Patent Application
20080075772
The invention involves tablets, methods of dosing by breaking tablets, and related embodiments. Tablets of the invention can comprise at least two compositionally different layered segments.
In general, disclosure of a drug or drug product would also comprise the pharmaceutically acceptable salts, complexes, polymorphs, hydrates, isomers, or derivatives thereof. This inclusiveness need not be recited repetitively herein.
The subject invention includes pharmaceutical tablets comprising functional scores wherein such products have heretofore never included a functional score. This includes without limitation a functional bisecting score in a product previously only containing a decorative bisecting score, a functional trisecting score in a product previously only containing a decorative trisecting score, a functional quadrisecting score in a product previously only containing a decorative quadrisecting score, and the like.
These functional scores are scores that are dimensioned such that by breaking through the score, a partial tablet, or tablette, is provided that contains an accurate or predictable partial dose. The dimensions of a decorative score are typically less than about 1 mm in depth and are often less than a few millimeters in depth (depth refers to the vertical height of the score as produced in the die). The depth of the score is determined by the height of the embossing forming the score during compression; therefore an embossing that is raised 0.5 mm from the face of the die or punch contiguous therewith produces a 0.5 mm score in the tablet face. Functional scores, in accordance with the subject invention, are scores that are deeper than a conventional or decorative score when applied to the drug product. Often, a functional score is greater than 0.8 mm and often greater than 1 mm in depth. Depth is measured relative to the adjoining punch surface to the embossing. The punch surface may be flat relative to the orientation of the tablet press or may itself have a slant.
A functional score may be less than 0.8 mm. This depth (height) relates in large part to the tablet dimensions. A low weight tablet may have a highly functional score of only 0.5 mm in depth, using an embossing of 0.5 mm. If all prior versions of the tablet product of the invention used no more than a 0.15 mm deep score, for example, the invention would represent an advance in the art.
Furthermore, any tablet containing a score, preferably formed from an embossing on a tablet punch but not limited to such a method, which is about 1.0 mm or greater in depth (height) is novel and is part of the invention. Other non-limiting means of scoring tablets include use of a knife or rasp, and a novel printer-scoring machine that utilizes a high-speed cutting method.
A functional score of the subject invention is preferably provided in at least one layer of a tablet, and advantageously provides accurate and predictable partial doses in the resulting tablettes. A predictable and accurate partial dose in the resulting tablette is suggested to meet certain criteria, which may include one or more of the following:
The European Pharmacopoeia has instituted various factory release tests for uniformity of mass upon the breaking of scored tablets. No definitive international criteria, or FDA criteria, for a “functional” score is accepted. Furthermore, an important part of certain embodiments of the invention relate to the use of a tablet that breaks accurately with regard to dose (and perhaps to mass) is that said breaking be readily accomplished by a patient, including a patient of ordinary or less than ordinary skill in tablet breaking. In medical practice, trained tablet breakers such as pharmacists are usually not available when treating most patients, who are home-based and break their own tablets.
The amount of drug may be determined according to a standard pharmacopoeial uniformity of content assay. See United States Pharmacopocia, 2006 and European Pharmacopoeia, 2005 Edition, which are incorporated herein by reference.
Tablets of the invention are preferably produced on a layer press, such as a tri-layer or five-layer (e.g., TRP 900)high speed manufactured by Korsch AG of Germany. Remington's Pharmaceutical Sciences 20th Ed., Mack Publishing Co., Easton, Pa. (2000), Chapter 45, which is incorporated by reference, describes the various techniques utilized in making compressed tablets. The tablets of the invention are primarily intended for oral administration but they may also be used for other applications, such as through a gastrostomy feeding tube. Except for an excipient or drug having intrinsic adhesive properties used in a composition that is used to form a layer or segment, tablets of the invention are not formed using a cement, glue, adhesive, or the like. These tablets are typically not coated with a semipermeable membrane.
Certain embodiments of the subject tablets are formed from compressing, e.g., vertically with one composition placed on top of another, at least two different pharmaceutical formulation compositions, e.g., granulations, configured as separate layers or tablet segments; certain preferred tablets comprise three vertically disposed segments. Embodiments of the subject invention include, but are not limited to, a vertically compressed tablet having a height greater than its width (a “taller than wide” tablet), and a unitary segmented tablet. These embodiments can comprise a separation mark or score.
A layer is produced by introducing an amount of an individual granulation into a tablet die to fill at least a part of the die. A layer is considered to be present whether it is the form of an un-tamped, tamped or fully compressed granulation.
Examples of specific embodiments of the invention can be understood with reference to the drawings. The drawings depict perspective or vertical cross-sectional views of tablets and tablettes of the invention. Tablets are depicted in
Separation marks in the tablets depicted in the Figures as scores that are present on or in the surface of the tablet and that do not extend deeply enough into the tablet to appear in the cross-sectional front views are depicted in the drawings as dotted lines to reflect the location of said scores on or in the surface of the tablet (not shown). It is to be understood that the depth of a separation mark or other score may be deeper than one-half the widest cross-section of the tablet in a particular embodiment, and thus the transverse dotted lines reflecting scores that are separation marks shown in the Figures imply no intention to limit the depth of any scores of the tablets of the invention. Similarly, the tablets shown that contain scores do not limit the width or extent of said scores. The horizontal dotted lines on the front view that represent the surface scores are schematic, and do not necessarily represent the full vertical extent of the score. (Perforations or discontinuous scores through the width or depth of the tablets are not depicted herein, but remain within the scope of the invention, as are other marks on or physical changes to the tablet that create a separation mark). Any scores or printed indicia that serve as separation marks are for convenience herein assumed to be on the front surface of the tablet, which is arbitrarily chosen from a vertically-oriented surface of the tablets. The “side view” of a tablet is a cross-sectional view of the tablet rotated 90 degrees from the front view, and is shown, for example, in
Turning to the Figures,
Breaking the tablet of
Breaking the tablet of
Tablets of the nature of that of
In addition, no limitation exists as to the presence of one or more additional segments created superior to (i.e., above) segment 270, or the composition of such. Also, though less likely, there could be another set of different unitary segments inferior to (i.e., below) segments 272 and 274.
As an example of a method of manufacture of a preferred tablet of the invention, first, a granulation containing a pharmacologically effective dose of a drug enters the die and is tamped to form a first segment. Second, a granulation lacking a drug (an “inactive granulation”) enters the die and is tamped. The inactive granulation creates a part of the tablet that can be identified and broken through so that a part of the drug containing a significant concentration of drug is not broken through. Last, a second granulation containing a pharmacologically effective quantity of a drug enters the die, is optionally tamped, and then final compression to form a third segment and a final compressed tablet occurs. While one or all segments may individually have a width greater than height, the tablet as a whole preferably has a height that exceeds its width.
