EP1965772A1 - Forme pharmaceutique adhesivement liee - Google Patents

Forme pharmaceutique adhesivement liee

Info

Publication number
EP1965772A1
EP1965772A1 EP05855981A EP05855981A EP1965772A1 EP 1965772 A1 EP1965772 A1 EP 1965772A1 EP 05855981 A EP05855981 A EP 05855981A EP 05855981 A EP05855981 A EP 05855981A EP 1965772 A1 EP1965772 A1 EP 1965772A1
Authority
EP
European Patent Office
Prior art keywords
subunit
dosage form
tablet
active
subunits
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05855981A
Other languages
German (de)
English (en)
Inventor
Lawrence Solomon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Accu Break Technologies Inc
Original Assignee
Accu Break Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Accu Break Technologies Inc filed Critical Accu Break Technologies Inc
Publication of EP1965772A1 publication Critical patent/EP1965772A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention is concerned with solid pharmaceutical dosage forms that comprise aggregations of preformed subunits that are adhesively joined together.
  • Said mode of manufacture consists of apposing ("mating") the unit tablets to be joined and then forming a "connecting part" with cement.
  • Said application does not disclose producing said tablets by applying adhesive to an inert subunit that is not simultaneously apposed to or adjacent to another subunit.
  • the current invention most clearly differs from Ito' s disclosures and the implications of his disclosures in that said application contemplates either that dosage forms of his invention are ingested whole or else are broken or divided only through the "cement" with the tablet subunits considered “building blocks" a Ia indivisible atoms that form a molecule.
  • the current invention discloses dosage forms that are adapted to being broken through a tablet subunit part of said dosage forms. Therefore the methods of breaking said dosage forms of the invention involve breaking through a tablet subunit and not through an adhesive (cement) .
  • the current invention utilizes the general term "inert” to describe a tablet subunit that lacks any active pharmaceutical ingredient (i.e., a "drug").
  • “Inert” is intended to include tablet subunits that either lack any controlled-release function or that have a controlled release function.
  • the term “inactive” is utilized to indicate a tablet subunit that lacks any active pharmaceutical ingredient and that also lacks any immediate release function. Therefore, any inactive tablet subunit is also considered inert, but an inert tablet subunit may or may not be inactive .
  • the present invention is concerned with novel dosage forms and methods of their manufacture, plus methods of breaking said dosage forms and administration of a broken part of said dosage form.
  • the invention provides a solid pharmaceutical dosage form comprising a plurality of adhesively-joined subunits .
  • Said dosage form contains at least one or more of the following:
  • the dosage forms consist of a suitable adhesive substance interposed between and joining (or, " " "connecting, " or “bonding,”) a plurality of preformed subunits, preferably tablets but possibly involving one or more capsule subunits.
  • the invention differs from the Ito disclosure in that the current invention involves at least one of the following novel aspects : A. In a preferred embodiment, dosage forms containing at least one tablet subunit with an active drug (“active subunit”) and at least one tablet subunit made of only pharmaceutically inactive material (“inert tablet subunit”) are disclosed herein, whereas Ito only discloses an exemplary placebo tablet made only of inactive subunits; B.
  • dosage forms contain two or more active subunits adhesively joined together where at least one of the active subunits has a separation mark that is preferably a score; C.
  • dosage forms have two or more active subunits adhesively joined to one or more inert tablet and in said embodiment, a separation mark such as a score is optional;
  • a capsule subunit may be adhesively joined to a tablet subunit;
  • the invention involves a dosage form comprising a plurality of active subunits each adjoining an inert subunit that may be readily breakable without damaging any active subunit .
  • An inactive tablet subunit of a dosage form of the invention is preferably adapted to be broken, such as a tablet subunit that is provided with a separation mark which may be a score; such a subunit may optionally be an active or an inactive subunit.
  • An active tablet subunit may also be adapted to be conveniently breakable and may be provided with a separation mark such as a score .
  • An active subunit herein contains a pharmacologically effective quantity of a drug or drugs.
  • drug active drug
