C. and 50 rpm.

  The core tablet may be a bilayer tablet in which each layer contains the same or different drug and each layer releases the drug at the same or different rate. One of the layers may be an immediate release layer and the other layer may be a sustained release layer, or both may be sustained release layers. The inner tablet may be formulated into a trilayer tablet with an intermediate layer that is later delivered later. The two outer layers may be delay layers or drug delivery layers having the same or different drugs and the same or different release profiles. The intermediate layer may again contain the same or different drug compared to the outer layer and be of sustained or immediate release. Thus, some can provide controlled release of two drugs to their desired release rates, and a third drug can be delayed release or delayed pulsed. Thus, the invention described herein provides a wide range of drug delivery capabilities that have not been addressed by the performance improvements of conventional dosage forms and other known delivery systems.

  The dosage forms of the present invention can also be formulated to deliver two drugs by localizing one of the two drugs to the core tablet and placing the other drug on the annulus. Such an arrangement makes it possible to independently control the release rate of each active ingredient, which is part of the dosage form, i.e. the core tablet or the annular ring, which can be very quickly or very slowly. And by formulation adjustment to the part containing the released drug. In addition, the shape of one part can be changed without adjusting the formulation. For example, powdered or granular material is compressed around the core tablet, resulting in a body with an oval cross section rather than an annular cross section to achieve a faster release rate (provided by an increase in surface area). In addition, the core tablet may have holes extending from one axial surface to the other to increase the surface layer and thereby increase the release rate. The release rate can be further adjusted by changing the hole diameter, as shown in Example 4.

  Suitable drug combinations for use with the present invention include levodopa / carbidopa, acetaminophen / caffeine, acetaminophen / codeine, acetaminophen / antihistamine, vitamin and mineral combinations and antibiotic combinations. Can be mentioned. The combination of levodopa / carbidopa is particularly preferred. In Example 5, a particularly preferred levodopa / carbidopa dosage form is illustrated, where levodopa is dispersed in a hydrogel matrix in a ring and carbidopa is directly compressed core mixture and super-degradable in a core tablet Compressed directly with the agent.

  The release rate of levodopa substance from the core tablet of the levodopa / carbidopa combination drug dosage form is less than about 35% weight per hour. A preferred release rate is from about 3% by weight per hour to about 30% by weight per hour, more preferably from about 6% by weight per hour to about 30% per hour. The levodopa / carbidopa combination dosage form is adapted to release the active agent over a period of about 2 hours or more, more preferably about 3 hours or more. The rate of release of the active ingredient was measured in a United States Pharmacopeia standard apparatus II solution tester at 37 ° C. with stirring at a speed of 50 rpm in 0.1 N HCl.

  A solid dosage form with a drug-containing core tablet contained in a compressed annulus of non-ulcer excipients can be produced using the novel tool set that constitutes the second aspect of the present invention. sell.

  This tool set can be used with conventional tablet machines, such as rotary and reciprocating machines or with specially designed and manufactured machines. Examples of commercially available rotary molding machines include the Manesty Express 25, the Kilian RUD or RTS series and comparable equipment. Commercially available reciprocating machine is Menesty F3 and comparable equipment, manufactured by Stokes, Kilian and Key Industries.

  An important element of the tool set is a punch assembly comprising a columnar punch and an annular punch having an annular (or bore), and a core rod that slidably engages within the ring of the annular punch, wherein the core rod Can move from the retracted position to the extended position, and the core rod is in the extended position. The columnar punch and punch assembly are sized and shaped to fit into the die bore of a rotary or reciprocating tablet press.

  The tool is well adapted for use with a conventional single station tablet press where the opposing upper and lower punches cooperate to compress the powdered or granular material in the die. Referring to FIG. 2, the single station molding machine is equipped with a horizontal die table 15 (having an opening 16 for receiving the die) and associated holding means for fixing the position of the die. A die for such a molding machine typically has a flat surface facing the centrally located bore 17 having a very well polished wall surface extending from surface to surface and a peripherally fixed groove 18 for engaging the retaining means. . The bore serves as a receptacle for receiving a powdered or granular material that is compressed when the lower punch is partially inserted. The cross section of the bore determines the size and shape of the cross section of the completed tablet. The amount of substance and the pressure of compression determine the height of the tablet. The bore may be cylindrical, but may have any other shape.

  In operation, the bore is filled with the substance, and an upper punch is inserted into the bore, and pressure is applied to the substance under high pressure, thereby pressing the powder or granular substance into a tablet and pressing the punch Molded, or contacted, compressed between surface layers.

  Together, the bore walls and upper and lower punch contact surfaces define the mold that determines the size and surface contour of the final product. The final product can have an arbitrary outer contour by selection of an appropriate bore shape and contact surface contour.

  After compression, the upper punch retracts and the lower punch moves forward to take out the tablet.

  The upper and lower punches are advanced and retracted by independently operated upper and lower reciprocating arms 19 and 20. Usually, a single punch molding machine is provided with a fixed installation part 21 under a die table coaxial with the opening.

  The tool set of the present invention adapted for use in a single station molding machine comprises a cylindrical punch and a punch assembly comprising a collar, a core rod and an annular punch.