Especially suitable dimensions for tablets for human use according to the invention are, without limitations, the following: height: 6 to 24 mm; preferable 10 to 18 mm and more preferably from 10 to 14 mm; width (at the widest dimension of the horizontal axis): 2 to 16 mm; preferable 3 to 10 mm and more preferably 4 to 8 mm. Without limitations, the dimensions of the tablet may be optimal if the ratio of the height to the width is between about 1.5:1 to about 3:1.
Subsequent to tablet formation, optionally a score may be placed in the side of said tablet, preferably transversely (horizontally). Alternatively, after tablet formation, a printed line or other forms of indicia such as dotted lines, symbols or perforations may be placed on or in the surface of the tablet, all of which serve the purpose of allowing identification of said tablet's desired breaking region from the standpoint of effecting accurate separation of the parts of a tablet containing isolated doses of drug. Other means of aiding identification of a region of potentially desired tablet breaking may be utilized such as the use of contrasting colors in different segments.
Additionally, the compressed tablet can be further processed to provide an inert covering or container, e.g., a capsule or a sachet. In use, the covering can be cut away or otherwise removed, such as by twisting apart or carefully cutting a conventional gelatin capsule, removing the tablet therein and dividing the tablet as described herein for a non-encapsulated embodiment. The covering or container can advantageously be useful to minimize or prevent confusion on the part of the patient user viewing a segmented or layered tablet of the subject invention.
In certain of the preferred tablets of the invention, a layer (and the granulation from which it is derived) will not need to be placed on top of or below (e.g., adjoining, or contiguous with) a substantially identical layer (or granulation). In such a case, one layer will give rise to the sub-type of segment that is a simple segment. The use of the term “segment” allows a segment to be simple or compound. Because the tablets of the invention have been adapted to be broken if and when desired, a term for the major fragments resulting from said breaking has been coined. The inventors use the term “tablette” in this regard.
An example of tablette formation is as follows: a standard single-scored, mono-layer, homogeneous pharmaceutical tablet is broken through the score to produce two “half” tablets. Each of said major fragments is called a tablette. Some chipping and crumbling, which are preferably minor in amount, may occur; these chips, crumbs etc. are not considered to be tablettes. It is often advantageous to place a score transversely into a segment, such as a substantially inactive segment that is not a top end segment (and therefore is an “inner” segment), as may be done with an instrument such as a file or a saw-like process. Successfully breaking said tablet through said score is designed to create two tablettes, representing the two major fragments of the tablet and not including smaller fragments such as crumbs or chips. The score or non-score separation mark such as printed indicia need not be placed in the middle of the height of the tablet, and therefore the tablettes may be intended to be of substantially different height and may be a 2:1 or 3:1 height ratio, for example.
Of the many tablets that can be produced according to the invention, examples of a tablet manufactured in a multilayer tablet press are as follows:
One embodiment comprises a pharmaceutical tablet having compositionally substantially identical first and second “unitary segments” that each adjoin the same face (surface) of a compositionally distinct first non-unitary segment. Said pharmaceutical tablets preferably comprise two or more compositionally identical unitary segments including a first unitary segment and a second unitary segment, said first unitary segment and said second unitary segment containing a drug or drugs, said first and second unitary segment having been formed from the same layer or layers that was or were divided; said first segment optionally having a score on its surface positioned between said first and said second unitary segments; said tablet optionally having additional unitary segments; and said tablet having at least one segment that is not a unitary segment. This embodiment of the invention is illustrated in
The term “unitary segment” means a physically separated, non-contiguous part of a divided layer or layers of a tablet and which may be made using a bottom embossed die that causes granulate to be divided as it enters the tablet die or after compression by an upper punch in the die; or, by a post-tabletting scoring that removes a part of a segment to a depth that exposes an underlying segment.
A layer is produced by introducing an amount of an individual granulation into a tablet die to fill at least a part of the die. A layer is considered to exist whether it is in the form of an un-tamped, tamped or fully compressed granulation. Because some migration of granulation may take place in the tabletting machine, some amount (preferably of no therapeutic importance) of a granulation that forms one layer may be transferred to another layer.
This unitary segment embodiment may have one or more additional unitary segments in addition to said first and second unitary segments that are optionally present and that are derived from the same layer or layers as said first and second unitary segments.
A preferred method of making this unitary segment embodiment of a tablet of the invention utilizes a protuberance known as an embossing that rises from the lower punch of a tablet die in a tabletting machine. In a preferred method of manufacturing, a granulation preferably containing a therapeutic amount of an active pharmaceutical ingredient enters the die, preferably forms a layer above the highest point of said embossing, and is tamped by the upper punch. Next, a second granulation that is different from said first granulation enters said die on top of said first granulation, preferably is tamped by the upper punch, and then the tablet is compressed by the upper punch so that said compression pushes said first granulation below the highest points of said embossing. In the invention, said embossing occupies a position on the lower punch that may bisect or quadrisect said lower punch, so that said compression causes said first layer to be divided into two or more non-contiguous segments. Said first layer formed from said first granulation is herein referred to as a divided layer; said segments formed from a divided layer are herein referred to as unitary segments. The invention therefore allows precise division of said tablet, when desired, by allowing breaking to occur only through the second layer that was formed by said second granulation so that maximal accuracy of dosing with a tablet fragment arising from intentional tablet breaking may occur. In the above example, said second granulation preferably lacks an active drug (i.e., it is an inactive granulation).
An alternative embodiment concerns a variation of the unitary segment tablet, but where the embossing does not completely separate the active layer into separate segments; rather, the embossing forms a deep score into the active segment, which is often formed from a single layer and is therefore often a simple segment. This embodiment of an accurately breakable dosage form of the subject invention is illustrated in FIG., and is described in detail in WO 2006/038916, which is incorporated by reference in its entirety.
Another embodiment of an accurately breaking dosage form of the subject invention is manufactured as follows: a first granulation comprising drug A enters into a die at a first filling station; a second granulation comprising inactive excipients enters on top of said first granulation at a second filling station; a granulation substantially identical in composition and quantity (weight) to said first granulation enters at a third filling station. After final compression, said tablet is ejected from the die. Each granulation, upon full entry into the die and thereafter, forms a layer, or segment, of the final tablet product. Appropriate tamping of each layer following each fill of a composition may be formed according to known or otherwise appropriate processes. Other procedures standard or appropriate for layered tablets are performed. There is no absolute requirement that the compositions be identical even if the drugs are identical. Different excipients may be used, and different colorings in the different drug-containing layers can be used. In certain preferred embodiments, a drug can be present in one of the active compositions in an immediate release composition, and the same drug can be present in the other active composition in a controlled release composition, such as a matrix or micro-particulate composition. In any of the active (drug-containing) tablets of the invention, the same drug may be present in the same quantity in different layers (segments) or in different quantities.