  • active pharmaceutical compound and the like herein include not only pharmaceuticals such as those that in the United States are regulated by the Food and Drug Administration, but also includes vitamins and minerals.
  • inert subunit will link two discrete active subunits.
  • inert tablet subunit 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 at the amounts used in the dosage form.
  • active subunit it is used to describe a subunit which has no detectable pharmacological effects and has no controlled release function.
  • the invention provides a method of accurately providing a predetermined part of a dosage form for administration as well as providing a whole dosage form.
  • breaking a subunit of the invention will not involve breaking, damaging, dissolving, etc. the adhesive bond between subunits .
  • the invention contemplates that one usage of a dosage form may- involve breaking through two or more subunits that also involves breaking through a discrete portion of the adhesive bond that joins them.
  • the invention also includes a method of administering a part of an active subunit of a solid pharmaceutical dosage form by breaking said pharmaceutical dosage form through an active subunit to obtain a part comprising an active subunit and then orally administering the part having the active subunit to a patient in need thereof.
  • a further embodiment is directed to a method of administering one active subunit of a dosage form having at least two active subunits adhesively joined to an inert tablet subunit by first breaking said inert tablet subunit to form two parts each of which comprises an active subunit and a part of said broken inert subunit and thereafter administering one of said parts to a patient or other appropriate host.
  • the dosage forms and parts formed by breaking are intended to be given enterally, such as orally.
  • Other means of administration such as through a naso-gastric tube or gastrostomy tube or per rectum, are contemplated as well.
  • the invention contemplates crushing a part of a whole dosage form that has been formed by breaking per the methods of the invention, so that administration through a feeding tube and the like may be conveniently accomplished.
  • the invention further includes a method of making a solid pharmaceutical dosage form by:
  • the final dosage form should be safe to use and is most preferably able to be taken into the body (e.g., ingested) by its intended user.
  • the invention utilizes substance (s) with sufficient adhesive ability to allow the subunits to adhere to one another to form one cohesive dosage form.
  • substance (s) with sufficient adhesive ability to allow the subunits to adhere to one another to form one cohesive dosage form.
  • said dosage forms will remain intact through the manufacturing and transport phases until it reaches a patient, nurse, pharmacist, etc.
  • These novel dosage forms have many embodiments and may comprise many different arrangements, many different shapes, types of active ingredient (s) , types of inactive ingredient (s) , number of subunits, etc. without any limitation. Examples representing 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.
  • a primary object of the invention to provide a novel pharmaceutical dosage form which contains one or more active or inactive ingredient (s) in more than one separately- produced active subunit which is adhesively bonded onto an inert linker subunit wherein said dosage form may be separated into two or more parts by breaking said dosage unit at a location or locations within the active subunit to provide a predetermined amount of a drug or drugs contained in said dosage form.
  • a ⁇ subunit is a preformed structure classified herein as either as an active subunit, a capsule subunit, or inert tablet subunit or an inactive tablet subunit.
  • Materials such as adhesive substance (s) or film such as hydroxypropyl methylcellulose that may be used to coat a subunit, are not themselves considered subunits.
  • Preformed refers to separate production of a subunit.
  • a tablet subunit of a dosage form of the invention is produced as a tablet, and becomes a subunit when it is part of the dosage form of the invention. Similar considerations apply to a capsule subunit of the invention.
  • Tablet subunits of the invention may be layered structures as are well known.
  • the invention may encompass a pharmacologically inactive layer of a tablet comprising a plurality of layers to serve as a breaking point and thus said pharmacologically inactive layer may serve a similar function in the invention as does an inert tablet subunit.
  • said inactive layer has a mass of at least 20 mg and more preferably 50-900mg; or 150mg-750mg or 400- ⁇ OOmg; 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.
