MX2008008569A - Adhesively bonded dosage form - Google Patents

Abstract

A pharmaceutical dosage form that is an adhesively bonded aggregate of preformed subunits that may be conveniently breakable into smaller parts.

Description

ADHESIVELY JOINTED DOSAGE FORM Field of the Invention The invention relates to solid dosage dosage forms comprising sets of preformed subunits that are adhesively bonded together. BACKGROUND OF THE INVENTION It is well known to provide dosage forms such as tablets or capsules for handling pre-measured quantities of materials that allow consumers to use various materials without the need for expensive and cumbersome measuring devices. One reason for the present invention is to allow flexible dosing of one or more drugs. Japanese Unexamined Patent Application Publication H6-9375 of Ito et al., (Hereinafter, "Ito") discloses tablets consisting of smaller "tablet units" (in the present "sub-units" or "tablets"). sub ^ tablet units "or" capsule sub-units ") which are joined by a" cement "that acts as an adhesive. The union part is explicitly established in those cases to be the cement, which is supposed to be breakable although it leaves the unit tablets intact. Leaving aside the practicality of breaking through said joint part with cement either mechanically or by dissolution, the application - - describes the production of smaller tablet structure tablets each comprising tablets of complete units. The request fails to describe tablet sub-units that are not "unit tablets". In addition, the application is specific as to the way of elaboration of said tablets that it describes. Said mode of elaboration consists of the apposition ("coupling") of the tablets of units to be joined and then forming a "joining part" with cement. Said application does not describe the production of said tablets by applying adhesive to an inert sub-unit that is not simultaneously opposite or adjacent to another sub-unit. In addition, because Ito states that the sub-units of said application are "tablets of units", it would not be contemplated to create a mark on a unit tablet, which is in general use, to facilitate the rupture of the tablet. In addition, a mark on a tablet, such as a printed mark, which can also facilitate the rupture of the tablet such as in delineating a bisection part of a tablet sub-unit, similarly would not be implicit in the Ito application. . The present invention uses the term "separation mark" or "separation mark" to indicate an incision, a printed mark or a similar addition to a tablet sub-unit that can guide or facilitate the rupture of the tablet.

The present invention differs more clearly from the descriptions of Ito and the implications of its descriptions, in that said request contemplates whether the dosage forms of its invention are fully ingested or otherwise broken or divided only through the " cement "being the tablet sub-units considered as" building blocks "as indivisible atoms that form a molecule. In contrast, the present invention describes dosage forms that are adapted to break through a sub-unit portion of said dosage forms. Therefore the methods of breaking up said dosage forms of the invention involve breaking through a tablet sub-unit and not through an adhesive (cement). The present invention uses the general term "inert" to describe a tablet sub-unit that lacks any pharmaceutically active ingredient (i.e., a "drug"). "Inert" is proposed to include tablet sub-units that either lack any release-controlled function or have a controlled-release function. The term "inactive" is used to indicate a tablet sub-unit that lacks any pharmaceutically active ingredient and that also lacks any immediate release function. Therefore, any inactive tablet sub-unit is also considered inert, but an inert tablet sub-unit may or may not be inactive. SUMMARY OF THE INVENTION The present invention relates to new dosage forms and methods for their preparation, more to methods for breaking such dosage forms and to the administration of a separate part of said dosage form. The invention provides a solid pharmaceutical dosage form comprising a plurality of adhesively linked subunits. Said dosage form contains at least one or more of the following: A. (i) a first inert tablet sub-unit and (ii) a second active sub-unit; B. (i) a first tablet sub-unit with a pharmaceutically inactive layer in which said layer has a mass of at least 20 mg and (ii) a second sub-unit; C. a separation mark on a tablet sub-unit; or D. (i) a first tablet sub-unit and (ii) a second capsule sub-unit. The dosage forms consist of a suitable adhesive substance interposed and linking (or, "connecting" or "linking") a plurality of preformed subunits, preferably tablets but possibly involving one or more capsule sub-units. The invention differs from the Ito description in which the present invention involves at least one of the following novel aspects: A. In a preferred embodiment, dosage forms containing at least one tablet sub-unit with an active drug ("active subunit"). ) and at least one tablet sub-unit made solely from pharmaceutically inactive material ("inert tablet sub-unit") are described herein, while Ito only describes an exemplary placebo tablet made solely from inactive subunits; B. In another preferred embodiment, the dosage forms contain two or more active sub-units adhesively joined together wherein at least one of the active sub-units has a separation mark that is preferably an incision; C. In another preferred embodiment, the dosage forms have two or more active sub-units adhesively bonded to one or more inert tablets and in said embodiment, a separation mark such as an incision is optional. D. In another embodiment, a capsule sub-unit can be adhesively attached to a tablet sub-unit; or E. In another preferred embodiment the invention involves a dosage form comprising a plurality of active units, each attaching an inert sub-unit that can be easily broken without damaging any sub-unit. active An inactive tablet sub-unit of a dosage form of the invention is preferably adapted to be disrupted, such as a tablet sub-unit that is provided with a separation mark that can be an incision; such sub-unit may optionally be an active or inactive sub-unit. An active tablet sub-unit may also be adapted to be conveniently broken and may be provided with a separation mark such as an incision. An active subunit herein contains a pharmacologically effective amount of a drug or drugs. Hereby the terms "drug", "active drug", "active pharmaceutical ingredient" or "active ingredient", "active pharmaceutical compound" and the like herein include not only pharmaceuticals such as those found in the United States. regulated by the Food and Drug Administration, but also include vitamins and minerals. In many cases, an inert sub-unit will join two separate active sub-units. The term "inert tablet sub-unit" as used herein means a structural unit made on a tabletting apparatus wherein the structural unit contains pharmaceutically acceptable materials, e.g., excipients, diluents, fillers etc. which have no detectable pharmacological effects in the amounts used in the dosage form. When the term "inactive sub-unit" is used, is used to describe a subunit that has no detectable pharmacological effects and has no controlled release function. The invention provides a method for accurately providing a predetermined part of a dosage form for administration, as well as for providing a complete dosage form. Preferably but not always, the breaking of a sub-unit of the invention will not involve breaking, damage, dissolution, etc. of the adhesive bond between the sub-units. The invention contemplates that a use of a dosage form may involve breaking through two or more sub-units which also involves breaking through a separate portion of the adhesive bond between them. The invention also includes a method for administering a portion of an active subunit of a solid pharmaceutical dosage form by rupturing said pharmaceutical dosage form through an active sub-unit to obtain a part comprising a sub-unit. active unit and then orally administer the part that has the active sub-unit to a patient in need of it.