Preferably, in any of the manufacturing processes employed to form a tablet of the subject invention, there is no mixing of drug or excipients from one segment to another. However, in reality, minimal, inadvertent mixing between different granulations in the formation of layers can occur. Therefore, some mixing is to be expected and does not alter the improvement in the art of creating accurate dosing from breakable tablets from the invention. Different granulations may be of the same or different colors. Wet granulations are often preferred to limit transfer of material from one granulation to another. Direct compression of powder is also a preferred manufacturing technique.
By convention herein, the term “segments” may be place of “layers” in general in discussing the finished tablets of the invention, for reasons that are explained below. In addition, for convenience of reference and consistency throughout this specification, the descriptions herein may refer to the segments as comprising or utilizing a particular “granulation”. Such term is not limited to the formation of granules, per se, as in a wet granulation process. Other formulation compositions, for example, homogeneous mixtures or blends used in direct compression matrix formulations, coated or uncoated beads or pellets used in compressed tablets, or like compositions as are well known in the art and suitable for use in conventional layered, compressed tablet technologies, can be readily substituted for such “granulations” and are considered within the scope of the invention. It is expressly intended that the subject invention include each of these alternatively available and well known compressible formulation technologies.
A segment represents the entirety of a substantially homogeneous contiguous part of a tablet. A segment may be formed from more that one layer, however. If two substantially identical granulations entered the tablet die successively, with the second entering directly after and onto the first, such as at two successive filling stations during automated high-speed tablet manufacture, then the two granulations would each form a separate layer after entering, but when compressed, they would comprise one segment. A segment therefore is a basic unit of how the tablets of the invention prove useful. If, however, two different active drugs, or different salts of the same active drug, were compressed one on top of the other, they would form two segments. Granulations comprising the same active drug but with dissimilar excipients would also form two segments if one granulation were compressed onto another.
A segment formed by a plurality of layers that are formed from substantially identical granulations is called a compound segment. Compound segments may prove useful in situations of relatively large quantities of an inactive granulation, or granulation containing a drug or drugs, so that two or more consecutive fills (“feeds”) of substantially identical granulation may occur.
A layer formed from a granulation that is neither disposed upon nor under (i.e., does not adjoin and is not contiguous with) a substantially identical granulation is a simple segment. A non-compound segment is a simple segment.
As used herein, such terms as “horizontal” (“transverse”) and “vertical” when used in relation to a tablet, are based on the spatial orientation of the tablet as, and after, it is produced in a die, but before removal or ejection from the die. Current methods of manufacture produce tablets with one granulation entering the die on top of another, so that tablets of the invention produced in such a manner comprise one or more top (outer) segments, one or more bottom (outer) segments, and optionally one or more middle (inner) segments. A segment that is not a top or bottom (i.e., outer) segment is considered to be an inner segment.
In any configuration of a tablet according to the subject invention, the lateral parts of any outer or inner segment have an externally exposed surface.
If separate granulations were to be sequentially placed in a horizontally (side-to-side) and not vertically as is currently the practice, then the tablets so produced would be within the scope of the present invention because the same resultant product would be produced by the horizontal compression process. When the tablet of
Tablets of the invention are preferably uncoated, but can be coated with conventional coatings for aesthetic or functional or other purpose. However, these coatings are not regarded as a “layer” or “segment” of the tablets of the subject invention. These coatings do not significantly alter the release kinetics of the drug or drugs of the tablets of the invention.
The terms “active agent,” “drug,” “active drug,” “active pharmaceutical agent,” “pharmacologically active agent,” “active pharmaceutical ingredient” and the like are interchangeable and include, without limitation, prescription and non-prescription pharmaceutical compounds, as well as pharmacologically effective doses of vitamins, cofactors, and the like.
The following list of possible combinations of a plurality of drugs is exemplary and not limiting.
The combinations referred to may include two or more members of the classes listed. Drugs listed below, and herein, may for convenience exclude mention of any salt of a drug; e.g., “atorvastatin” is listed even though its marketed form is atorvastatin calcium.
Without limitation, useful combinations may include a plurality of drugs from within the following six drug classes. In addition, tablets of the invention may be created containing only one drug from the following list. With regards to combination use, two methods of use may apply to the invention. One of these methods is to place an individual drug in a granulation and a different individual drug (or combination of drugs) in a different granulation, potentially with an inactive granulation interposed between them; another method is to place a plurality of drugs in one or more segments.
Examples of drugs that may be used in the invention are, without limitation, the following. Where drug classes are provided, the entirety of the class is intended, with examples given.
1. Anti-anginal agents, for example:
2. Anti-anginal agent plus an anti-platelet agent, such as aspirin, clopidogrel, or ticlopidine.
3. Two hypoglycemic agents (see list below).
4. Potassium chloride and any thiazide-type or loop diuretic (see lists below).
5. Lipid-lowering agent plus: hypoglycemic agent, anti-platelet agent, anti-anginal agent, and/or antihypertensive agent (see lists above and below)
Hypoglycemic agents include: thiazolidinediones: pioglitazone, rosiglitazone; sulfonylureas: glyburide, glipizide, glimepiride, chlorpropamide; Biguanides: metformin; Meglitinides: nateglinide, repaglinide; Glucosidase inhibitors: acarbose, miglitol.
6. Antihypertensive agents: Beta-blockers: acebutolol, atenolol, bisoprolol, celiprolol, metoprolol, mebivolol, carvedilol (a mixed alpha-beta blocker), nadolol, oxprenolol, penbutolol, pindolol, propranolol, timolol, betaxolol, carteolol;
Calcium antagonists (calcium-channel blockers): nifedipine, amlodipine, verapamil, diltiazem, nisoldipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, manidipine, aranidipine, atosiban, azelnidipine, barnidipine, belfosdil, bisaramil, buflomedil, cilnidipine, clentiazem, clevidipine, darodipine, diperdipine, dopropidil, dotarazine, dronedarone, efonidipine, elogodipine, emopamil, etomoxir, fantofarone, fasudil, furnidipine, iganidipine, ipenoxazone, lemildipine, leualacin, lifarizine, lomerizine, lubeluzole, mibefradil, monatepil, nefiracetam, nexopamil, Nifelan, nilvadipine, nimodipine, oxodipine, palonidipine, pranidipine, ranolazine, semotiadil, siratiazem, tamolarizine, temiverine, terodiline, vexibinol, zatebradine, and ziconotide.