  • said inactive layer may play a role in dosage form subdivision by serving as a breaking region.
  • Tablets and capsules are defined in their usual ways. Active subunits may contain one or more drugs.
  • “Pharmaceutical dosage form” herein refers to a solid dosage form containing two or more subunits adhesively bonded together.
  • the preferred solid dosage form is an oral dosage form.
  • Fig. 1 is a drawing of a top view of the dosage form of the invention depicting three subunits .
  • Fig. 2 is a schematic top view of a dime-shaped dosage form that has three subunits, one of which is scored.
  • Fig. 3 is a schematic top view depicting four active subunits each joined by an adhesive substance to an inert tablet subunit .
  • Fig. 4 depicts five tablet subunits, two of which each adhesively join three other subunits.
  • Fig. 5 is a schematic top view that depicts a dosage form of the present invention in the shape of a capsule.
  • the inert tablet subunit has two indentations that each contain a preformed active subunits.
  • Fig. 6 is a schematic side view depicting a dosage form consisting of three scored, adhesively joined active tablet subunits .
  • Fig. 7 is a schematic side view depicting a dosage form consisting of three active tablet subunits each of which is adhesively joined to two inert tablet subunits.
  • Fig. 8 is a schematic top view of a three-subunit dosage form.
  • Fig. 9 is a schematic top view of a four-active subunit dosage form in which the four active subunits are adhesively bonded together .
  • Fig. 10 depicts a side view of a dosage form containing four tablet subunits .
  • Fig. 11 depicts a dosage form with five subunits.
  • Fig. 12 depicts a dosage form with three subunits joined together adhesively.
  • Fig. 13 depicts a dosage form with three tablet subunits, none of which are scored.
  • Fig. 14 depicts a dosage form with three subunits, one of which is scored.
  • Fig. 15 is an exploded depiction of a two-subunit dosage form, one of which is a trilayer tablet subunit.
  • Fig. 16 is a partially exploded perspective view of a dosage form having two active subunits, one of which is a tablet subunit and one of which is a capsule subunit, and an inert tablet subunit .
  • Fig. 17 is a perspective view of a partially exploded dosage form having four active subunits and an inert tablet subunit adjoining said active subunits.
  • Fig. 18 is a perspective view of a partially exploded dosage form having two active subunits and an inert tablet subunit with score marks placed in the inert tablet subunit.
  • an active subunit comprise a drug or drugs
  • a capsule subunit is an active subunit (excepting placebo formulations for clinical trials and the like)
  • inert tablet subunits lack a drug.
  • the dosage forms of the invention may be made by joining individual tablets or capsules which are shaped in any desired configuration by such means as the use of tablet punches and dies (tablets), or encapsulating equipment (capsules). Said methods of manufacture are not limiting.
  • the method of joining involves material (s) with adhesive properties. There may be additionally be materials with non-adhesive characteristics between the subunits.
  • the dosage forms may comprise active subunits and inert tablet subunits having a plurality of various cross-sectional shapes, including without limitation round tablets, half-round, quarter-round, oval, trapezoidal, triangular, rectangular, etc., that are be adhesively bonded to each other.
  • the active subunits and/or capsule subunits may be separated from each other in a convenient manner by an end-user, nurse, pharmacist, etc. without damaging the function of said subunits.
  • the invention contemplates dosage forms comprising subunits with a variety of shapes, with some dosage forms containing more than two subunits, it may not be 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 ease of non-damaging subunit separation.
  • an effective amount of an adhesive is used to join any two surfaces together.
  • the amount of adhesive needed is dependent on multiple factors, such as the size and density of the dosage form..
  • a minimum amount of adhesive is preferable.
  • the amount of adhesive may comprise from 0.1 to 5 mils of adhesive spread over an area of approximately 0.5 to 100 sq mm., more or less, depending on the particular tablet size and area and number of the surfaces being joined together. In the case of veterinary dosage forms, such areas may be increased significantly.
  • Fig. 1 is a schematic side view of the invention that depicts two active subunits, 52 and 54, respectively, joined by inert tablet subunit 56.
  • Adhesive joins active subunit 52 to one side of the inert tablet subunit 56 and also joins active subunit 54 to the other side of the inert tablet subunit 56.