A further embodiment is directed to a method of administering an active subunit of a dosage form having at least two active subunits adhesively bound to an inert tablet sub-unit by first breaking said sub-unit of Inert tablet to form two parts each comprising an active sub-unit and a portion of said separate inert sub-unit and subsequently administering one of said parts to a patient or other appropriate host. Dosage forms and parts formed by disruption are proposed to be administered whole, such as orally. Other means of delivery are also contemplated, such as through a naso-gastric tube or gastrostomy tube or per rectum. The invention contemplates the grinding of a part of a whole dosage form that has been formed by breaking by the methods of the invention, so that administration via a feeding tube and the like can be conveniently achieved. The invention further includes a method for making a solid pharmaceutical dosage form by: (a) first, applying adhesive to a first active sub-unit or first inert sub-unit; and (b) second, contacting said first active or inert sub-unit containing the adhesive, with a second sub-unit of active or inert tablet (which optionally may also have 'adhesive applied) and optionally apply pressure to the sub-units. It will be appreciated that no limitation is established on the nature, content, active or inactive ingredients, size or shape of any of the subunits or the final dosage form, except that the final dosage form must be safe for use. and is more preferably capable of being assimilated by the body (eg, ingested) by the proposed user. The invention uses substance (s) with sufficient adhesive capacity to allow the subunits to adhere to each other to form a cohesive dose form. For commercial use, preferably said dosage forms will remain intact through the processing and transport phases until they reach the patient, nurse, pharmacologist, etc. These novel dosage forms have many modalities and may comprise many different arrangements, many different forms, types of active ingredient (s), types of inactive ingredient (s), number of subunits, etc. , without any limitations. The examples representing the embodiments of the invention are given herein to exemplify but not to limit the number of useful possibilities that are within the scope of the invention.

Accordingly, it is a primary objective of the invention to provide a novel pharmaceutical dosage form containing one or more active or inactive ingredients in more than one active sub-unit separately produced which is adhesively bound to an inert binding sub-unit wherein said dosage form can be separated into two or more parts by breaking said dose unit at a location or locations within the active subunit to provide a predetermined amount of a drug or drugs contained therein. dosage form. It is also an object of the invention to provide a novel pharmaceutical dosage form containing one or more active or inactive ingredients in more than one active sub-unit separately produced which are adhesively bonded to an inert sub-unit where said dosage form can be separated into two or more parts by breaking said dose unit at a location or locations within the inert subunit to provide a predetermined amount of a drug or drugs contained in said dosage form. It is also an object of the invention to provide a novel pharmaceutical dosage form containing one or more active or inactive ingredients in more than one separately produced active sub-unit that adhesively bonds to an inert sub-unit wherein said form of The dose can be separated into two or more parts by breaking said dose unit at a location or locations within the inert subunit to provide a predetermined amount of a drug or drugs contained in said dosage form. It is also an object of the invention to provide a novel pharmaceutical dosage form containing one or more active or inactive ingredients in more than one separately produced active sub-unit that is adhesively bound to an inert binding sub-unit. wherein said dosage form can be separated into two or more parts by breaking said dose unit at locations within one or more of the active subunits and within the inert binding subunit to provide a predetermined amount of a drug or drugs contained in said dosage form. These and other objects of the invention will be apparent from the present specification. A "sub-unit" is a preformed structure classified herein as either an active sub-unit, a sub-unit of capsule or inert tablet sub-unit or an inactive tablet sub-unit. Materials such as adhesive substance (s) or film such as hydroxypropyl methylcellulose which can be used to coat a subunit, are not considered by themselves as sub-units. "Preformed" refers to the separate production of a sub-unit. A tablet sub-unit of a dosage form of the invention is produced as a tablet and is transformed into a sub-unit when it is part of the dosage form of the invention. Similar considerations apply to the capsule sub-unit of the invention. The tablet sub-units of the invention may be stratified structures as is well known. The invention may comprise a pharmacologically inactive layer of a tablet comprising a plurality of layers to serve as a breaking point and thus said pharmacologically inactive layer can serve a similar function in the invention as the inert tablet sub-unit does. Preferably said inactive layer has a mass of at least 20 mg and more preferably 50-900 mg; or 150 mg-750 mg or 400-600 mg; a volume of at least 10 cubic mm and more preferably 25 cubic mm; and / or a length along the longest axis of the dosage form of at least 1 mm and more preferably 2 mm. Therefore said inactive layer can play a role in the sub-division of the dosage form by serving as a rupture region. "Tablet" and "capsule" are defined in their usual ways. Active subunits may contain one or more drugs.