  Referring to FIG. 3, the columnar punch 22 is a conventional columnar shape and has a gripping means, for example a fixing plane 23 for fixing it to the upper reciprocating ram 19 of the tablet press.

  The columnar punch 22 is accompanied by a contact surface layer 24. The contact surface layer 24 may have any desired contour, for example a standard concave surface, a deep concave surface, in particular a deep concave surface, a modified sphere or a plane. Preferably, the contour of the contact surface layer 24 is flat and beveled.

  The cylindrical punch for use in producing the dosage form of the present invention having an embedded core also has a protrusion 25 located in the center of the contact surface layer 24 as shown. Preferably, the height of the protrusion 25 is about 0.5 mm to about 4 mm, more preferably about 1.5 mm. The shape of the protrusion is preferably cylindrical or tapered, but an oval, ellipse, oval or any other shape is also desired. The protrusions are preferably cylindrical and have a flat and raised surface 26. The protrusion 25 preferably has a diameter of about 3 mm to about 7 mm, more preferably about 4.5 mm. In other embodiments particularly suitable for use when a non-ulcer active pharmaceutical ingredient is administered, there are no protrusions 25.

  The punch assembly 27 includes a collar 28, a core rod 29 (slidably engaged with the collar), and an annular punch 30 (slidably engaged with the core rod).

  The collar 28 is provided with an attaching means, for example, an external thread 31 for attaching to the fixed attachment portion 21 which surrounds the periphery and is located under the die table. As shown, the distal end of the collar 28 distal to the die table, when installed, is a grip section (optionally with a hexagonal cross section, optionally) for attachment to the fixed attachment portion 21 by a wrench. Shown). The end 33 of the collar 28 adjacent to the die table is dimensioned to receive and guide the core rod 29 when installed.

  Apart from the distal end of the collar, the diameter of the ring is substantially larger than the core rod, providing a housing 34 for biasing means such as a spring 35. The coil of the spring 35 surrounds the core rod. The coil spring 35 is a suitable biasing means, but biasing can also be achieved by other means, such as a stack of Belleville washers or resilient inserts.

  The spring 35 or other biasing means meshes with the retaining ring 36 that is numbered with respect to the core rod 29. The retaining ring 36 can be numbered by tightening and engaging with the core rod in a groove 37 around the rod. The retaining ring is a conventional C-clip that engages the groove or it is a clamp or any other core rod in the direction in which the biasing means can exert the biasing force and is parallel to the long axis of the core rod 29 It may be a structure in which movement with respect to is suppressed.

  As shown, the annular locking bolt 38 meshes with the inner thread 39 at the distal end of the collar 32. The bore 40 through which the fixing bolt 38 is sized for acceptance and restrains movement of the core rod 29 relative to the axis in cooperation with the annulus in the proximal portion of the collar. The core rod 29 is urged in the direction of the die table when the collar is mounted on the fixed mounting portion 21 and is held slidably engaged with the collar 28 by the retaining ring 36 and the fixing bolt 38. The The height of the rod tip 41 is adjusted by advancing or even retracting the collar 28 relative to the fixed mounting portion 21, for example, rotating the collar when engaged and engaged with the fixed mounting portion.

  The diameter of the core rod 29 can be changed according to its length. The preferred diameter of the rod tip 41 is about 0.5 mm to about 10 mm, more preferably about 4.5 mm. However, for rigidity, the core rod should be thick, preferably about 4 mm to about 12 mm, and more preferably about 9 mm over most of its length. The rod may taper from a smaller diameter at the tip to a larger shaft diameter or may change abruptly at the shoulder 42.

  The core rod may be a two-piece structure. For example, the core rod tip 41 may be adapted to couple to the core rod, which provides an external thread at its lower end and a socket with an internal thread at the upper end of the core rod, or By the reverse. The two piece structure allows the tip of the core rod to be replaced if the tip of the core rod is damaged or if a different shaped core rod tip is desired.

  The punch assembly 27 further comprises an annular punch 30. The annular punch 30 is provided with means for coupling to the lower reciprocating ram 20, for example a fixed plane 43. A bore 44 through the annular punch is dimensioned to receive and surround the core rod 29 and still allow axial movement of the annular punch 30 independent of the core rod. The bore through the annular punch can vary in diameter according to the length of the punch and serve to engage the annular flange 45 with the shoulder 42 on the core rod. The engagement of the flange 45 and shoulder 42 prevents the annular punch and collar 28 from contacting each other during operation and installation. The annular punch contact surface 46 applies pressure to the powdered or granular material during compression. The contact surface layer 46 may have any desired contour, such as a standard concave surface, a deep concave surface, in particular a deep concave surface, a modified sphere or plane. Preferably, the contact surface layer 46 has beveled edges to facilitate removal of the finished tablet.

  The columnar punch, annular punch, core rod and collar are preferably made from metal, more preferably steel, most preferably stainless steel.

  In the final dosage form with an embedded core tablet, the depth of the first space 13 (FIG. 1) is determined by the height of the protrusion 25. The depth of the second space 14 is determined by the filling depth, the biasing force against the core rod, the compressibility of the substance, and the thickness of the core tablet. These parameters may be adjusted by routine experimentation to adjust the depth of the second space 14 (proportional to the depth of the first space 13).