  • Active subunits 52 and 54 are conveniently separable from each other by, for example, cutting through the inert tablet subunit 56, or by grasping active subunits 52 and 54 and applying force centered on the inert tablet subunit 56, including rotary force or perpendicular force.
  • Active subunits 52 and 54 are substantially identical.
  • Inert tablet subunits such as subunit 56 in Fig. generally may have a mass greater than 20mg or more preferably form 50r ⁇ g to 900mg, or even more preferably from 150-600mg or even more preferably form 400-500mg.
  • the length and thickness will be selected ensure that the dosage form may be enterally administrable while being sufficiently robust to avoid undue amounts of breakage during packing, shipping and handling.
  • a dosage form that is circular is shown on top view having active tablet subunits 62 and 6, that are each joined to a scored inert tablet subunit 66 with score 68.
  • Inert tablet subunit 66 may be conveniently manually or mechanically broken without damaging either active subunit 62 or active subunit 64.
  • a dosage form of this form could have one or both active tablets scored as well.
  • Figure 3 depicts four active subunits, 72, 74, 76 and 78 joined via an adhesive substance to an inert tablet subunit element 79 that if broken can provide one or more subunits to be ingested.
  • Figure 4 is a drawing which shows three active subunits, 80, 82 and 84, none of which are connected to each other, but all of which are connected to inert tablet subunits 85 and 86 on opposite ends of the active subunits. Breaking the dosage form through the inert subunits may be accomplished without damaging any active subunit . Not shown is a similar design in which the active subunits are attached only on one end to an inert tablet subunit. ' In practice, the gaps 87 and 89, between the active subunits, may be smaller than shown. Figure 4 does not exclude the possibility that the active subunits so arranged may actually touch.
  • Figure 5 is a drawing of a dosage form comprising three subunits .
  • Active subunits 92 and 94 are adhesively bonded to indentations (depressions) 92A and 94A which are formed in subunit 90.
  • Subunit 90 could be a active subunit containing an active ingredient (s) or subunit 90 could also be an inert tablet subunit.
  • Dosage forms similar to Fig.5 may be made in a variety of shapes with varying shaped indentations or depressions. The entire dosage form is ingestible. The dosage form may be broken at score 96 to separate the active subunits in the dosage form into two parts.
  • a dosage form of the invention may comprise a stacked multilayer arrangement of substantially flat active subunits 8, 10 and 12 that contain, respectively, score marks 5, 7, and 9 and which are adhesively bonded together with small quantities of adhesive 6 to form a layered structure .
  • Fig. 7 shows a dosage form in which three active subunits, 14, 16, and 18 are held together with inert tablet subunits 20 and 22 that are adhesively joined to a side of each of the active subunits. While Fig. 7 shows two inert tablet subunits on the side of the tablets, it is possible to use only one, two, or a plurality of inert tablet subunits that may be positioned to form a stable and useful dosage form.
  • Fig. 8 depicts a top view of a dosage form haying an inert tablet subunit 34 that joins ends 36 and 38 which contain active ingredients. Lines 40 and 42 represent the adhesively joined edges of the active subunits. If desired, it is convenient to break through the inert tablet subunit without affecting either active subunit.
  • Fig. 9 shows a top view of a four-active subunit dosage form that is made by adhesively bonding together segments 24, 26, 28 and 30, which each contribute 90° of 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.
  • Score 27 approximately bisects subunit 30 and score 29 approximately bisects subunit 26.
  • the dosage form is therefore conveniently divisible through both scores, that form a continuous linear indentation across the dosage form.
  • Adhesive 6 that is the same type of adhesive used in Fig. 6 joins the subunits together.
  • Fig. 10 shows a drawing of a three-active subunit dosage form in which an outer active subunit 100 is bonded with adhesive layer 101 to a middle active subunit 102.
  • Outer subunit 104 is bonded with adhesive to inert tablet subunit 103, which is adhesively bonded to middle active subunit 102.
  • Fig. 11 shows a drawing of a three-active subunit dosage form in which the outer active subunits 105 and 109 are each adhesively bonded to inert tablet subunits 106 and 108, respectively, said inert tablet subunits being adhesively bonded to middle active subunit 107.