- - As used herein, "pharmaceutical dosage form" refers to a solid dose form containing two or more sub-units adhesively bonded together. The preferred solid dosage form is an oral dosage form. BRIEF DESCRIPTION OF THE DRAWINGS All the drawings represent dosage forms of the invention in which the adjacent sub-units are adhesively bonded. All views are external views. Figure 1 is a top plan view drawing of the dosage form of the invention representing three sub-units. Figure 2 is a schematic top plan view of a coin-shaped dosage form having three sub-units one of which contains an incision. Figure 3 is a schematic top plan view showing four active sub-units each linked by an adhesive substance to an inert tablet sub-unit. Figure 4 depicts five tablet sub-units, two of which adhesively join each other three sub-units. Figure 5 is a schematic top plan view showing a dosage form of the present invention in the form of a capsule. The inert tablet sub-unit has two incisions each containing a preformed active sub-unit. Figure 6 is a schematic side view which represents a dosage form consisting of three active tablet sub-units adhesively bonded with incisions. Figure 7 is a schematic side view depicting a dosage form consisting of three sub-units of active tablet each of which is adhesively bonded to two inert tablet sub-units. Figure 8 is a schematic top plan view of a dosage form of three subunits. Figure 9 is a schematic top plan view of a dosage form of four active sub-units in which the four active sub-units are adhesively bonded together. Figure 10 depicts a side view of a dosage form containing four tablet sub-units. Figure 11 depicts a dose form with five subunits. Figure 12 depicts a dosage form with three sub-units adhesively bonded together. Figure 13 represents a dose form with three tablet sub-units, none of which contains incisions. Figure 14 depicts a dosage form with three sub-units one of which contains an incision. Figure 15 is an exploded representation of a dosage form of two subunits, one of which is a three layer tablet sub-unit. Figure 16 is a partially exploded perspective view of a dosage form having two active subunits, one of which is a tablet sub-unit and one of which is a capsule sub-unit and a sub-unit. Inert tablet unit. Figure 17 is a perspective view of a partially exploded dose form having four active subunits and an inert tablet sub-unit joining said active subunits. Figure 18 is a perspective view of a partially exploded dose form having two active subunits and an inert tablet sub-unit with incision marks located in the inert tablet sub-unit. DETAILED DESCRIPTION OF THE INVENTION The invention contemplates that an active sub-unit comprises a drug or drugs, that a sub-unit of capsule is an active sub-unit (excepting the placebo formulations for clinical trials and the like) and that inert tablet sub-units lack drugs. The dosage forms of the invention can be made by joining individual tablets or capsules which are formed in any desired configuration by means such as the use of tablet dies or matrices (tablets) or encapsulating equipment (capsules). Said methods of elaboration are not limiting. The joining method involves material (s) with adhesive properties. Additionally, there may be materials with non-adhesive characteristics between the sub-units. Dosage forms may comprise active subunits and sub-units of inert tablet having a plurality of various cross-sectional shapes, including, without limitation, round, semi-round, quarter-round, round, trapezoidal, triangular, rectangular, etc. tablets. ., that are adhesively linked together. In a preferred embodiment of the invention, the active subunits and / or capsule sub-units can be separated from one another in a convenient manner by the end user, a nurse, pharmacologist, etc., without harming the function of said sub-units. It is preferred that such non-harmful separation of at least one active sub-unit (with or without a potion of the inert tablet sub-unit) of the dosage form be possible. performed manually; however, there may be cases in which manual separation is inconvenient or impossible without damaging one or more sub-units. In such cases it is within the scope of the invention that there may be convenient mechanical means of separating at least one sub-unit from the entire dosage form, using implements such as a commercially available tablet cutter, a kitchen knife. , etc., It is also within the scope of the invention that, because the invention contemplates dose forms comprising sub-units with a variety of forms, with some dosage forms containing more than two sub-units, it is not convenient to use a standard tablet cutter and it may therefore be desirable to create a tablet cutter specifically adapted for the specific dosage form to optimize the ease of separation. of the sub-unit without harm. By using the methods of the invention, pharmaceutical dosage forms containing two or more separate subunits can be made. In general, an effective amount of an adhesive is used to join any two surfaces together. No limitation is proposed as to the amount of adhesive required. The amount of adhesive needed depends on multiple factors, such as size and density of the dosage form. In general, a minimum amount of adhesive is preferable. Generally, the amount of adhesive may comprise from 0.1 to 5 mils dispersed on more or less an area of about 0.5 to 100 square mm adhesive, depending on the size and area of the particular tablet and the number of the surfaces to be joined together. In the case of veterinary dosage forms, such areas can be significantly increased. Figure 1 is a schematic side view of the invention depicting two active sub-units, 52 and 54, respectively, joined by an inert tablet sub-unit 56. An adhesive joins the active sub-unit 52 with one side of the inert tablet sub-unit 56 and also joins the active sub-unit 54 to the other side of the inert tablet sub-unit 56. The active sub-units 52 and 54 are conveniently separable from each other by, for example, cutting through of the inert tablet sub-unit 56o holding the active sub-units 52 and 54 and applying a force centered on the inert tablet sub-unit 56, including the rotating die or perpendicular force. The active subunits 52 and 54 are substantially identical. The figures are not necessarily drawn to scale and are not intended to limit the size or shape of the dosage form or some subunit. The inert tablet sub-units such as sub-unit 56 in the Figure may generally having a mass greater than 20 mg or more preferably from 50 mg to 900 mg or even more preferably from 150-600 mg or even more preferably from 400-500 mg. The length and thickness will be selected ensuring that the dosage form can be fully administered, although being strong enough to avoid undue amounts of rupture during packing, shipping or handling. As shown in Figure 2, a dosage form that is circular (in the form of a coin such as in the form of a 10 cent coin) is shown in a top plan view having the active tablet sub-units 62 and 6 , which are each attached to an inert tablet sub-unit 66 with an incision 68. The inert tablet sub-unit 66 can be conveniently broken in a manual or mechanical manner without damaging either the active sub-unit 62 or active sub-unit 64. Optionally also a dosage form of this form may have one or both active tablets with incisions. Figure 3 depicts four active sub-units, 72, 74, 76 and 78 joined by an adhesive substance to an inert tablet sub-unit element 79 which, if broken, can provide one or more subunits to be ingested. Figure 4 is a drawing showing three active sub-units, 80, 82 and 84, none of which is connected to each other, but all of which are connected to each other. they are connected to the inert tablet sub-units 85 and 86 at opposite ends of the active sub-units. The breakdown of the dosage form through the inert subunits can be achieved without damaging any active subunit. A similar design is not shown in which the active sub-units are only attached at one end to an inert tablet sub-unit. In practice, spaces 87 and 89, between the active sub-units, may be smaller than those shown. Figure 4 does not exclude the possibility that active sub-units sorted in this way may in fact be touched. Figure 5 is a drawing of a dosage form comprising three subunits. The active subunits 92 and 94 are adhesively bonded to indentations (depressions) 92A and 94A that are formed in sub-unit 90. Sub-unit 90 may be an active sub-unit containing an ingredient (s). s) or sub-unit 90 can also be an inert tablet sub-unit. Dosage forms similar to those of Figure 5 can be made in a variety of shapes with indentations or depressions. The entire dosage form is ingestible. The dosage form can be broken in the incision 96 to separate the active subunits in the dose form into two parts. As shown in Figure 6, a dosage form of the invention may comprise a multi-layer array stacking of substantially flat active sub-units 8, 10 and 12 containing, respectively, score marks 5, 7 and 9 and which are adhesively bonded together with small amounts of adhesive 6 to form a layered structure. Figure 7 shows a dosage form in which three active subunits 14, 16 and 18 are held together with inert tablet sub-units 20 and 22 which are adhesively bonded to one side of each of the sub-units. active units. Although Figure 7 shows two inert tablet sub-units on the side of the tablets, it is possible to use only one, two or a plurality of inert tablet sub-units that can be placed to form a stable and useful dosage form. Figure 8 depicts a top plan view of a dosage form having an inert tablet sub-unit 34 joining ends 36 and 38 containing active ingredients. Lines 40 and 43 represent the adhesively bonded edges of the active subunits. If desired, it is convenient to break through the inert tablet sub-unit without affecting any of the active sub-units. Figure 9 shows a top plan view of a dosage form of four active sub-units that was made by adhesively joining the segments 24, 26, 28 and 30, each of which contributes 90 ° of the arc to the final shape of the dosage form. This dosage form is particularly useful when it is desirable to simultaneously administer several different active drugs. The incision 27 bisects approximately the sub-unit 30 and the incision 29 bisects approximately the sub-unit 26. The dosage form is therefore conveniently divisible through both incisions, which form a continuous linear indentation through the form of dose. The adhesive 6 which is the same type of adhesive used in Figure 6, joins the sub-units together. Figure 10 shows a drawing of a dose form of three active sub-units in which an external active sub-unit 100 is bonded with a layer of adhesive 101 to an intermediate active sub-unit 102. The external sub-unit 104 is adhesively bonded to an inert tablet sub-unit 103, which is adhesively bonded to an intermediate active sub-unit 102. Figure 11 is a drawing of a dosage form of three active sub-units in which the external active sub-units 105 and 109 are each adhesively bonded to inert tablet sub-units 106 and 108, respectively, said inert tablet sub-units being adhesively bonded to an intermediate active sub-unit 107.