  In the second dosage form, one or both of the facing layers 3 and 4 of the core tablet are flush with the annular surfaces 6 and 7 of the annular body 2. Such an alternative embodiment can be produced by using columnar punches as previously described (but lacking protrusions 25). The surface layer 3 may generally be flush with the annular surface layer 6 if the columnar punch has a flat contact surface. Whether the facing surface layer 4 is flush with the annular surface layer 7 will depend on the filling depth, the compressibility of the powdered or granular material and the thickness of the core tablet, and such factors are relative to the annular surface layer 7. It may be prepared by routine experimentation to obtain a dosage form with the surface layer 4 retracted at the desired distance.

  To further illustrate the present invention and to illustrate the operation of the tool set, a cycle of operation will be described. The cycle of operation is embodied in a method that provides the third aspect of the present invention.

  The operating cycle is first described by a single station molding machine. This cycle begins with a first action performed after removal of the tablet formed in the previous cycle. Referring to FIG. 4a, the feed shoe 47 moves laterally over the die bore while the annular punch is in the advanced position, so that the contact surface 46 is substantially flush with the tip surface of the die. By doing so, the feed shoe sweeps the completed tablet from the top of the annular punch to a chute (where the tablets are collected) leading to the receptacle. The annular punch 30 is retracted while the tip 41 of the core rod 29 is flush with the die surface layer (FIG. 4b). The retraction of the annular punch results in the formation of an annular hole, in which particles of powdered or granular material are fed from the feed shoe by gravity and / or various pressures. Once the hole is filled, the feed shoe is screened away from the die bore.

  The pre-compressed core tablet 1 is placed on top of the core rod by using any conventional device for producing tablets with a compression coating such as, for example, a Kikian RUD machine (FIG. 4c). . This arrangement means does not constitute any part of the invention and omits its details.

  The columnar punch 22 is advanced by the upper reciprocating ram 19 (FIG. 4d). As the columnar punch 22 approaches the bore, the surface layer 26 that is one step higher than the protrusion 25 presses the core tablet 1. As the columnar punch 22 enters the bore, the core tablet 1 is pushed into the bore by a protrusion that opposes the biasing force exerted by the core rod 29. The continuous movement of the columnar punch 22 into the die bore compresses the powdered or granular material into the annular body around the core tablet. A strong compressive force may be exerted on the powdered or granular material without destroying the core tablet because the core tablet is completely compressed before the powdered or granular material is fully compressed. But by entering the bore.

  Those skilled in the art will also note that the protrusion 25 may be replaced by a core rod in a columnar punch, which is extended so that the tip of the rod applies pressure against the core tablet 1 during compression. It is urged to face. The core rod for the columnar punch does not necessarily have to be attached to the fixed attachment part at the time of molding. It will be biased with a greater force than the core rod 29 so that the pressure exerted by the columnar punch will press the core tablet into the bore against the resistance of the core rod.

  After the powdered or granular material is compressed, the columnar punch is retracted. Simultaneously or thereafter, the annular punch 30 is advanced by the lower reciprocating ram 20 to a position where the contact surface 46 is substantially flush with the upper surface of the die, and the finished tablet is moved over the die, At this location it can be swept from the die table to a later cycle of operation (FIG. 4e). On the other hand, the core rod is returned to a position flush with its original die surface layer.

  This tool set is well adapted for use in a rotary tablet press. The cross-sectional dimensions and shape of the columnar punch, and the dimensions and shape of the protrusions (if present) are the same as the punches adapted for use in a reciprocating molding machine. Other dimensions of the tool set are generally based on the dimensions and layout of the particular tablet press. These dimensions can be readily determined by one skilled in the art. The cut surface size and shape of the annular punch and the cut surface size and shape of the core rod are the same as in a punch adapted for use in a reciprocating machine, and again, other dimensions are specified for a particular tablet machine. Based on the dimensions and layout. These dimensions can be easily determined by one skilled in the art. In addition, as seen in the patents incorporated by reference herein, the punch has a conventional support surface at the distal end with respect to the contact surface to provide cam and roller movement along the axis of the die bore. For controlling and fixing them.

  In an annular punch for use in a rotary tablet press, suitable core rod biasing means are housed in the annular punch, and means for adjusting the extent of core rod elongation and / or biasing, such as Includes set screws or similar devices.

  Conventional rotary molding machines are known to those skilled in the art. Several rotary molding machines and related improvements are disclosed in US Pat. Nos. 5,462,427, 5,256,046, and 5,635,223, which are incorporated herein by reference in their entirety. The rotary molding machine has a movable die table that rotates around the vertical axis. Mounted above and below the die table are upper and lower punch carriers that rotate in synchronization with the die table. The punch carrier is generally a drum-shaped body approximately the same diameter as the die table, or may have an arm extending outwardly from a ring with a shorter diameter. The punch carrier is provided with a plurality of vertical holes or slots at equal intervals around them or over the end of the arm. When the molding machine is operated, punches are inserted into each slot and their contact surface is directed towards the die table. Each punch has support means at the opposite end of the contact surface. The support means meshes a fixed cam and roller that control the vertical movement of each punch during the cycle of operation. The cam and roller are arranged so that powdered or granular material is fed into the die during the cycle of operation while the lower punch is inserted into the die. Pressure is applied to the powdered or granular material to produce a compact. After compression, one or more punches are removed from the die and the dosage form is released. Rotary molding machines are particularly suitable for high volume production because they typically include many punch and die sets that are operated simultaneously.