  • Fig. 12 shows a drawing of a three-active subunit dosage form in which active subunit 110 is bonded with adhesive 111 to middle active subunit 112. Active subunit 114 is bonded with adhesive 113 to middle active subunit 112.
  • Fig. 13 shows inert tablet subunit 116 adhesively bonded to active subunits 115 and 115A.
  • the active subunits contain the same drug.
  • the dosage form may be broken conveniently between subunits 115 and 115A through subunit 116.
  • Fig. 14 depicts inert tablet subunit 118 with a score that is between different active subunits 120 and 120A, facilitating tablet breaking when desired.
  • Fig. 15 depicts in an external view a dosage form consisting of two tablet subunits adhesively joined together at interface 308 that comprises an adhesive substance.
  • the tablet subunit that consists of layers 300, 302 and 304 is produced) separately on a tri-layer tablet press.
  • the vertical lines in 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 quantity of amlodipine besylate (amlodipine) and layer 304 contains a therapeutic quantity of chlorthalidone.
  • Layer 302 is formed from an inactive granulation and, due to mixing between layers in the tablet-forming process, contains pharmacologically ineffective quantities of both amlodipine and chlorthalidone.
  • Said trilayer tablet that is a subunit of the dosage form depicted in Fig. 15 is produced first by allowing a granulation containing amlodipine and suitable excipients into the die, then tamping; then allowing a granulation lacking an active ingredient into the die, then tamping, then allowing a granulation containing amlodipine into the die, then pre- compressing and then fully compressing to form a coherent tablet.
  • the upper punch is beveled and the lower punch is flat-faced.
  • Tablet subunit 306 contains benazepril and is produced separately in a conventional fashion. Subunit 306 is adhesively joined to the tri-layer tablet described above with shellac.
  • An advantage of the dosage form depicted in Fig. 15 is that a tri-layer tablet such as is described above (layers 300,302 and 304) may be used to produce the more complex, three-active drug, dosage form of Fig. 15 while retaining the ability to break the dosage form through layer 302 and producing two useful dosage forms.
  • One dosage form would contain a therapeutic quantity of amlodipine only and the other would only contain therapeutic quantities of chlorthalidone and benazepril only.
  • Fig. 16 is a partially exploded perspective view of a dosage form that consists of part 203 adhesively joined to subunit 208.
  • Subunit 200 in this example is a capsule subunit.
  • Part 203 contains subunit 200 and inert tablet subunit 204.
  • subunit 204 The length of subunit 204 relative to the other subunits makes it relatively easy to break through.
  • Fig. 17 depicts an external view of a dosage form that contains four active tablet subunits that are all adhesively joined to linker tablet subunit 218 that is inactive.
  • Subunits 210, 212, 214, and 216 are all active.
  • each of said active subunits contains a therapeutically effective quantity of a different drug.
  • two or more active subunits may contain the identical drug.
  • tablet subunit 214a is shown in its proper position in the dosage form of Fig. 17 and also is shown in a phantom exploded view as 214b.
  • Fig. 18 depicts a partially exploded external view of a dosage form containing part 234 comprising a double-scored inactive tablet subunit 227, interface 230, tablet subunit 232, and shellac layer 224; and tablet subunit 220.
  • Top score 226 and bottom score 228 are created manually with a file.
  • Scores 226 and 228 adapt tablet subunit 227 to be broken more easily than if no scores were present.
  • subunit 227 could have been a scored active tablet subunit.
  • the tablet subunits that are adhesively bonded together may be made using such techniques as are employed in the pharmaceutical industry to produce conventional tablets. These techniques include, without limitation, wet granulation methods; dry granulation techniques, such as slugging and grinding; or direct compression powder blends.
  • many useful solid dosage forms may be usefully produced by the methods of the invention.
  • the invention allows a tablet and a capsule to be joined together in one dosage form, which advances the pharmaceutical art in a novel and potentially important way.
  • the invention is well-suited for formulating combination drug products, i.e. dosage forms which contain two more active ingredients .
  • the dosage forms of the invention may provide a convenient manner of improving patient compliance with 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 removal of one or more subunits containing a particular drug from the dosage form.
  • a further benefit is the simplification of the prescribing and dispensing of multiple individual drug products.