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, 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): furosemide, torsemide, ethacrynic acid, bumetamide;
Aldostcrone antagonist diuretics: spironolactone, eplerenone;
Alpha-blockers: doxazosin, terazosin, prazosin, indoramin, labetolol (a mixed alpha-beta blocker);
Central alpha-agonists: clonidine, methyldopa;
Imidazoline: moxonidine;
Direct vasodilators: hydralazinc, minoxidil;
Adrenergic neuronal blocker: guanethidine.
Lipid-lowering agents include:
Others: ezetimibe, niacin, acipimox, ciglitazone, englitazone, acarbose, miglitot, voglibose, repaglinide, gliquidone, nateglinide, gliclazide, glimepiride, aliskiren, remikiren, zolasartin, cilexitil, tasosartan, fentiapril, pivalopril, zoefenopril, alacepril, amalopril, spirapril, indolapril, pentopril, cilazapril, imidapril, and dronedarone
The drugs disclosed herein are for illustrative purposes and are not intended to limit the scope of the invention. Any available drug that can be tabletted may be used in accordance with the subject invention. Such drugs are listed in The Physicians' Desk Reference (PDR), Secions 2 and 3, 2006 Edition, which lists numerous classes and names of drugs, as well as the European Pharmacopoeia (EP). The relevant portions of the PDR and EP, e.g., the listing of drug substances that can be used in accordance with the subject invention, are incorporated herein in their entirety by reference. A copy of Section 2 (Brand and Generic Name Index) and Section 3 (Product Category Index) of the PDR, as well as an Alphabetical Index of drug substances are attached as an Appendix hereto. These drugs and drug categories are considered to be within the scope of the invention, and are exemplary only, as other drugs useful for treating humans or animals, but not included in one or more of the attached lists, may also be used in accordance with the subject invention.
A partial list of drug substances useful in accordance with the subject invention, including controlled substances, are listed below:
Ethylenediamines
Ethanolamines
Alkylamines
Piperazines
Tricyclies
Second-generation H1-receptor antagonists
Third-generation H1-receptor antagonists
Other agents
Inhibitors of histamine release
H3-receptors antagonists
H4-receptors antagonists
Antihistamines
STATINS
ACE inhibitors
Angiotensin II antagonists
Barbiturates
BETA BLOCKERS
Butoxamine
Benzodiazepines
Others:
In addition, it would be understood that these listed active drugs can exist as different optical isomers, as different polymorphs, or as salts, derivatives, prodrugs or metabolites of the named active ingredient. It would be understood that the invention encompasses each of these variations of the named active drug, and is intended to be included as part of the claimed invention.
The term “undetectable amount” means that when using conventional analytical techniques such as high performance liquid chromatography (HPLC), nuclear magnetic resonance imaging (NMRI), and the like, the presence of an active compound can not be identified. The term “pharmacologically ineffective amount” means an amount of a drug or drugs that has or have no measurable pharmacological effect. Due to the conditions under which high speed automated tabletting equipment are operated, mixing of different granulations may occur during tablet formation which may cause material such as drug substance present in one granulation to appear in a layer or segment where it was not intended to be placed.
The term “relatively inactive segment” refers to a segment that either contains an undetectable amount of any drug or contains a decreased concentration of any drug or drugs contained in another segment or segments in a pharmacologically effective quantity. The term “decreased concentration” means that the concentration of a drug or drugs in said relatively inactive segment is no more than 80% that of said drug or drugs in another segment, more preferably no more than 20% of said other segment'3 s drug or drugs concentration; most preferably said ratio is no more than 5%, however. The concentration of a drug or drugs in a segment means, herein, the ratio, on a weight to weight basis, of the drug or drugs in said segment to the total weight of said segment, which includes said drug or drugs and inactive excipients.
The tablets of the invention are preferably broken transversely in order to realize their benefits or advantages. They may be broken in standard ways, according to the invention such as either by applying force manually (or “by hand” as the term is commonly understood) to cause the tablet to break at a desired location, or by use of an instrument, such as a cutting edge, to apply force directly to a separation mark provided in a desired breaking region.
Separation marks are intended to guide optional tablet breaking in the usual manner that is well known with scores, so that, if tablet breaking is desired, force can be applied to break the tablet at or about the separation mark in a direction that is substantially perpendicular to the surface on which it is desired that breakage of the tablet will be initiated. The tablet according to the invention may be broken either by applying force manually or by an instrument such as a cutting edge directly to the separation mark, or to other areas of the tablet, such as the outer segments, to cause the tablet to break at or about the separation mark and in the direction of the separation mark.
The separation mark or marks may comprise one or more of the following:
The subject invention can be readily understood by describing specific examples, which are intended as illustrative of the invention, and are not intended as limiting.
1 SPECIFIC DRUGS
As one example, warfarin sodium may be usefully produced as a trisected, quadrisected, or pentasected tablet, which can be accurately broken into predictable partial doses. If the tablet were taken whole, such a scoring pattern would be irrelevant. Preferably, the quadrisected warfarin tablet can be provided as a tablet which is manufactured according to the techniques, and to provide the advantages of the tablets disclosed in WO 2005/112900 and WO 2006/038916. A trisected product may also be produced according to known techniques with a five layer tablet such as one that can be produced with the Korsch TRP 900, in which, for example, the first, third, and fifth layers (segments) comprise equal and therapeutic amounts of warfin sodium, and the second and fourth layers (segments) lack significant amounts of warfarin sodium.
Methods of treatment of the invention involve breaking a warfarin tablet into three tablets or four tablettes followed by ingestion of the appropriate dose. Most preferably this method involves breaking a trisected or quadrisected tablet that readily can be broken into predictable doses such as thirds of the whole tablet or quarters of the whole tablet. Breaking a warfarin tablet into four parts has been taught against.
Another example involves the antihypertensive agent torsemide, which has favorable properties at low doses. A trisected 6 mg tablet would be novel and useful, especially if accurately divisible into three 2 mg tablettes. Also, a useful and advantageous composition considered part of the subject invention is a quadrisected 8 mg torsemide tablet, breakable into four 2 mg “tablettes. ”A quadrisected 4 mg torsemide tablet would be useful to produce the known effective antihypertensive doses of 2, 3, and 4 mg doses; and the 1 mg tablet can be useful as a low dose alternative to provide antihypertensive efficacy in cases of an adverse reaction to a higher dose or in pediatric cases, and may have activity against hypertension in some patients. Torsemide tablets according to the subject invention may be provided as scored tablets embodied as shown in
As with numerous other embodiments of the invention, it has not been taught to treat hypertension with torsemide by beginning at a fractional part of a whole tablet, whether that is a half dose, third dose, or quarter dose, then increasing the dose such as to a whole tablet from a half tablet, a half tablet from a quarter tablet, etc. based on clinical results, side effects, and the like. “Dose adjustment” includes without limitation upward and downward dose adjustments, which occur often on beginning a new medication, ending a medication, or during ongoing therapy with a medication. “Dose adjustment” also includes periodic dosing, such as is common with a hypnotic agent or a tranquilizer, where doses vary based for example on level of sleepiness (hypnotic), level of anxiety (tranquilizer), or need to drive a car (benzodiazepine, etc.). The method of the invention as applied to torsemide and the many other drugs where such method of dose adjustment has not been taught may involve scored or unscored drugs, and predictably breaking or unpredictably breaking drugs with regard to the doses created by tablet breaking. Of course, it is most preferred under the invention that these methods involve predictable dosing upon tablet splitting.