  A cycle of operation using the tool of the present invention adapted for use on a rotary molding machine will be disclosed. As the die table rotates, one of the dies passes under the fill shoe or force feeder. While the die passes under the shoe or feeder, the annular punch is retracted by the cam. The core rod remains in the extended position (maximum above the die plane). The annular space left by the retraction of the annular punch is filled with powder or granules. At the next station, the core tablet is inserted onto the tip of the core rod by conventional means, such as used in a “press coat” such as Kilian RUD. The core tablet may be placed over the core rod by any method. Further rotation leads the die to the compression station, where the columnar punch with or without protrusions moves downward and presses the core tablet into the bed of powdered or granular material. The force of the columnar punch retracts the core rod against the bias and the powdered or granular material is compressed into an annular shape surrounding the core tablet. In dosage form products, one dent depends on the height of the protrusion and the other dent depends on the strength of the bias, the filling depth, the compressibility of the powdered or granular material and the thickness of the core tablet. After the powder is compressed, the die rotates further, in which case the columnar punch retracts from the die. Simultaneously or later, the annular punch is raised until it reaches the die surface. The core rods simultaneously rise to the die surface by energizing. The tablets are swept from the die by the removal element and collected.

  While reference is made to the “upper” and “lower” elements in the description of the tool set and method for making solid dosage forms of the present invention, the particular relationship of the elements is what they use. This is determined by the design and configuration of the molding machine to be used. The terms “upper” and “lower” are not intended to limit the present invention to a vertical arrangement of the elements.

  The invention will be described by reference to the preferred predetermined embodiments, which will be further illustrated by the following examples.

Example Example 1
Immediate release monosodium alendronate tablet This example is designed to measure the rate and extent of alendronate sodium absorption by administering a solid pharmaceutical dosage form of the present invention ("precoated tablet") to a human subject. The research that was done was summarized.

Materials and Methods Precoated tablets were prepared as follows.
Tablet core : 85.4 g alendronate trihydrate (TEVA Assia Ltd.) and 2.6 g xylitol (Danisco Sweetenners OY) in 20 minutes water with Diosna (model P1 / 6) granulator in 3 minutes Crushed over. The granules were dried in a fluid bed dryer at 40 ° C. for 1 hour and ground with a 0.8 mm screen. The granules were mixed with 11 g crospovidone NF (BASF Pharma) for 5 minutes. 1 g of magnesium stearate NF / EP (Mallinkrodt Inc.) was added and the granules were mixed for an additional 0.5 minutes. The mixture was compressed using a Manesty F3 single punch tablet press with a 5 mm flat bevel pan. The tablet weight was 94.9 mg ± 1.0 RSD. The hardness of the core tablet was 3-6 kP.

Pre-coated tablets : 94 g compressible sucrose (Nu-Tab®, DMV International) and 5 g microcrystalline cellulose (Avicel® pH 102, FMC International) were mixed for 5 minutes. 1 g of magnesium stearate (NF / EP, Mallinkrodt Inc.) was added and the mixture was mixed for an additional 30 seconds.

  A spring-biased columnar punch and punch assembly constructed in accordance with the present invention were secured to a Manesty F3 single punch tablet press. The core rod was designed for a 5 mm round core tablet and the die and punch for the outer tablet were designed to produce a round, 9 mm diameter flat beveled solid pharmaceutical dosage form. The upper punch has a protrusion with a diameter of 4.5 mm and a height of 1.2 mm. The tablet press was operated and protective tablets were produced. The tablet weight was 474 mg ± 0.62 RSD and the hardness of the protective tablets was 12-15 kP. The alendronate trihydrate content (expressed as alendronate) was 66.8 mg ± 13.8% RSD (82.4 mg alendronate trihydrate equals 70 mg alendronate). It was.

  The internal tablet containing the drug was retracted about 1 mm from the surface layer of the annular body.

Pharmacokinetic study A clinical trial with 12 human volunteers was conducted to verify the pharmacokinetics of the solid dosage form of the present invention containing 70 mg alendronate. Its pharmacokinetics were comparable to the prior art commercially available 70 mg Fosalan® (Merck, Sharpe & Dohmn).

Methods This study was conducted in a randomized, open-label, two-treatment, two-period, two-line crossover scheme under fasting conditions. Twelve healthy adult men (18-55 years) were entrusted to the study.

  The study was divided into first and second periods, each with a duration of 36 hours, with a 14-day “washout” period between study periods. All subjects who completed both studies were included in the analysis. Subjects were randomly divided into two groups. One population received alendronate via protective tablets for the first period and control Fosalan for the second period. The order of administration for the second population was reversed.

  In both periods, alendronate was administered on an empty stomach. A standardized meal was provided 4 hours after dosing. Snacks were delivered on a standardized schedule, which was the same for all subjects in both study periods. Water was given as appropriate. In addition, subjects were encouraged to drink more than 200 ml of water at appropriate intervals during each study period.