  • Patients allergic to one member of a combination product can break some preferred embodiments of the invention and ingest one drug of the combination tablet, something not able to be safely done currently.
  • the invention provides a method of making a dosage form of a combination of different drugs where the different drugs may be separated from the combination without any trace amount of another drug being present in combination with another drug.
  • the different drugs may be separated from the combination without any trace amount of another drug being present in combination with another drug.
  • the present invention allows the separate components of the combination dosage form to be separately tabletted and adhesively joined in such a manner that there is no cross- migration of the individual drugs between the separate active units in a dosage form according to the present invention.
  • the active subunits are obtained apart from the dosage form of the invention, there is no cross-contamination of the individual drugs. This is particular important when patients are allergic to a particular drug.
  • Combinations of anti-anginal agents include any combination of the following drug classes:
  • A. Calcium channel blocking agents (amlodipine salt, diltiazem, lercanidipine)
  • Beta-blocker (atenolol, metoprolol, propranolol)
  • anti-anginal agent see above
  • antiplatelet agent such as aspirin or clopidogrel
  • potassium salt preferably KCl
  • any thiazide-type or loop diuretic preferably KCl
  • Hypolipidemic agent may be a: Statin (simvastatin, atorvastatin with or without torcetrarib, rosuvastatin, lovastatin, rosuvastatin, fluvastatin) , a fibrate (fenofibrate, gemfibrozil, bezafibrate, ciprofibrate, clofibrate) , or member of other classes (niacin, ezetimide, acipimox)
  • Thiazolidinediones Pioglitazone, rosiglitazone Sulfonylureas: Glyburide, glipizide, glimepiride, chlorpropamide
  • Meglitinides Nateglinide, repaglinide
  • Glucosidase inhibitors Acarbose, miglitol;
  • Beta-blocker approved for congestive heart failure treatment (metoprolol, carvedilol) ;
  • Combinations of two or more antihypertensive agents most preferably one member from different classes as described below:
  • Calcium antagonists (calcium-channel blockers) :
  • Thiazide-type diuretics (with or without potassium-retaining diuretics such as triamterene, amiloride, or spironolactone: Hydrochlorothiazide, chlorothiazide, cyclopenthiazide, polythiazide, bendrofluazide, hydroflumethiazide, chlorthalidone, indapamide, methylclothiazide, metolazone
  • Angiotensin converting enzyme inhibitors :
  • Captopril enalapril, lisinopril, ramipril, trandolapril, quinapril, perindopril, moexipril, benazepril, fosinopril
  • Angiotensin receptor blockers Losartan, valsartan, candesartan, telmisartan, eprosartan, irbesartan
  • High-ceiling (loop) diuretics (with or without potassium- retaining diuretics such as triamterene, amiloride, or spironolactone) :
  • Aldosterone antagonist diuretics Spironolactone, eplerenone
  • Adrenergic neuronal blocker Guanethidine . It will be appreciated that certain combinations, such as a beta-blocker and a diuretic, are more preferred than others, such as verapamil and a beta-blocker, or furosemide and hydrochlorothiazide. The same is true for other combinations.
  • Preferred adhesive substances include, without limitation, the following:
  • suitable adhesive materials may be selected from the following list: As synthetic adhesives, one may cite the following specific examples .
  • thermosetting resin adhesives the chemical reaction types of urea resin, melamine resin, phenol resin, epoxy resin, polyester resin, polyimide resin, and the like.
  • thermoplastic resin adhesives the solvent vaporization types of solvent-type vinyl acetate resin, 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 chemical reaction types of cyanoacrylate, anaerobic acrylic resin, urethane resin, and the like; the cooling (hot-melt) types of ethylene-vinyl acetate copolymer resin, polyamide, polyester, and the like; the pressure sensitive type of acrylic resin, and the like.
  • adhesives one may cite the following specific examples. • As rubber adhesives, mixtures of tackifiers, softeners, antioxidants, and the like with elastomer.
  • silicone adhesives the substances produced from silicone rubber and silicone resin of the aqueous-emulsion type, oligomer type, and hot-melt type.
  • cellulose ethers carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, crystal cellulose-carboxymethyl cellulose sodium, and the like.
  • 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 blends.
  • the blending both of the ar ⁇ lodipine formulation and the benazepril formulation is performed in a Patterson-Kelly "V" blender.