Figure 12 shows a drawing of a dose form of three active sub-units in which the active sub-unit 110 is attached with adhesive 111 to the intermediate active sub-unit 112. The active sub-unit 114 is found attached with adhesive 113 to intermediate active sub-unit 112. Figure 13 shows the sub-unit of inert tablet 116 adhesively bonded to active sub-units 115 and 115A. The active subunits contain the same drug. The dosage form can conveniently be broken between the sub-units 115 and 115A through the sub-unit 116. Figure 14 represents the inert tablet sub-unit 118 with an incision that is between different active sub-units 120 and 120A, facilitating the rupture of the tablet when desired. Figure 15 depicts in an external view a dosage form consisting of two tablet sub-units adhesively bonded together in the inferno 308 comprising an adhesive substance. The tablet sub-unit consisting of the layers 300, 302 and 304 is produced separately on a three-layer tablet press. The vertical lines between layers 300 and 302 and between layers 302 and 304 represent the interfaces between the layers that are all of different colors. Layer 300 contains a therapeutic amount of amlodipine besylate (amlodipine) and layer 304 contains a therapeutic amount of chlorthalidone. Layer 302 is formed from an inactive granulation and, due to mixing between the layers in the tablet formation process, contains pharmacologically inefficient amounts of both amlodipine and chlorthalidone. Said tri-layer tablet which is a subr unit of the dosage form shown in Figure 15 is first produced by allowing a granulation containing amlodipine and suitable excipients in the matrix, then tampering; then allowing a granulation without an active ingredient in the matrix, then tampering, then allowing the granulation containing amlodipine in the matrix, then pre-compressing and then fully compressing to form a coherent tablet. The upper punch is chamfered and the lower punch is flat. Tablet sub-unit 306 contains benazepril and is produced separately in a conventional manner. The sub-unit 306 is adhesively bonded to the tri-layer tablet described above with shellac. An advantage of the dose form shown in Figure '115 is that a tri-layer tablet as described above, (layers 300, 302 and 304) can be used to produce the most complex dose form of three active drugs of the Figure 15 while retaining the capacity of the dosage form is broken through layer 302 and producing two useful dosage forms. One dosage form would contain only a therapeutic amount of amlodipine and the other would contain only therapeutic amounts of chlorthalidone and benazepril. Numerous other variants of the design of the dosage form depicted in Figure 15 may be used in the present invention. Figure 16 is a partially exploded perspective view of a dosage form consisting of a part 203 adhesively attached to the subunit. 208. Sub-unit 200 in this example is a capsule sub-unit. Part 203 contains sub-unit 200 and inert tablet sub-unit 204. The length of sub-unit 204 relative to the other sub-units makes it relatively easy to break through it. Figure 17 represents a external view of a dosage form containing four active sub-units of tablet which are all adhesively bound to a sub-unit of binding tablet 218 which is inactive. The sub-units 210, 212, 214 and 216 are all active. In the present example, each of said active subunits contains a therapeutically effective amount of a different drug. In the modalities alternatives two or more active subunits may contain the same drug. Note that tablet sub-unit 214a is shown in its correct position in the dose form of Figure 17 and is also shown in an exploded view in transparency as 214b. Figure 18 depicts an external, partially exploded view of a dosage form containing part 234 comprising an inactive dual-cut tablet sub-unit 227, interface 230, tablet sub-unit 232, and lacquer wax layer 224; and the tablet sub-unit 220. The upper incision 226 and the lower incision 228 are created manually with a file. The indentations 226 and 228 adapt the tablet sub-unit 227 to break more easily than if the incisions were not present. Optionally, sub-unit 227 may be a sub-unit of active tablet with incisions. Tablet sub-units that are adhesively bonded together can be made using techniques such as those used in the pharmaceutical industry to produce conventional tablets. These techniques include, without limitation, wet granulation methods, granulation techniques in, such as compression and grinding; or direct compression powder mixtures.