The bioavailability of alendronate was determined by measuring the cumulative amount of alendronate excreted in the urine over 36 hours after oral intake of test and control tablets (hereinafter “Ae _0-36 ”). The first (t = 0) urine sample was collected immediately after administration. Urine samples were collected regularly at 11 time points planned over a 36 hour test period. All collected urine samples were analyzed for alendronate using a validated HPLC-FLC assay.

Results The main pharmacokinetic parameters obtained from analysis of urine samples are collected in Table 1.

A comparison of the pharmacokinetic parameters of the dosage forms of the present invention and the pharmacokinetic parameters of prior art dosage forms is provided in Table 2.

With reference to Tables 1 and 2 and FIG. 5, those skilled in the art will recognize that alendronate administered via the solid dosage form of the present invention has essentially the same pharmacokinetic results as those administered by fosalan. You will see that you give. The total amount of alendronate delivered in the urine over 36 hours is essentially the same for both treatments and is comparable to the maximum rate of excretion (C _max in a pharmacokinetic study of the plasma level of the drug) ) Is also disclosed.

The urinary excretion profile was similar for all subjects and was similar for both treatments. Most subjects had a maximum excretion rate (R _max ) in 1-2 hours. For 5 subjects, if they took fosaran, R _max occurred 1 hour earlier after dosing. Four of the subjects experienced R _max in less than 1 hour when they took protective tablets. One of the subjects, while he had a R _max at 3 hours when ingested Fosaran, two of subjects, R _max to 3 hours when they were ingested protected tablet Had.

  The total amount of alendronate excreted was 36.9 μg to 158.6 μg when administered with fosaran and 30.1 μg to 284.4 μg when administered with the solid oral dosage form of the present invention. . Only in two subjects the total amount of alendronate excretion was more than twice different between the two treatments. Other subjects had very little alendronate excreted with any alendronate dose.

  The bioavailability of alendronate administered via the novel solid dosage form of the present invention was comparable to alendronate administered by prior art dosage forms. However, the prior art dosage forms do not provide any protection against the esophagus and the gastric mucosa, while the bio-budgetically equivalent new dosage forms of the present invention provide such protection.

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

  It took about an hour or more for the outer mantle to melt.

  Tablets were tested in human pharmacokinetic studies and shown to be bioequivalent to commercially available alendronate (70 mg).

Example 2
Sustained release (0th order release) oxybutynin tablets cyclic coated tablets are uniquely suitable for sustained release, particularly when approximate sustained release is required over time. The drug is delivered from the exposed shaft surface of the delivery system. These surfaces remain constant in cross-section during drug delivery, thus helping to achieve a constant rate of drug release.

A. Internal tablet oxybutynin (50 g) was mixed with anhydrous lactose (50 g) in a Zanchetta Rotolab® one-pot grinder. The granulation solution, 5% hydroxypropylcellulose (Klucel® LF, 21 ml) was added and stirred at 500 rpm until totally mixed. The granules were dried in a one pot grinder at 45-50 ° C. by gas stripping for about 20 minutes. The granules were milled in a Quadro Comil® mill using a 1143 μm size screen.

  Oxybutynin granules (27.6 g) were mixed with hydroxypropyl methylcellulose (HPMC, Methocel® K15M, 19 g) and compressible sucrose (Nu-Tab® 52.4 g). 1 g of magnesium stearate was added and mixed. The mixture was compressed into tablets using a Manesty f3 single punch tablet press using a 6 mm flat bevel punch to produce tablets weighing about 110 mg and having a hardness of 4 Kp.

B. Non-degradable outer mantle polyethylene glycol (PEG 4000) with a cylindrical surface layer was pulverized and passed through a 500 μm screen. The ground PEG4000 (24 g) was mixed with polyvinylpyrrolidone (Povidone®, PVB K-30, 5 g) and ethylcellulose (Ethocel® 7 cps, 71 g) for 3 minutes. Magnesium stearate (1 g) was added and mixed for an additional 0.5 minutes. The inner core produced above was squeezed into the outer mantle using this mixture and the 9 mm outer cylindrical spring loaded core rod tool described above. The diameter of the core rod was 4.5 mm. The upper punch has a protrusion with a diameter of 5 mm and a height of 1.2 mm that tapers to 4.5 mm on the upper surface. The final product, an annular coated tablet with a back exposed axial surface, had an outer diameter of 9 mm, a total weight of 350 mg, and contained 15 mg of oxybutynin (Formulation A).

C. Drug Release Profile The drug release profile of oxybutynin from the delivery system of Example 1 was measured using 900 ml phosphate buffer (pH = 6.8) in a USP apparatus II degradation tester at 37 ° C. and 50 rpm. The oxybutynin content of the sample was measured by HPLC method with UV detection. Results are reported in Table 4 below and illustrated in FIG.

D. Controlled release by altering the formulation of the inner tablet The above method for preparing an inner tablet was repeated using 30 g Methocel® K15M and 41.4 g Nu-Tab®, Increased the content of gel-forming HPMC and decreased the content of degrading sucrose (Formulation B). The results of the degradation experiment are reported in Table 5 below and illustrated in FIG.

  A significant decrease in drug release was observed in the first 10 hours.