In another example, the anticonvulsant lamotrigine is currently produced as a bisected tablet including a 100 mg dose, but is instructed to be taken whole. It may therefore be advantageous to produce, for example, a quadrisected 100 mg lamotrigine tablet if predictable 25 mg dosages (tablettes) can readily be obtained by quartering said tablet according to the quadrisect pattern. Lamotrigine tablets according to the subject invention may be provided as scored tablets embodied as shown in
Glyburide is currently typically provided as scored 1.25, 2.5 and 5 mg tablets. Dosing is up to 20 mg daily in either once or twice daily doses. In the PI for drug products containing glyburide as the active ingredient, dose titration is mentioned but no instruction to split the scored tablets is expressly recited or otherwise provided. In accordance with the subject invention, the use of a scored 2.5 mg tablet which is predictably and accurately divisible into two 1.25 mg tablettes can be employed to achieve a daily dose of 3.75 mg without having to purchase a 1.25 mg tablet in addition to the 2.5 mg tablet. In accordance with the subject invention, a predictably and accurately breakable 5 or 10 mg quadrisected tablet may also be utilized. Dosing in this example begins using ¼ tablet daily and may increase to the use of half tablets or a combination of a quarter-, half- or whole tablet as tolerated and as glycemic response necessitates. Additionally, the initial tablet utilized could be a 4, 6 or 8 mg tablet. There is no requirement in the subject invention that introduction of a new version and/or a new method of administration requires dosing to utilize the same doses as were previously available.
Less preferred dosing methods of the invention, again, can involve tablets provided with one or more separation marks that break relatively unpredictably, such as by patients, or by trained pharmacists.
Synthroid® (L-thyroxine) is currently marketed in the U.S. as a scored tablet (apparently a decorative score). Again, despite the presence of a score, no PI instruction exists to utilize the drug as a half-tablet. Dosing per the invention may, for example, utilize a 100 mcg quadrisected tablet, with instructions to the patient to begin using ¼ tablet (predictably providing a tablette containing an accurate 25 mcg dose) daily for 8 days (a total of two 100 mcg tablets), then ½ tablet daily (predictably providing a tablette containing an accurate 50 mcg dose) for 24 days (i.e., administering a total of six 100 mcg tablets), then to have an office visit and blood test to determine the appropriateness of a further dose increase to 75 or 100 mcg. Thus, a single prescription and two visits to the physician are required by this dosing schedule using a dosage form which is breakable into predictably accurate doses. By contrast, previous dosing schedules would require at least three prescriptions (one each for 25, 50, and 75 or 100 mcg tablets, and often a physician visit for each new prescription. Therefore, prescription costs and medical expenses such as physician visitation costs can be substantially decreased by employing compositions and methods in accordance with the subject invention.
Prominent brands of this thyroid replacement hormone are Synthroid® and Levoxyl®. Each has a bisect mark or marks that is (are) shallow and likely non-functional. The PI's for each product do not mention tablet splitting. Levoxyl is shaped like a thyroid gland. The titration schemes in the PI's involve what could beneficially be used as half or quarter doses of whole tablets. The Synthroid.com Web site discusses money-saving actions consumers can take, including buying a larger quantity of drug at one time and using a coupon. Not mentioned as a way to save money is tablet splitting, even though pricing rises much less proportionately than dosage.
The invention teaches a non-homogeneous pharmaceutical tablet comprising L-thyroxine, preferably a tablet in which L-thyroxine is the only drug. The invention may involve a taller-than-wide tablet with one or more non-L-thyroxine-containing and preferably drug-free segments, and two or more segments comprising L-thyroxine.
This may for example involve a tablet of the structure AIA, AIAIA, AIAIAIA. The “I” segments are optionally and preferably all scored.
In another preferred embodiment, the invention involves a compressed tablet comprising unitary segments in which L-thyroxine is preferably the only drug. The scoring pattern may most preferably involve bisection, trisection, or quadrisection; or, less preferably, pentasection through “octa-section” (e.g., seven parallel scores in an elongated tablet delineating 8 preferably equal sections of the tablet). Less preferred are tablets in which L-thyroxine is contained within deeply scored rather than unitary segments.
It is believed that L-thyroxine has not been taught to be scored beyond bisection, and in fact the manufacturers in the U.S. of L-thyroxine do not recommend breaking said tablets through the score, and do not price their tablets as if they were intended to broken or were to be utilized as broken.
Thus the invention also involves L-thyroxine-containing pharmaceutical tablets with more than a bisect score pattern.
The invention also involves novel methods of dose titration and dose adjustment. The Synthroid and Levoxyl labels contain similar methods of initiating L-thyroxine for different types of patients and for different conditions. Advantageously, the novel method utilizes the inventions to allow dose titration and dose adjustment to be performed conveniently by a patient without necessarily having to purchase or obtain an additional strength. For example, a patient beginning treatment on 25 mcg of L-thyroxine daily could in the instant invention's method utilize a quadrisected 100 mcg L-thyoxine tablet, a quarter of a tablet at a time. Dose increments could be to a half a tablet and then if needed to a whole tablet.
Utilization of an accurately breakable dosage form would enhance the utility of the invention. Dose adjustment by breaking a tablet other than the lowest manufactured dose of 25 mcg is also novel if it involves breaking in half a tablet of a higher L-thyroxine strength. It will be apparent that scoring patterns of trisection, quadrisection, and even more complex scoring patterns allow more complex dosage titration/adjustment regiments than bisection.
Olanzapine is marketed in the US as Zyprexa®. This “atypical” anti-psychotic agent is indicated for Tx of mania as well as psychosis.
Dosing involves titration, often starting with 5 mg. Zyprexa/olanzapine tablets are unscored in the US and bisected or unscored elsewhere.
Dose-related side effects, such as somnolence and hypotension, are present with Zyprexa and tend to affect the elderly and the frail patients the most.
Novel tablets containing olanzapine as, preferably, the only drug include those with a plurality of unitary segments comprising olanzapine; a deeply scored segment comprising olanzapine; and taller than wide tablets comprising a plurality of segments comprising olanzapine, preferably separated by a substantially inactive segment(s).