PHARMACEUTICAL USES Generally, many forms of useful solid doses can be usefully produced by the methods of the invention. There are numerous practical advantages in the invention. These include, without limitation: A. There will be no need to co-formulate different products when it is desired to combine them in a dosage form. The methods of the invention will not only save time and money in such development, but such savings will facilitate the initiation of tests of combination therapies. The annoying problem of incompatibilities between different formulations will no longer be limiting. Also numerous other physical and chemical considerations will no longer be limiting. B. Two or more doses of the same drug product can be produced separately, then joined as tablet sub-units or capsule sub-units. If they are carefully separated from one another, then a more accurate dosage will be available than those that can currently be achieved with conventional incision tablets. With respect to the two capsules attached, there is currently no product marketed in the United States that provides the ability to separate a capsule dosage form into two capsule sub-units. C. the invention allows a tablet and a capsule bind together in a dosage form, which improves the pharmaceutical technique in a novel and potentially important manner. D. Acceptance of combination therapy by physicians and patients as well as acceptance by academics, government, regulatory bodies and society in general can be improved by allowing flexibility in the dosing of combination products following the methods of the invention. E. The invention is well suited to the formulation of combination drug products, i.e., dosage forms containing two or more active ingredients. When the dosage forms of the invention comprise more than one active drug, the dosage forms of the invention may provide a convenient way to improve patient acceptance with respect to dosing regimens while at the same time minimizing formulation problems. These benefits are in addition to the advantage of being able to discontinue therapy with one or more drugs by removing one or more subunits that contain a particular drug from the dosage form. An additional benefit is the simplification of the prescription and supply of multiple individual drug products. F. Patients allergic to a member of the combination product can separate some modalities of the invention and ingest a combination tablet drug, something that is currently not possible to perform safely. The invention provides a method for making a dosage form of a combination of different drugs wherein the different drugs can be separated from the combination without any trace amount of another drug in combination with other drugs being present. For example, when multi-layer tablets are formed on a multi-layer tablet press, it is difficult or almost impossible to exclude all traces of granulation for one layer and prevent them from appearing in a compressed layer of another granulation because the air currents and vibration that cause the granulations to disperse or form aerosol-like dispersions in the area where the granulations are fed into the matrices on the multi-layer press. The present invention allows the separate components of the combination dosage form to be formed into separate tablets and adhesively bound in such a manner that there is no cross-migration of the individual drugs between the separate active units in a dosage form in accordance with the present invention. Therefore when the active subunits are obtained apart from the dosage form of the invention, there is no cross-contamination of the drugs individual This is particularly important when patients are allergic to a particular drug. As mentioned above, the invention contemplates that solid dosage forms can generally benefit from the teachings of the invention. The following are some specific examples of the products that can be combined in any way. Some useful combinations of drugs are, with examples in parentheses: Combinations of anti-anginal agents. These include any combination of the following classes of drugs: A. Calcium channel blocking agents (salt of amlodipine, diltiazem, lercanidipine) B. Beta-blocker (atenolol, metoprolol, propranolol) C. Preparation of organic nitrate (mononitrate or dinitrate) of isosorbide); Combination of anti-anginal agent (see above) with an anti-platelet agent, such as aspirin or clopidogrel; Combination of any of two hypoglycemic agents; Combination of potassium salt (preferably KC1) and any thiazide-type or loop-type diuretic; Combination of hypolipidemic agent with any of a variety of representative classes of drug: hypoglycemic agent, anti-platelet agent, anti-anginal agent, organic nitrate, antihypertensive agent: The hypolipidemic agent may be a: Statin (simvastatin, atorvastatin with or without torcetrarib, rosuvastatin, lovastatin, rosuvastatin, fluvastatin), a fibrate (fenofibrate, gemfibrozil, bezafibrate, ciprofibrate, clofibrate) or a member of other classes (niacin, ezetimide, acipimox) Hypoglycemic agents: Thiazolidinediones: Pioglitazone, rosiglitazone Sulfonylureas: Glyburide, glipizide, glimepiride, chlorpropamide Biguanides: Metformin Meglitinides: Nateglinide, repaglinide Glucosidase inhibitors: Acarbose, miglitol; A member of two or more of the following three classes: A. Diuretic (HCTZ, furosemide) B. Digoxin (and other cardiac glycosides) C. Beta-blocker approved for treatment of congestive heart failure (metoprolol, carvedilol); The combinations of two or more antihypertensive agents, more preferably a member of the different classes as described below: beta-blockers: acebutolol, atenolol, bisoprolol, celiprolol, metoprolol, mebivolol, carvedilol (a mixed alpha-beta blocker), nadololoxprenolol, penbutolol, pindolol, propranolol, timolol, betaxolol, carteolol. Calcium channel blockers (calcium channel blockers): Nifedipine, amlodipine, verapamil, diltiazem, nisoldipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, manidipine Thiazide-type diuretics (with or without potassium-retaining diuretics such as triamterene, amiloride or spironolactone: Hydrochlorothiazide, chlorothiazide, cyclopentiazide, polythiazide, bendrofluazide, hydroflumethiazide, chlorthalidone, indapamide, methylclothiazide, metolazone. convert angiotensin: Captopril, enalapril, lisinopril, ramipril, trandolapril, quinapril, perindopril, moexipril, benazepril, fosinopril Angiotensin receptor blockers: losartan, valsartan, candesartan, telmisartan, eprosartan, irbesartan.