E. Controlled Release by Change in Outer Mantle Formulation The procedure for preparing formulation B was repeated, and the outer mantle contained 14 g PEG4000 and 81 g Ethocel® (formulation C). The results of the degradation experiment are reported in Table 6 below and illustrated in FIG.

  Again, a significant change in drug release rate was confirmed, indicating that the release rate of the active drug substance can be determined by changing the formulation of the inner core tablet or outer ring.

Example 3
Rapidly disintegrating tizanidine tablets for sublingual delivery Sublingual tablets were formed into an inner core of a rapid disintegrating formulation containing tizanidine (2 mg) and an outer annular ring of protective excipients.

Moisture content
A. Inner tablet An inner core was made by mixing tizanidine hydrochloride (4.5 parts) and crospovidone (20 parts) over 2 minutes. Saccharin sodium (0.5 parts), MicrocelLac100 (registered trademark) (73.6 parts) and methanol (0.4 parts) were added and mixed for 3 minutes or more. Magnesium stearate (1 part) was added and mixing continued for 30 seconds. The mixture was compressed on a Manesty f3 tablet press suitable for a 5 mm flat bevel punch. The tablets formed were each 5 mm in diameter, weighed about 45 mg, were about 2 mm thick, and had a hardness of 1-35 Kp.

B. Dissolving outer mantle outer annular ring, Nu-Tab® (48.5 parts), MicrocelLac100® (25 of microcrystalline cellulose and lactose commercially available for direct compression: 75 mixture, 45 parts), sodium saccharin (0.5 part) and sodium crospovidone (5 parts) were mixed over 5 minutes. Magnesium stearate (1 part) was added and mixed for 30 seconds. The mixture was compressed on a Manesty f3 tablet press suitable for the spring loaded core rod tool described above. The total weight of the tablet was 290 mg, the outer diameter was 9 mm, the tablet height was about 4.5 mm and the hardness was 5-9 Kp.

C. Drug Release Profile The drug was tested for total disintegration rate of the internal tablets within 4 minutes of 3 ml of water, and the degradation rate of thiazarin was> 85% in 450 ml of water at 37 ° C. and 50 rpm in 15 minutes in the USP Device II degradation system. there were. The external mantle broke down after about 15 minutes.

Example 4
Release rings of two drugs at different rates can be formulated to contain different drugs and release the drugs with totally different release profiles. The rate of release can be controlled by the core tablet and annular ring formulation and by their geometry. In this case, we used an oval tablet with controlled release of levodopa from the annulus and surrounding either a cylindrical tablet or an inner oval tablet as an annular ring, so that carbidopa immediate release profile in the core tablet Was prescribed. Both the inner core, cylindrical and oval were themselves drilled with cylindrical holes.

A. Cylindrical tablets carbidopa (160 g) were mixed with xylitol (40 g) pre-screened (500 μm screen) in a Diosna p1 / 6 grinder. Water (45 ml) was added as a granulation solution. The mixture was ground at 500 rpm for 5 minutes and further agglomerated at 800 rpm for 1.5 minutes. The granules were air dried overnight at room temperature and milled through a 1.6 mm screen while slightly wet. The ground granules were dried in a fluid bed dryer at 40 ° C. for 30 minutes and ground through a 0.8 mm screen. 56.3 g of this granule was mixed with crospovidone (10 g) and MicrocelLac100® for 3 minutes. Magnesium stearate (1 g) was added to the mixture and it was mixed for an additional 0.5 minutes. The mixture was compressed in a Manesty f 3 single punch tablet press using three different core rod punches to produce hollow cylinders with the following dimensions.
that is:
Formulation D: outer diameter of cylinder 7.5 mm, inner diameter 2.5 mm,
Formulation E: Cylindrical outer diameter 7.0 mm, inner diameter 4.6 mm,
Formulation F: Egg-shaped outer diameter 12 × 6 mm, inner diameter 3 mm
It is. Each tablet contains 54 mg carbidopa.

B. Drug-containing, non-degradable, egg-shaped external mantle levodopa (150 g) was mixed with xylitol (75 g) and hydroxypropyl methylcellulose (Klucel® LF, 25 g) at 500 rpm for 5 minutes. Ethanol (50 ml) was added slowly and the granules were molded at 500 rpm for 1.5 minutes. The granules were air dried overnight at room temperature and milled with a 0.8 mm screen.

  Levodopa granules (44.4 g) are mixed with ethyl cellulose (Ethocel® 7 cps, 30 g) and Cellactose® (powdered cellulose for direct compression: 25:75 mixture of lactose, 24.6 g) for 3 minutes. Mixed. Magnesium stearate (1 g) was added and mixed for an additional 0.5 minutes.

  Pre-formed internal tablets, Formulations D, E and F were prepared by using an egg-shaped spring loaded core rod punch as described above (with dimensions 17.6 x 8.8 mm, 5 mm diameter internal core rod) and upper punch (front Were compressed into an egg-shaped core on the radial surface using a rim of 4.5 mm, with a projection of 1.8 mm in height and 5 mm in diameter. The total weight of each tablet was 750 mg and contained 200 mg levodopa.