  • the tablets are compressed using H inch flat faced beveled edge tablet punches to a hardness of 25 kiloponds .
  • the tablet weight is 62.0 mg for the amlodipine tablet and 54.0 mg for the benazepril tablet. Weights in mg of the granulation comprising each segment follow:
  • the wet granulations are all made using the following fluid bed granulator procedure.
  • Lightnin mixer with a propeller shaft Mix for a minimum of 10 minutes. Mix continuously > during the granulation procedure .
  • Microcrystalline Cellulose into a Mendel Fluidbed Dryer/Granulator set up with the 20 liter bowl and a top spray nozzle. Mix for a minimum of 10 minutes before starting to spray. Set up parameters are: Inlet Temp: 60 to 70 0 C Spray Rate: 25 to 35 g/min Atomization Pressure: 1 bar
  • the tablets are compressed on a Manesty 16 station Beta Press, single layer rotary tablet press.
  • the tablets are compressed using H inch flat faced beveled edge tablet punches to a hardness of 20-25 kiloponds.
  • the amlodipine tablet weight is 60.0 mg and the chlorthalidone tablet weights 70r ⁇ g.
  • the following formulations are used in making single layer tablets that may be subsequently adhesively joined to other tablets.
  • a Manesty 16 station Beta Press (single layer rotary tablet press) is used to make the tablets.
  • the three formulations are directly compressible powder blends. The blending is performed in a Patterson-Kelly "V" blender. The tablets are compressed using H inch flat faced beveled edge tablet punches to a hardness of 20-25 kiloponds . Weights in mg of the granulation comprising each tablet follow:
  • the following formula is used to manufacture a wet inactive granulation which is subsequently compressed into a single layer tablet.
  • the wet granulation is made using the following fluid bed granulator procedure.
  • the tablets are compressed on a Manesty 16 station Beta Press, single layer rotary tablet press.
  • the tablets are compressed using H inch flat faced beveled edge tablet punches to a hardness of 20-25 kiloponds .
  • the tablet weight is 70.0 mg .
  • the following formula may be used to produce a granulation that may produce tablet subunits of the invention.
  • the above active and inactive formulas are also suitable for capsule filling.
  • the formulas have to be adjusted to accommodate the desired capsule fill volume.
  • a tablet may be made using one of the formulas above to compress an amlodipine tablet using techniques well known in the art of tablet manufacture.
  • An inert tablet could be made using one of the above formulas .
  • One of the above formulations may be used to manufacture a chlorthalidone tablet according to standard techniques.
  • Adhesive such as, Mantrose-Heauser #4 Pharmaceutical Glaze (shellac) 45/200 is applied to both mating sides of the inert tablet.
  • the mating side of the amlodipine tablet is joined to one of the inert tablet mating sides and the chlorthalidone tablet (mating side) to the other.
  • Adhesive may or may not be applied to the mating sides of the active tablets prior to mating to the inert tablet.
  • the tablets are allowed to dry with or without pressure applied under ambient conditions or in a drying tunnel .
  • Shellac solutions preferably ranging from 29% w/w to 36% w/w solids in a solvent comprising ethanol may be used as an adhesive.
  • An applicator is dipped into thoroughly-mixed shellac and the shellac solution is applied to the joining surfaces.
  • a tablet subunit i,s joined to a tablet subunit(s); a capsule subunit is joined to a capsule subunit (s); tablet subunits may be joined to a capsule subunit (s) and tablet subunits or capsule subunits are joined with linkers between them. No limitation to the number of subunits or linkers is intended. Examples of Methods of Joining the Subunits of the Dosage Form:
  • the joining surface in the case of a tablet subunit is typically any flat surface on the tablet subunit, but is not limited to such a surface.
  • About ten to twenty seconds are allowed to elapse while some or all of the solvent (alcohol) present in the shellac solution evaporates, leaving a sticky adhesive residue on the tablet subunit.
  • the joining surface of the second tablet subunit is brought into contact with the sticky surface of the first subunit.
  • the subunits are held together by light hand pressure for about twenty seconds, and then allowed to dry in the ambient air.
  • An alternate method comprises placing the shellac solution on the joining surface of both subunits at about the same time, manually applying light pressure to both subunits for twenty seconds, and allowing the dosage form to air dry for about one minute to allow evaporation of the solvent.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Adhesives Or Adhesive Processes (AREA)