Maximum limit diuretics (loop) (with or without diuretics that retain potassium such as triamterene, amiloride or spironolactone): Furosemide, torsemide, ethacrynic acid, bumetamide Aldosterone antagonist diuretics: Spironolactone, eplerenone Alpha blockers: Doxazosin, terazosin, prazosin, indoramin, labetolol (a mixed alpha-beta blocker) Central alpha agonists: Clonidine, methyldopa Imidazoline: oxonidine Direct vasodilators: Hydralazine, minoxidil Adrenergic neuron blocker Guanethidine. It will be appreciated that certain combinations, such as a beta blocker and a diuretic, are more preferable than others, such as verapamil and a beta blocker or furosemide and hydrochlorothiazide. The same goes for other combinations. In addition to the above, many products benefit from an exact separability, such as in half doses, quarters of doses, etc. Some prominent examples that may benefit more than most include drugs with narrow therapeutic index. Examples of these are the sodium of warfarin and other coumarins, L-thyroxine and digoxin Other examples that I know. They especially benefit from being formulated to be exactly separated when desired such as vasoactive drugs such as calcium antagonists and beta-blockers. For example, many if not all of the drugs listed above with respect to the combinations can be usefully formulated by the invention and could then be the only active drug in a dosage form of the invention. Therefore, a large number of single drug products can be precisely separated from one another by the invention; a drug product can also be placed in combination, together in a subunit and thus accurately separated as a fixed dose combination. In the foregoing, no limitation is proposed regarding the number of sub-units or any of the instructional examples provided. No limitation is proposed with respect to the many examples of useful combinations of dose subunits that may benefit from this invention. Numerous other monoagents, in addition to those listed above, can be formulated alone or in combination with other drugs using the methods of the invention. PREPARATION Preferred adhesive substances include, without limitation, the following: In addition, suitable adhesive materials can be selected from the following list: As synthetic adhesives, the following specific examples may be cited. • As thermosetting resin adhesives, the types of gum reaction of urea resin, melamine resin, phenol resin, epoxy resin, polyester resin, polyimide resin and the like. • As thermoplastic resin adhesives, the types of solvent vaporization of acetate resin solvent-type vinyl, emulsion-type vinyl acetate resin, vinyl chloride-vinyl acetate copolymer resin, nitrocellulose, acryl-vinyl acetate copolymer resin, ethylene-vinyl acetate copolymer resin and the like; the types of chemical reaction of cyanoacrylate, anaerobic acrylic resin, urethane resin and the like; the refrigerant types (hot melt) of ethylene-vinyl acetate copolymer resin, polyamide, polyester and the like; the type sensitive to the pressure of acrylic resin and the like. • As synthetic rubber adhesives, the types of solvent vaporization of chloroprene rubber, nitrile rubber, recovered rubber, latex and the like; the type of chemical reaction of urethane rubber, and the like; the refrigerant type (hot melt) of polystyrene-polyisoprene-polystyrene block copolymer and the like; the types sensitive to the pressure of butyl rubber, polyisobutylene rubber, silicone and the like. • As polymer-alloy adhesives, the reaction-chemistry types of vinyl-phenolic, phenolic-rubber, epoxy-phenolic, nylon-epoxy, nitrile-epoxy and the like. As natural adhesives, the following specific examples can be cited: • The types of solvent vaporization of starch, casein, dextrin, gum arabic and the like; the refrigerant types (hot melt) of asphalt, glue, rosin and similar; and the pressure-sensitive types of conjugated polysaccharides, natural rubber and the like. As adhesives, the following specific examples can be cited: • As rubber adhesives, blends of adherents, softeners, antioxidants and the like with elastomer. • As acrylic adhesives, synthetic products of ester acrylate and the like. • As silicone adhesives, the substances produced from silicone rubber and silicone resin of the emulsion-aqueous type, type of oligomer and type of hot melt. • Otherwise, polyether adhesive, polyurethane adhesive, etc. In addition, it is possible to process these adhesives in the form of tape and sheet for use. As viscous substances that produce viscosity by water, the following specific examples can be cited: • As polymers having carboxylic groups, copolymers of acrylic acid and the like with acrylic acid as the constituent monomers; and as substances with salt there are monovalent and bivalent salts and the like of sodium salt, potassium salt, magnesium salt and calcium salt.