C. Drug release profile degradation was performed in 0.1N HCl (900 ml) at 37 ° C. in a USP instrument II degradation tester at 50 rpm, and the concentration of levodopa and carbidopa in each sample was determined by HPLC. The results of the degradation experiment are provided in Tables 7, 8 and 9 and illustrated in FIGS.

  Thus, two drugs with totally different release profiles can be delivered by independently controlling the release rate of each drug. It should be noted that this control can be achieved by determining the shape and size of the core tablet, for example, by not necessarily changing the formulation, but by providing a hole of a predetermined size or shape.

Example 5
An annular coated tablet for masking flavor
A. Internal tablet Sumatriptan succinate (70 parts) was coarsely pulverized with microcrystalline cellulose (Avicel® PH101, 80 parts) in water (20 parts). The granules were dried in a fluid bed dryer at 40-50 ° C. for 30 minutes and ground through a 0.8 mm screen. Granules (75 parts) with anhydrous lactose (9 parts), microcrystalline cellulose (Avicel® PH101, 10 parts) and sodium croscarmellose (AC-DI-SOL®, 5 parts) for 3 minutes Mixed over. Magnesium stearate (1 g) was added and mixed for an additional 0.5 minutes. Tablets were pressed using a Manesty f3 single punch tablet press using a 6 mm flat bevel punch. The tablet weight is 100 g and contains 25 mg equivalent of sumatriptan.

B. A mixture of degradable external mantle compressible sucrose (Nu-Tab®, 94 g), microcrystalline cellulose (Avicel® PH102, 5 g) and methanol (1 g) were mixed over 5 minutes. . Magnesium stearate (1 g) was added and the mixture was mixed for an additional 30 seconds.

  Tablets were formed using the inner core described in Example 4, above, and the 9 mm outer cylinder spring loaded core rod tool described above. The obtained tablet is a cylindrical tablet, has an outer diameter of 9 mm, and the shaft surface is not covered and retracted from the surface layer. The total tablet weight was 475 mg.

  The release profile of the tablets was measured on a USP apparatus II disintegration tester at 900 ° C. in water at 37 ° C. and 50 rpm. This tablet is expected to provide more than 80% drug release in 30 minutes.

  The invention has been described with reference to certain preferred embodiments, and other embodiments will be apparent from this description to those skilled in the art to which the invention relates. It is intended that the specification be intended as exemplary only, with the scope and spirit of the invention being indicated by the following claims.

FIG. 2 is a partial perspective, side view, and lower view of a solid dosage form with a core tablet with an active ingredient retracted within a compressed annulus of powdered or granular material according to the present invention. It is a perspective view of the single station tablet press which installed the tool set. It is a sectional side view of a cylindrical punch and a punch assembly. 4a-4e are side cross-sectional views depicting the stages in the operational cycle of a tableting station with the tool set of the present invention, from the delivery of powdered or granular material to the removal of the finished tablet. 1 is a plot of the average rate of alendronate excretion in urine of a human who has taken a dosage form of the present invention containing 70 mg monosodium alendronate and a prior art 70 mg monosodium alendronate dosage form. FIG. 4 is a plot of the release rate of oxybutyrin from a dosage form of the present invention, where the release rate is maintained at 3% h ⁻¹ and 12% h ⁻¹ over 7 hours. 2 is a plot of the release rate of oxybutyrin from a dosage form of the present invention. The proportion of hydrogel in the core tablet was increased compared to the dosage form that produced Figure 6, resulting in a decrease in the maximum rate of release and an extended release of 3% to 12% per hour over about 12 hours. 2 is a plot of the release rate of oxybutyrin from a dosage form of the present invention. The percentage of release-inhibiting hydrogel in the annulus is increased compared to the dosage form that produced FIG. The maximum rate of release was further reduced to 7% h- ¹ . 2 is a plot of the release rate of carbidopa from a core tablet of the dosage form of the present invention and levodopa from a ring. The core tablet has a cylindrical shape, and the annular body has a hole with a diameter of 2.5 mm throughout. 2 is a plot of the release rate of carbidopa from a core tablet of the dosage form of the present invention and levodopa from a ring. The core tablet of this dosage form has a 4.6 mm hole larger than the dosage form that produced FIG. 9, resulting in a larger surface area and faster carbidopa release rate. 2 is a plot of the release rate of carbidopa from a core tablet of the dosage form of the present invention and levodopa from a ring. The dosage form that produced this figure has an oval core tablet with a 3 mm hole throughout, resulting in a release similar to a cylindrical core tablet with a 2.5 mm hole (FIG. 9).