Abstract

La présente invention concerne une forme pharmaceutique qui est un agrégat adhésivement lié de sous-unités préformées qui peuvent être commodément divisibles en parties plus petites.
EP05855981A 2005-12-30 2005-12-30 Forme pharmaceutique adhesivement liee Withdrawn EP1965772A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2005/047499 WO2007078290A1 (fr) 2005-12-30 2005-12-30 Forme pharmaceutique adhesivement liee

Publications (1)

Publication Number Publication Date
EP1965772A1 true EP1965772A1 (fr) 2008-09-10

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EP05855981A Withdrawn EP1965772A1 (fr) 2005-12-30 2005-12-30 Forme pharmaceutique adhesivement liee

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EP (1) EP1965772A1 (fr)
JP (1) JP2009522259A (fr)
CN (1) CN101370483A (fr)
AU (1) AU2005339699A1 (fr)
BR (1) BRPI0520830A2 (fr)
CA (1) CA2635566A1 (fr)
IL (1) IL192500A0 (fr)
WO (1) WO2007078290A1 (fr)

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FR2962647B1 (fr) * 2010-07-19 2013-05-24 Duo Ge Dispositif et installation d'assemblage d'au moins deux capsules medicamenteuses par collage
EP3302442A4 (fr) 2015-06-03 2019-02-06 Triastek, Inc. Formes galéniques et leur utilisation
CN113133980A (zh) * 2015-06-03 2021-07-20 南京三迭纪医药科技有限公司 药品剂型及其使用
WO2018137686A1 (fr) * 2017-01-26 2018-08-02 Triastek, Inc. Formes posologiques de libération contrôlée à des sites gastro-intestinaux spécifiques
US11571391B2 (en) 2018-01-09 2023-02-07 Triastek, Inc. Oral drug dosage forms compromising a fixed-dose of an ADHD non-stimulant and an ADHD stimulant

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Publication number Priority date Publication date Assignee Title
US5009896A (en) * 1989-10-04 1991-04-23 Akzo N.V. Multi-fractionable tablet structure
JPH069375A (ja) * 1992-04-10 1994-01-18 Takeda Chem Ind Ltd 分割可能な連結錠剤
JP3048815B2 (ja) * 1993-12-27 2000-06-05 協和醗酵工業株式会社 レーザビームを用いた錠剤の分割線加工方法
GB0027471D0 (en) * 2000-11-08 2000-12-27 Smithkline Beecham Plc Processes
GB0102342D0 (en) * 2001-01-30 2001-03-14 Smithkline Beecham Plc Pharmaceutical formulation
CN1606434A (zh) * 2001-12-19 2005-04-13 株式会社三和化学研究所 控制释放成型品
TW201240679A (en) * 2004-03-12 2012-10-16 Capsugel Belgium Nv Pharmaceutical formulations
AU2005245026B2 (en) * 2004-05-21 2010-07-01 Accu-Break Technologies, Inc. Immediate release pharmaceutical tablets with height greater than width
JP5046501B2 (ja) * 2005-08-18 2012-10-10 帝人ファーマ株式会社 複数の薬物を分離して保持する錠剤

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Title
See references of WO2007078290A1 *

Also Published As

Publication number Publication date
CA2635566A1 (fr) 2007-07-12
IL192500A0 (en) 2009-02-11
JP2009522259A (ja) 2009-06-11
AU2005339699A1 (en) 2007-07-12
CN101370483A (zh) 2009-02-18
WO2007078290A1 (fr) 2007-07-12
BRPI0520830A2 (pt) 2009-05-19

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