• As cellulose ethers, carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, sodium cellulose cellulose-carboxymethyl cellulose and the like. • As natural viscous substances, mucin, agar, gelatin, pectin, carrageenan, sodium alginate, locust bean gum, chitin, chitosan, tragacanth powder and the like. • polyethylene glycol with a molecular weight of 200,000 or more and the like. As viscous substances that produce viscosity by organic solvents such as alcohol and the like, the following specific examples may be cited. • Hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, acrylic acid copolymer, shellac, waxes and the like. ACTIVE FORMULAS Direct Compression Formulas The following formulations are used in the manufacture of single-layer tablets that subsequently bond adhesively. A Manesty 16 station Beta Press (single layer rotary tablet press) is used to make the amlodipine and benazepril tablets. The Two formulations are directly compressible powder mixtures. The mixture of both the amlodipine formulation and the benazepril formulation is carried out in a "V" mixer from Patterson-Kelly. The tablets are compressed using 1/4 inch flat-faced bevel edge flatbed dies at a hardness of 25 kiloponds. The weight of the tablet is 62.0 mg for the amlodipine tablet and 54.0 mg for the benazepril tablet. The weights in mg of the granulation comprising each segment are indicated below: Formula for Amlodipine Mg Tablet. Dibasic Calcium Phosphate Anhydrous 51.13 Amlodipine Besilate, 7.15 Sodium Starch Glicolate (Explotab®) 2.48 Magnesium Stearate. 0.93 Blue Aluminum Lacquer # 1 of FD &C 0.31 Total 62.00 Formula for Benazepril Mg Tablet. Lactose Monohydrate 310 > 42.03 Benazepril HC1 9.00 Crospovidone 2.16 Magnesium Stearate 0.54 Red Aluminum Lacquer # 40 from FD &C 0.27 Total 54.00 Formulations for Wet Bed Wet Granulation The following two formulas are used to make wet granulations which are subsequently compressed into single layer tablets and can be adhesively bonded together. The wet granulations are all made using the following fluid bed granulator process. 1. Filter the Active Pharmaceutical Ingredient (API) (amlodipine or chlorthalidone), Starch 1500, Sodium Starch Glycolate and icrocrystalline Cellulose through a 20 mesh US sieve. 2. Filter Magnesium Stearate through a 30 mesh US sieve. 3. Weigh all the ingredients. The rest. 4. Prepare a 12% starch mixture adding the 150 g. of Starch 1500 at 1100 g. of Water while stirring with a Lightnin mixer with a drive shaft. Mix for a minimum of 10 minutes. Mix continuously during the granulation process. 5. Place 1/2 of Cellulose and Microcrystalline, API, 22.5 g. of Sodium Starch Glycolate and the remaining Microcrystalline Cellulose in a - - Mendel Fluid Bed Dryer / Granulator conditioned with a 20 liter tub and a top rolling nozzle. Mix for a minimum of 10 minutes before starting to spray. The preparation parameters are: Inlet Temperature: from 60 to 70 ° C Dew Ratio: from 25 to 35 g / min Atomizing Pressure: 1 bar 6. Sprinkle all the Starch 1500 mixture on the mixture. 7. Dry the granulation to approximately 2% moisture. 8. Grind the dry granulation using the Cornil with a screen equivalent to 20 mesh. 9. Place the crushed granulation in a 4-quart V-Mixer and add the rest 12.5 g of Sodium Starch Glycolate and mix for 5 minutes. 10. Add the Magnesium Stearate to the V-Mixer and mix for 3 minutes. The tablets are compressed on a Manesty station 16 Beta Press, single layer rotary tablet press. The tablets are compressed using 1/4 inch flat-faced bevel edge flatbed punches at a hardness of 20-25 kiloponds. The weight of the amlodipine tablet is 60.0 mg and the weight of the tablet of chlorthalidone is 70 mg. The following provides the formulas for use in the production of granulations that can be used in the tablets of the invention.

INACTIVE FORMULAS Direct Compression Formulas The following formulations are used in the manufacture of single-layer tablets that can subsequently be adhesively bonded to other tablets. A station Beta Press 16 of Manesty (press is used for single layer rotary tablet) to make the tablets. .The three formulations are directly compressible powder mixtures. The mixing is done in a "V" mixer by Patterson-Kelly. The tablets are compressed using 1/4 inch flat-faced bevel edge die dies at a hardness of 20-25 kiloponds. The weights in mg of the granulation comprising each tablet are shown below: Tablet 1 Mg. Nu-Tab® (compressible sugar 30/35 N.F.) 194.00 Tablet 2 Dibasic calcium phosphate anhydrous 158.59 Magnesium stearate 2.79 PVP K-30 2.62 Total 164.00 Tablet 3 Mg. Lactose 316 Fast Fio 70.00 Microcrystalline Cellulose (Avicel) PH102® 24.00 Crospovidone 4.00 Colloidal Silicon Dioxide 0.50 Hydrogenated Vegetable Oil 1.00 Red Aluminum Lacquer # 40 of FD &C 0.50 Formulation of Wet Granulation in Fluid Bed The following formula is used to elaborate an inactive wet granulation that subsequently compress in a single-layer tablet. The wet granulation is done using the following fluid bed granulator process. 11. Filter the Starch 1500, Sodium Starch Glycolate and Microcrystalline Cellulose through a 20 mesh US sieve. 12 Filter the Magnesium Stearate through a 30 mesh US sieve. 13. Weigh all the ingredients. The rest. 14. Prepare 12% of the Starch mixture by adding 150 g of Starch 1500 to 1100 g of Water while stirring with a Lightnin mixer with a drive shaft. Mix for a minimum of 10 minutes. Mix continuously during the granulation process. 15. Place 1/2 of the Microcrystalline Cellulose, 22.5 g of Sodium Starch Glycolate and the rest of the Microcrystalline Cellulose in the Mendel's Fluidized Bed Drier / Granulator equipped with a 20-liter tub and an upper rolling nozzle. Mix for a minimum of 10 minutes before starting to spray. The preparation parameters are: Inlet temperature: from 60 to 70 ° C Dew Ratio: from 25 to 35 g / min Atomization pressure: 1 bar 16. Spray all the Starch 1500 mixture on the mixer. 17. Dry the granulation to approximately 2% moisture. 18. Grind the dry granulation using the Cornil with a screen equivalent to 20 meshes. 19. Place the crushed granulation in a 4-quart V-Mixer and add the rest 12.5 g of Sodium Starch Glycolate and mix for 5 minutes. 20. Add the Magnesium Stearate to the V-Mixer and mix for 3 minutes. The tablets are compressed on a Benest Press station Manesty 16, single layer rotary tablet press. The tablets are compressed using 1/4 inch flat-faced bevel edge flatbed punches at a hardness of 20-25 kiloponds. The weight of the tablet is 70.0 mg. The following formula can be used to produce a granulation which can produce sub-units of tablets of the invention.