Specifically claimed are tablets comprising olanzapine with a trisect, quadrisect, or more complex than quadrisect scoring pattern. These tablets of the instant invention are preferably but not necessarily accurately and readily breakable.
Novel methods of treatment involve dosage titration and dosage adjustment using an olanzapine-containing tablet, ideally but not necessarily one that is accurately breakable with regard to dose. The greatest flexibility will be obtained from a tablet that is trisected or quadrisected rather than one that is bisected, though the invention involves treating with bisected tablets for the purpose of dose adjustment and titration.
Olanzapine is also provided in combination with fluoxetine (Symbyax®) in the US. Similar methods and pharmaceutical tablets for this combination, and similar methods for other potential combinations, as described herein for olanzapine as the only drug in the tablet, are part of the invention.
Several other antipyschotic medications have been developed. These include quetiapine, risperidone, paliperidone, ziprasidone, and Seroquel®. Whether in immediate release (“IR”) or controlled release (“CR”) form, the methods and novel scored trisected or quadrisected tablets as applicable to olanzapine, and any combinations containing these medications, are part of the invention.
Chemically distinct but pharmacologically containing similar therapeutic effect and similar adverse dose-related effects involving somnolence and hypotension are antipsychotic phenothiazines. Examples include haloperidol, Compazine®, promethazine and many others.
These agents have a variety of therapeutic uses. Beta blockers are typically alcohols. Certain beta blocking agents also have peripheral effects on alpha adrenergic receptors, blocking these receptors and are therefore called alpha-beta blocking agents. These drugs are used for treatment (“Tx”) of HTN, CHF, arrhythmia, migraine prophylaxis, and other uses. Separately, relatively pure alpha blocking agents are used for hypertension and prostatic dysfunction.
Novel scored tablets, and novel methods of use, are disclosed herein for members of these drug classes.
I. Alpha-beta blockers.
The invention involves novel scored tablets comprising carvedilol as the only drug, or carvedilol and lisinopril as the only drugs. These scoring patterns involve trisected, quadrisected, and more complex than quadrisected tablets. Preferably these tablets are readily breakable into fractional predictable doses.
Methods of use involve dose adjustment and dose titration. Examples include the follow.
Carvedilol for CHF.
Provide a starting dose of 3.125 mg BID as ½ of 6.25 mg tablet given BID. Most preferably this involves an accurately breakable dosage form. In addition, this starting dosage could involve a preferably accurately breaking quadrisected 12.5 mg carvedilol tablet, which could then also be utilized to provide 6.25 mg BID and then 12.5 mg BID. Ongoing dosage adjustments could also be provided by such tablets. Doses involving bisected or quadrisected 25 mg or 50 mg tablets could be used, as well. Dosing for hypertension does not typically utilize the 3.125 mg dose, but BID usage would provide utility for the invention in such ways as using a quadrisected 25 mg carvedilol to allow a starting dose of 6.25 mg BID, then upward titration to 12.5 mg Bid, followed by 25 mg Bid or even a simplified regimen of 25 or 12.5 mg QD.
Recently, Coreg CR, a capsule formulation of immediate and controlled release microparticles containing carvedilol, has been approved for marketing in the U.S. The label emphasizes the importance of careful up-dose titration, beginning with 10 mg QD. The invention can involve placing the components of Coreg CR into tablet form, with appropriate scoring or tablet format as needed to allow 20 mg or 40 mg, for example, to be used as partial tablets to provide a 10 mg starting dose for dose initiation for CHF. Extensive dosage adjustments and titration dosage variations are expected to be needed based on individual sensitivities, presence of diuretic treatment, and medical conditions, for example. As Coreg CR has beta-blocking capabilities, downward titration with care is expected to be needed in some patients so that issues of rapid beta-blocket withdrawal will not be unnecessarily raised. Accurate dosage adjustments will provide important medical benefits for this product, especially when it is used for CHF treatment.
Alpha Blockers
Terazosin, doxazosin, prazosin and tamsulosin for benign prostatic hyperplasia (or, benign prostatic hypertrophy, “BPH” in either terminology) and all of the above other than tamsulosin
I. Benign prostatic hypertrophy (“BPH” or benign prostatic hyperplasia)
Because of a first-dose effect that may cause syncope, the antihypertensive drugs terazosin, doxazosin, and prazosin in their immediate release forms require 1 mg starting doses and then upward titration to a therapeutic dose.
The invention involves utilizing these drugs in up-titration schemes and during ongoing therapy by starting with a fractional tablet to provide the 1 mg starting dose and then either a whole 2 mg tablet or such as a fractional 4, 6 or even 8 mg tablet to provide an increased, 2 mg dose, and then increasing doses as needed. Even though these drugs are often provided once daily, they can also be used as BID drugs. This dose regimen also can very usefully involve a fractional tablet taken BID rather than two smaller strength tablets each taken QD. Because of the side effects, accurate dosing is very important for this class of drug, as it is for chemically unrelated drugs such as hydralazine and other direct vasodilators. Alpha blockers and alpha-beta blockers are among the drugs for which the invention teaches a method of dose titration on dose initiation which, while novel and having certain potential benefits, it would be clearly medically preferred to have dosing be accurate upon tablet splitting. It would not be obvious to quadrisect an alpha-blocker or alpha-beta blocker unless accurate dosing upon tablet breaking could occur. Under current thinking and knowledge, it would currently not be obvious to place a decorative score into an alpha blocker tablet, especially a trisect or quadrisect pattern, because patients would tend to misuse the score to guide tablet splitting rather than accepting the score as decorative only. This issue of misuse of decorative scores is relevant to many other embodiments of the invention, where the prior art involves decorative scores only into a tablet, whether they are bisect or even quadrisect decorative scores. The invention's preferred tablets overcome this problem by providing highly functional scores as well as unscored tablets that break into tablettes containing predictable doses. Similar uses for the above three drugs relate to their use for BPH as well as HTN.
In the case of tamsulosin, the drug can be produced as a tablet of 0.4 bisected, 0.6 trisected, and 0.8 mg trisected to allow a variety of dosing adjustments. This could include beginning 0.4 mg therapy with a half of 0.8 mg and then up-titrating if indicated, otherwise continuing on ½ tablet daily. Due to orthostatic hypotension, the more accurate the tablet splitting, the better medically it would be. A quadrisected 0.8 mg tablet and a trisected 0.6 mg tablet would allow significant dosage flexibility. For example, certain men would benefit from 0.4 mg HS and 0.2 mg in the AM, which is beneficially able to be provided by a 0.6 mg trisected tablet if accurate dosing can be obtained by breaking said tablet in said manner. Of course, similar benefits in safety and/or efficacy could accrue to a quadrisected 0.8 mg tamsulosin tablet. Less preferred would be a single-scored 0.6 mg tamsulosin tablet which divided the tablet into 0.4 and 0.2 mg rather than a bisecting score. As is the case for all the other tablets described herein, unscored but accurately dosed tablets can be created by using a taller than wide tablet with one or more interposed non-tamsulosin-containing (often, preferably inactive) segments.