Claims (39)

  A pharmaceutical dosage form for oral administration to a patient comprising a core tablet comprising an active ingredient contained in a ring of compressed powdered or granular material, wherein the active ingredient is the core tablet From about 3% per hour to 12% per hour for over 7 hours.   The pharmaceutical administration according to claim 1, wherein the active pharmaceutical ingredient is selected from the group consisting of oxybutynin, alendronate, carbidopa, levodopa, tizanidine, sumatriptan and pharmaceutically acceptable salts and solvates thereof. Form.   The pharmaceutical dosage form according to claim 2, wherein the active pharmaceutical ingredient is oxybutynin.   The pharmaceutical dosage form of claim 1, wherein the core tablet further comprises hydroxypropylmethylcellulose and a compressible sugar.   The pharmaceutical dosage form according to claim 1, wherein the cyclic body comprises solid polyethylene glycol, polyvinyl pyrrolidone and ethyl cellulose.   The pharmaceutical dosage form of claim 5, wherein the polyethylene glycol is polyethylene glycol 4000.   The rate at which oxybutynin is released from the core tablet is measured in a United States Pharmacopeia standard apparatus II solution tester in an aqueous solution buffered to 6.8 with an agitation rate of 50 rpm at 37 ° C. Pharmaceutical dosage form.   2. The pharmaceutical dosage form of claim 1, wherein the active ingredient is released from the core tablet at a rate of 3% per hour to 12% per hour over 10 hours.   A pharmaceutical dosage form for oral administration to a patient comprising a core tablet containing an active ingredient contained in a ring of compressed powdered or granular material, the active ingredient being the core A pharmaceutical dosage form that releases about 90% or more from a tablet within about 30 minutes.   10. The pharmaceutical dosage form of claim 9, wherein the release rate is measured at 37 [deg.] C in a United States Pharmacopeia standard device III degradation unit.   10. A dosage form according to claim 9, wherein the active ingredient is monosodium alendronate.   12. The dosage form of claim 11, wherein about 85% monosodium alendronate is released within about 15 minutes.   12. The monosodium alendronate dosage form of claim 11, wherein the core tablet further comprises xylitol and crospovidone.   12. The monosodium alendronate dosage form according to claim 11, wherein the annular body comprises compressible sucrose and microcrystalline cellulose.   A pharmaceutical dosage form for oral administration to a patient, comprising a core tablet comprising an active ingredient contained in a ring of compressed powdered or granular material, suitable for sublingual delivery Pharmaceutical dosage form.   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 about 85% or more of tizanidine is released from the core tablet within about 15 minutes.   18. The tizanidine dosage form according to claim 17, wherein the core tablet further comprises crospovidone, sodium saccharin, microcrystalline cellulose and methanol.   18. The tizanidine dosage form according to claim 17, wherein the ring comprises microcrystalline cellulose, sodium saccharin and crospovidone.   17. The pharmaceutical dosage form of claim 16, wherein the release rate is measured in a United States Pharmacopeia standard apparatus II degradation system at 37 ° C. with 50 rpm agitation.   A pharmaceutical dosage form for oral administration to a patient comprising a core tablet comprising an active ingredient contained in a ring of compressed powdered or granular material, wherein the active ingredient is administered in the oral cavity Pharmaceutical dosage forms suitable for degradation within about 5 minutes   22. The pharmaceutical dosage form of claim 21, wherein the release rate is measured in a United States Pharmacopeia standard apparatus II degradation system at 37 [deg.] C with 50 rpm agitation.   A method for independently controlling the rate of release of a coactive component in one dosage form, comprising a core tablet, wherein the first active component is contained in a compressed annulus of pharmaceutical excipients. Formulating into a core tablet of the dosage form and formulating a second active ingredient into the compressed annulus.   Two active pharmaceutical ingredients for a patient, comprising a core tablet containing a first active pharmaceutical ingredient and containing a second active pharmaceutical ingredient, contained in an annular body of compressed powdered or granular material A pharmaceutical dosage form for co-administration.   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 of claim 25, wherein levodopa is released from the annulus at a rate of 3% per hour to 30% per hour over 3 hours.   27. The pharmaceutical dosage form of claim 26, wherein levodopa is released from the annulus at a rate of 6% per hour to 30% per hour over 3 hours.   27. The pharmaceutical dosage form of claim 26, wherein the time of 3 hours or more begins 1-2 hours after contact of the dosage form with water and the time begins with an initial, more rapid release of carbidopa.   26. The pharmaceutical dosage form of claim 25, wherein the carbidopa is completely released within about 3 hours after the dosage form comes into contact with water.   30. The pharmaceutical dosage form of claim 29, wherein the carbidopa is completely released within about 1 hour after the dosage form is contacted with water.   27. The pharmaceutical dosage form of claim 26, wherein the release rate is measured in a United States Pharmacopeia standard apparatus II degradation tester in 0.1N HCl at 37 [deg.] C with 50 rpm agitation.   25. The pharmaceutical dosage form of claim 24, wherein the core tablet further comprises xylitol, crospovidone, microcrystalline cellulose and lactose.   The pharmaceutical dosage form according to claim 24, wherein the annular body further comprises ethyl cellulose, powdered cellulose and lactose.   A pharmaceutical dosage form for oral administration to a patient comprising a core tablet comprising an active ingredient contained in a ring of compressed powdered or granular material, wherein the active ingredient is taste masked A pharmaceutical dosage form suitable for.   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 about 80% or more of sumatriptan succinate from the core tablet within about 30 minutes.   36. The sumatriptan succinate solid dosage form of claim 35, wherein the core tablet further comprises microcrystalline cellulose, lactose and sodium croscarmellose.   36. The sumatriptan succinate solid dosage form of claim 35, wherein the ring comprises sucrose, microcrystalline cellulose and methanol. 36. The sumatriptan succinate solid dosage form of claim 35, wherein the taste of sumatriptan succinate is masked when the dosage form is held in the mouth.

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