Inactive Wet Granulation The above active and inactive formulas are also suitable for filling capsules. The formulas have to be adjusted to accommodate the desired capsule filling volume. To produce an adhesively bound pharmaceutical dosage form, a tablet can be produced using one of the above formulas for compressing an amlodipine tablet using techniques well known in the art of tablet making. An inert tablet can be produced using one of the above formulas. One of the above formulations can be used to make a chlorthalidone tablet according to standard techniques. The adhesive, such as, Mantrose-Heauser Pharmaceutical Glaze # 4 (Lacquer) 45/200 is applied to both sides of the inert tablet coupling. The coupling side of the amlodipine tablet is attached to one of the coupling sides of the inert tablet and the chlorthalidone tablet (coupling side) to the other. The adhesive may or may not be applied to the coupling sides of the active tablets before coupling with the inert tablet. The tablets are allowed to dry with or without pressure applied under ambient conditions or in a drying tunnel. Numerous other means can be produced to create dosage forms of the invention using the formulas given above to allow the production of tablets or capsules. An almost infinite number of dosage forms according to the invention can be produced using any of the many tablet or capsule formulas that are known to those skilled in the art and will be, but have not yet been, developed. You can use as solutions the solutions of lacquer, preferably in the range of 29% w / w to 36% w / w solids in a solvent comprising ethanol. An applicator is immersed in the completely mixed lacquer and the lacquer solution is applied to the surfaces to be joined. A tablet sub-unit is attached to a tablet sub-unit (s); a capsule sub-unit is attached to a capsule sub-unit (s); some tablet sub-units may be attached to one capsule sub-unit (s) and tablet sub-units or capsule sub-units are joined together with linkers. No limitation is proposed with respect to the number of sub-units or linkers. Examples of Methods for Attaching the Sub-Units of the Dosage Form 1. Approximately one ml of lacquer solution is applied to the entire binding surface of a tablet sub-unit. The binding surface in the case of a tablet sub-unit is typically any flat surface on the tablet sub-unit, but is not limited to such a surface. Approximately ten to twenty seconds are allowed to pass while some or all of the solvent (alcohol) present in the lacquer solution evaporates, leaving a sticky adhesive residue on the tablet sub-unit. Then the connecting surface of the second one is brought into contact tablet sub-unit with the adherent surface of the first sub-unit. The sub-units are held together by light pressure of the hand for approximately twenty seconds and then left to dry in the ambient air. An alternative method comprises placing the lacquer solution on the bonding surface of both sub-units at about the same time, manually applying light pressure to both sub-units for twenty seconds and allowing the dosage form to air dry for approximately one minute to allow the evaporation of the solvent. Similar procedures can be followed in joining capsules together and using linkers (sub-units) to join tablet to tablet, capsule to capsule and tablet to capsule, creating dosage forms in which preformed tablets and capsules then function as sub-units. tablet units and capsule sub-units. No limitations are proposed in terms of the dilution of the lacquer, the selection of specific adhesive, the time or degree of pressure applied to adhesively bond the subunits, the time allowed for any solvent to evaporate, the number of sub-units together, etc. The invention - - expressly contemplates automated or semi-automated methods for adhesively joining the sub-units.

Claims (20)

1. REVINDING 1. A solid pharmaceutical dosage form comprising a plurality of adhesively linked subunits and also comprising one or more of the following: A. (i) a first inert tablet sub-unit and (ii) a second sub-unit of inert tablet. active sub-unit; B. (i) a first tablet sub-unit with a pharmaceutically inactive layer in which said layer has a mass of at least 20 mg and (ii) a second sub-unit; C. a tablet sub-unit that is provided with a separation mark; or D. (i) a first tablet sub-unit and (ii) a second capsule sub-unit that adhesively bonds to said first tablet sub-unit.
2. 2. A solid pharmaceutical dosage form as defined in claim 1 comprising two active subunits.
3. 3. A solid pharmaceutical dosage form as defined in claim 1 in which all subunits contain an active ingredient and a tablet sub-unit are provided with a separation mark.
4. 4. A solid pharmaceutical dosage form as defined in claim 3 wherein said separation mark comprises an incision.
5. 5. A solid dosage dosage form as defined in claim 2 comprising an inert tablet sub-unit adhesively bonded to two active subunits and said active subunits are not adhesively bonded together.
6. 6. A solid pharmaceutical dosage form as defined in claim 5 wherein the inert tablet sub-unit is provided with a separation mark.
7. 7. A solid pharmaceutical dosage form as defined in claim 6 wherein said separation mark comprises an incision.
8. 8. A solid pharmaceutical dosage form of claim 1 wherein an inert tablet sub-unit is provided with a separation mark.
9. 9. A solid pharmaceutical dosage form as defined in claim 8 wherein said separation mark comprises an incision.
10. 10. A solid pharmaceutical dosage form as defined in claim 1 comprising an active sub-unit with a separation mark.
11. 11. A solid pharmaceutical dosage form as defined in claim 10 wherein said separation mark comprises an incision.
12. 12. A solid pharmaceutical dosage form as defined in claim 1 wherein the adhesive comprises lacquer, a pharmaceutically acceptable acrylic polymer or hydroxypropyl methylcellulose.
13. 13. A solid pharmaceutical dosage form as defined in claim 1 wherein all active subunits contain the same drug or drugs.
14. 14. A solid pharmaceutical dosage form as defined in claim 1 wherein two active subunits contain a different drug or drugs.
15. 15. A method for subdividing a solid dosage dosage form as defined in claim 1 comprising breaking said dosage form through a sub-unit of undissolved tablet, removing or breaking through said bonding agent. a plurality of sub-units among themselves.
16. 16. A method as defined in the claim 15 which implies breaking through a separation mark.
17. 17. A method as defined in the claim 16 wherein said separation mark comprises an incision.
18. 18. A method for administering a portion of an active subunit of a solid pharmaceutical dosage form as defined in claim 1, said method comprising first breaking said pharmaceutical dosage form through an active sub-unit and then administering it. said part, said part optionally including one or more additional sub-units or parts thereof, to a patient human or another mammal or other animal in need thereof, who then fully ingests said part of said dosage form. ·
19. 19. A method for administering an active pharmaceutical ingredient that is present within an active subunit of a solid pharmaceutical dosage form as defined in claim 1 which comprises breaking said dosage form through a sub-unit of inert tablet and then administer a portion of said dosage form containing all or part of a sub-unit of active tablet and a sub-unit of inert tablet to a human patient or other mammal or animal in need of same, who then completely ingests said part of said dosage form.
20. 20. A method for making a solid pharmaceutical dosage form as defined in claim 1 comprising: (a) first, applying an adhesive to a first active sub-unit or inert tablet sub-unit; and (b) second, contacting said first active sub-unit or inert tablet sub-unit containing the adhesive with a second active sub-unit or sub-unit of inert tablet which optionally is provided with adhesive so that said first sub-unit and said second sub-unit adhere to each other, optionally pressing said first and second sub-units among themselves.