In the case of beta blockers that lack alpha-blocking ability, such as metotprolol, atenolol, and many others, the ability to titrate or dose adjust by using preferably accurately breakable dosage forms can be very beneficial. A patient could for example begin therapy with atenolol 25 mg BID by breaking a quadrisected 100 mg atenolol tablet, then increase the dose as needed to 50 mg BID or even to 75 mg in the AM and 25 mg in the PM. A trisected 150 (or 75) mg atenolol could be beneficial if utilized to start therapy at 50 (25) mg once daily and then increase the dosing in various ways as allowed by the scoring pattern (or breaking pattern for dosage forms involving interposed preferably inactive segments between active drug-containing segments of appropriate therapeutic or at least pharmaceutically active dosage.
2. TREATMENT METHODS
In the treatment of hypercholesterolemia, current methods employed in the U.S. include beginning with the maximum dose that is hoped by the prescriber to be tolerated, taking into account such factors as a patient's age, weight, hepatic function, cholesterol level, and/or current and desired cholesterol levels. Because potential side effects such as myalgias and rhabdomyolysis are dose dependent, physicians tend to start with a lower “safe” dose, even if that dose is predicted to be inadequate to bring a patient to a desired goal. Because all statins marketed in the U.S. are currently unscored, are likely to be difficult to break and therefore provide unpredictable doses if broken or otherwise divided, physicians often initially prescribe a lower dose than they expect to ultimately be needed. Thus atorvastatin may be prescribed at 10 mg daily, then, as shown to be tolerated by the patient, new prescriptions may be subsequently given for 20 mg and then 40 mg tablets. This dosing routine may require multiple visits to a physician or pharmacy, additional costs, and other disadvantageous aspects.
In accordance with the subject invention, dosing may begin with one-quarter of a 40 mg tablet, which predictably provides an accurate 10 mg dose. Then, when tolerability of this 10 mg dose is demonstrated, such as after 4 or 8 days, dosing may increase to one-half of the 40 mg tablet daily (providing a predictable 20 mg dose), and potentially then to one 40 mg tablet daily. Advantageously, using the compositions and methods of the subject invention, it is expected that patient compliance with the ultimate goal of dosing 40 mg daily will be increased, as compared to purchasing three separate tablet strengths, for reasons that include the starting dose appearing cautiously low at only ¼ of a tablet daily. Moreover, the compositions and methods of the subject invention are advantageous in that fewer visits to the physician or receipt of prescriptions from the physician for any one patient are required. A preferred means of utilizing the invention as in this example of a quadrisected statin tablet is to utilize the inventions described in International Appliction, WO 2005/112900.
It is also expected that the method of the invention will increase the percentage of physicians who get patients to goal. It has been well documented that many physicians under-treat generally asymptomatic conditions such as elevated hyperlipidemia, so that having a high dose that can be initially used as a low dose is likely to increase the number of physicians who utilize that dose. Not only do compositions and methods of the subject invention allow titration upwards to occur in a fully acceptable manner, but if a patient receives a dosage that is double the starting dose, an accurately breakable dosage form allows the patient to go to, for example, a half dose (i.e., said starting dose) if a side effect appears at the higher dose that was not present at the starting dose.
Another advantage of the invention applied to statins and other drugs is that it is known to the inventor that certain patients need to start as low as 5 mg daily on atorvastatin, increase the dose gradually as guided by muscle aches, but eventually “learn” to tolerate maximal doses. The invention greatly cases the ability of patients to adjust to statin doses while maintaining “full speed ahead” on dose increases as may be medically required. Similar considerations can apply to hypertension remedies, antipsychotic agents, and other drug classes.
In the treatment of hypertension, whether essential or secondary, it is recognized that many patients are sensitive to medication commonly prescribed to treat this condition. It is also recognized that many patients require higher doses than the starting doses, even if their degree of hypertension is (at least initially) considered by the physician to be mild (Stage1). Thus, it is common to begin with a starting dose of a medication below that expected to be needed as a final or maintenance dose. In the invention, a predictable starting dose that is a fraction of a larger dose is utilized for an adequate period of time to demonstrate tolerability and safety, and to evaluate adequacy of dosing, then dosing is increased by providing either the whole tablet or a larger fraction of the dose thereof. Beginning treatment of hypertension with lisinopril 2.5 mg, as one-quarter of a quadrisected 10 mg dose is an example of the invention, with increasing dosing to 5 mg (one-half of a scored 10 mg dose), and then to 7.5 or 10 mg, using tablettes that are preferably predictable in dose, and/or whole tablets as needed.
Another example involves dosing schedules using an alpha-adrenergic blocking agent, such as doxazosin, terazosin, or prazosin. The mandated starting dose for each is 1 mg, preferably taken before bed. The above alpha-adrenergic blocking agent drugs are indicated for hypertension and also for benign prostatic hypertrophy/hyperplasia (“BPH”). In accordance with the method of the subject invention, an accurately breakable bisected 2 mg tablet (accurately yielding two 1 mg tablettes), trisected 3 mg tablet (accurately yielding three 1 mg tablettes, of quadrisected 4 mg tablet (accurately yielding four 1 mg tablettes) may be used to provide the 1 mg starting dose, and then upward dose adjustment would be made using the tablet of the invention, and tablettes created therefrom, as medically appropriate.
Management of anxiety and pain also can benefit from the procedures of the invention. A physician can devise, and a PI can authorize or instruct, a treatment regimen that for example could comprise 0.5 mg (one tablet) of alprazolam nightly and 0.25 mg (=½ tablet) as needed during the day. It has not been taught to adjust doses with precision. The invention for anxiety is primarily directed to, in addition to novel scored tablets, novel methods of treatment with tablets that readily break into tablettes of predictable dose.
In yet a different embodiment of the invention, a drug such as prednisone is commonly utilized to treat a condition such as an acute allergic or asthmatic reaction. In one of many potential examples of the usefulness of the invention, a 40 mg quadrisected prednisone tablet may come to be created which is predictably breakable into tablettes containing accurate 20 mg (halved) or 10 mg (quartered) doses, and this 40 mg tablet can be prescribed for asthma. The subject method comprises a treatment whereby the patient is initially administered a whole 40 mg tablet, then per physician's instruction, the dose may be reduced to 30 mg (¾ of a predictably and accurately breakable 40 mg tablet), or 20 mg (one-half of a predictably and accurately breakable 40 mg tablet), then administering 10 mg (¼ of a predictably and accurately breakable 40 mg tablet). The treatment method can then include administration of a dose as directed by the physician. After the patient reaches the 10 mg dose (¼ tablet), the invention may be utilized again by prescribing a sub-10 mg bisected, trisected, or quadrisected dose and having the patient taper off the medication by utilizing progressively smaller fractions of the whole dose.
In different embodiment of this de-escalation dosing regimen in accordance with the invention, an acute allergic reaction involving laryngeal edema may be treated using two 40 mg tablets, each quadrisected, then lowering the dose by 10-20 mg per day as directed utilizing whole tablets that predictably and accurately breakable into tablettes containing a fraction of the dose in the whole tablet, or fractions thereof.
In the above examples, quadrisection and dosing using a defined portion of a whole tablet is provided as a preferred embodiment of the invention. No limitation is intended. For example, a tablet may be sectioned to provide more than four sections. These and other embodiments of the invention that are contemplated by or suggested to persons of ordinary skill in the art using this disclosure and/or which is known within the art is within the scope of the invention. Alternatively, fewer than four sections of a tablet may be formed. For example, when bisection (providing two halves) is adequate to allow dose titration and adjustment, then such is also within the scope of the invention.
Further, it is preferred that accurate division of a tablet with regard to the fractional doses be obtained, such as, but not limited to the dosage forms described in published International patent applications WO 2005/112898 and WO 2005/112900 and other means of creating pharmaceutical tablets optimized for accurate breaking using known, homogeneous tablets, including elongated tablets.
Among the benefits of the subject invention are improvements in patient compliance. Patients typically prefer taking a fraction of a dose to start treatment and then increasing the dose by taking a larger portion of the tablet and/or the whole tablet. Patient compliance can be enhanced especially for asymptomatic conditions such as hypertension and hypercholesterolemia. Patient compliance is also expected to be enhanced by a decrease in the number of prescriptions required.
From a physician's standpoint, or that of other prescribers, the level of complexity of prescribing may advantageously be decreased by the methods of the invention. By use of compositions or methods of the subject invention, a prescriber can recommend safe usage of a partial dose, such as in a titration dosing scheme without concern of inaccurate doses resulting from breaking of a tablet where the inaccurate dose may not protect the patient, or may cause unwanted side effects, such as can happen in a dose-dependent way in epilepsy, diabetes, hypertension, and the like.
More generally, the prescriber can authorize a patient to achieve a predictable dose outside a titration dosing scheme. For example, a patient whose use of the drug lamotrigine (currently available only in 100 and 25 mg doses), could involve administration of 100 mg in the morning and 50 mg (one-half tablet) in the evening or before bed. Use of the currently available dosage forms would, per the label (Patient Instruction), may require two separate prescriptions, prescribed as one 100 mg tablet and a separately prescribed 25 mg tablet (two tablets for the 50 mg dose) each day. Per the invention, the patient could safely utilize one whole and one-half 100 mg tablet daily. Such use can therefore be advantageous for physicians and patients.
A further benefit of the invention may relate to pediatric or geriatric doses, which may not be produced in appropriate dose strengths. In the case of amlodipine, a 1.25 mg daily dose may be useful in either small children with hypertension, or in frail elderly patients with angina or hypertension, who may have hepatic dysfunction. Even though the United States Food and Drug Administration (FDA) has not approved a 1.25 mg dose, precise divisibility of the approved 2.5 mg dose would allow a 1.25 mg daily dose. In addition, precise divisibility of the approved 2.5 mg dose will allow accurate dosing of 3.75 mg daily.
Another use of the invention is to enable a method of cost savings to insurers and patients. The invention allows this because many drugs have pricing that differs little (if at all) between different doses. Because tablet splitting is imprecise for most scored tablets, the practice of mandatory splitting has been met with disapproval by most physician and pharmacist organizations. The invention enables tablet splitting due to provide accurate dosing when a tablet (or some tablettes) of the invention are broken as described herein. Substantial benefits are foreseen from this innovation. In addition, the ability to separate one active drug from another in a combination product has cost saving advantages, as well.
The subject invention applies to methods and compositions useful for treatment of animals, preferably mammals, and more preferably to humans.
It would be readily understood that the compositions useful for application to the methods in accordance with the subject invention may be scored or unscored. It would be further understood that the term “bisected” dosage form or tablet refers to the dosage from bearing one or more marks or scores indicating divisibility of that dosage form into two portions or fractional doses, preferably two equal portions or halves. The bisecting mark or score may be a single line, for example a score line collinear with the diameter of a conventional round tablet, or may be transverse to the longest dimension of a capsule-shaped tablet. Similarly, references herein to a “trisected” dosage form or tablet identifies a dosage form bearing one or more marks or scores that indicate division of the dosage form into three portions, preferably three equal portions or thirds. “Quadrisected,” accordingly, refers to at least one mark or score in or on a dosage form that indicates division of the dosage form into four portions, preferably four equal portions or quarters. Further numbers of divisions of a dosage form into five or more portions or fractional doses may also be employed in the subject invention, and may only be limited by the result of requiring a predictably accurate lower dose upon such division of the dosage form.
Moreover, the subject invention further includes an article of manufacture, or kit, that comprises a finished dosage form which is breakable or otherwise divisible into a predictably accurate lower dose, and an instruction, preferably a written or electronic instruction for breaking the dosage form and administering a fractional dose of said finished dosage form, or divided dosage form. Preferably, the article of manufacture includes a packaged tablet or tablets and a separate instruction for use in accordance with the subject method, more preferably co-packaged for sale as a single unit.
It is recognized that related inventions may be within the spirit of the disclosures herein. Also no omission in the current application is intended to limit the inventors to the current claims or disclosures. While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modifications to the disclosed embodiments may occur to those who are skilled in the art.
Other drug products, e.g., drug products comprising any of the active ingredients described or incorporated herein, can be embodied in tablets uniquely scored with the subject score patterns to advantageously provide predictably accurate lower or partial doses to a patient. Accordingly, the examples and the accompanying drawings are not intended to be limiting, and are provided for illustration purposes only.
This is a continuation-in-part of U.S. Provisional Application Ser. No. 60/792,601 filed Apr. 17, 2006; and is also a continuation-in-part of U.S. Provisional Application Ser. No. 60/792,933 filed Apr. 18, 2006; and is also a continuation-in-part of U.S. Provisional Application Ser. No. 60/861,898 filed Nov. 30, 2006.
| Number | Date | Country | |
|---|---|---|---|
| 60791834 | Apr 2006 | US | |
| 60792601 | Apr 2006 | US | |
| 60792933 | Apr 2006 | US | |
| 60861898 | Nov 2006 | US |
