WO2020212822A1 - Multi-component pharmaceutical single dosage forms and process employed thereof - Google Patents

Abstract

Exemplary embodiments of the present disclosure are directed towards multi-component pharmaceutical single dosage forms and process employed thereof. The multi-component pharmaceutical single dosage form comprising: a plurality of tablet sub-units being selected from an uncoated, a film coated, a placebo, a delayed release coated (enteric coated), a modified release coated or combinations thereof, wherein ends of the plurality of tablet subunits are held together with a film in the form of a linker or a closure cap or tablet sub-units are enclosed together with a film. As disclosed herein, more than one tablet sub-unit can be held together either by enrobing/banding/encapsulating to form multi-component pharmaceutical single dosage form.

Description

“MULTI-COMPONENT PHARMACEUTICAL SINGLE DOSAGE FORMS AND

PROCESS EMPLOYED THEREOF

TECHNICAL FIELD

[001] The present disclosure relates generally to the field of tablet formulations In particular, the present disclosure is related to multi-component pharmaceutical single dosage forms and process employed thereof.

BACKGROUND

[002] Many oral dosage forms have been developed over the years and the more popular oral dosage forms are tablets, capsules and gelcaps. Tablets are compressed or molded solid dosage forms of various sizes or various shapes. Oblong-shaped tablets may sometimes be referred to as caplets. Tablets remain popular with consumers, however uncoated tablets suffer from drawbacks such as medicinal taste, a tendency to powder or flake (i.e., physical disintegration) when packaged in bottles, and/or the perception by consumers that they are not easy to swallow. These limitations are overcome by coating the tablets with a polymeric coating.

[003] Hard gelatin capsules are popular dosage forms consisting of two halves, a body and a cap. Over the years these hard gelatin capsules are used to deliver medicament in the form of powder, liquid or suspension form.

[004] Soft gelatin capsules are the dosage forms made of gelatin films and are used to deliver medicament in liquid or suspension form.

[005] Enrobed tablets are the dosage forms wherein solid tablet core is enrobed in soft elastic film material such as a gelatin film has significant advantages like tamper evident and ease of swallowing making it one of the most desired dosage form. The enrobed tablets can be further processed to have enteric coatings for acid resistant properties and also the enrobed tablet can be enrobed to have significantly more strength and resistance to breakage during handling.

[006] One characteristic of tablet dosage form is that it may be manufactured with a score or scores. This characteristic is useful because the score can be used to facilitate the splitting of the tablet into fractions when less than a full tablet is desired for a dose. Regulatory agencies have widely recognized the importance and benefits of the scoring in dose division for patient population. The splitting of the tablets into fractions is dependent on many factors like hardness, size, shape and pattern of score line. Due to these factors accurate splitting of the tablet into fractions is difficult and is often associated with errors. Due to this many times the tablet fractions often contain either higher or lower amount of the active than the desired amount.

[007] There are efforts to overcome inaccurate splitting of the tablet into fractions with technologies like Accu-break, wherein the placebo layer is compressed in between two active segments. Also Accu-break approach provides methods of achieving accurate splitting of the tablet into equal fractions in bi-layer tablets. As these approaches can’t be adapted to many of the active ingredients due to various reasons like high doses of active ingredient, incompatibility between active ingredient and processing difficulties there is a need for development of other methods of achieving uniform splitting of tablets into equal fractions.

[008] Many times patients during treatment need to be administered with multiple dosage units or formulations as the active ingredients are available as different formulations. Multiple layer tablets make it possible to formulate different active ingredients into one tablet dosage form wherein one or more than one active may be included in each layer and/or immediate release and extended release layers can be combined in single tablet. However, bilayer formulations are often associated with challenges like difficulty in formulation development, processing difficulties, low manufacturing yield, incompatibility and stability issues. Hence there is a need for development of methods wherein number of dosage units can be reduced during the treatment to improve patient compliance.

[009] Enrobed formulations available contain single tablet core wherein one tablet is enrobed with film. Based on the aforementioned discussion, there still remains an unmet need in the art to ameliorate or overcome the lacunae in the process of manufacture/preparation of stabilized multi-component pharmaceutical single dosage forms. The above discussion of documents is included solely for the purpose of providing a context for the present invention. BRIEF SUMMARY

[010] The following presents a simplified summary of the disclosure in order to provide a basic understanding to the reader. This summary is not an extensive overview of the disclosure and it does not identify key/critical elements of the invention or delineate the scope of the invention. Its sole purpose is to present some concepts disclosed herein in a simplified form as a prelude to the more detailed description that is presented later. A more complete appreciation of the present invention and the scope thereof can be obtained from the accompanying drawings which are briefly summarized below and the following detailed description of the presently preferred embodiments.

[011] An objective of the present disclosure is directed towards providing a multi- component pharmaceutical actives in a single unit of dosage form i.e., multi-component pharmaceutical single dosage forms.

[012] An objective of the present disclosure is directed towards providing a multi- component pharmaceutical single dosage forms wherein more than one tablet/pharmaceutical composition can be held together either by enrobing/banding/encapsulating to form single unit of dosage form.

[013] An objective of the present disclosure is directed towards providing two or more tablet units for preparation of single dosage unit. The tablet units may be of same formulation comprising same active ingredient or tablets may be of different formulation comprising same active ingredient or tablets may be of different formulation comprising different active ingredients.

[014] Another objective of the present disclosure is directed towards enrobing/banding/encapsulating of multiple tablets in such a way, to obtain a product, which allows for reducing the number of dosage units during treatment thereby improving patient compliance.

[015] Another objective of the present disclosure is directed towards different formulation requirements followed during the enrobing/banding/encapsulating of the tablets units/sub units to obtain a product, which upon splitting provides equal halves. [016] In another aspect of the present disclosure, the multi-component pharmaceutical single dosage form may be extended release or immediate release tablets.

[017] According to an exemplary embodiment of the present disclosure, a multi-component pharmaceutical single dosage form comprising: a plurality of tablet sub-units being selected from an uncoated, a film coated, a placebo, a delayed release coated (enteric coated), a modified release coated or combinations thereof, wherein ends of the plurality of tablet sub units are held together with a film.

[018] Furthermore, the objects and advantages of this invention will become apparent from the following description.

BRIEF DESCRIPTION OF THE DRAWINGS

[019] Other objects and advantages of the present invention will become apparent to those skilled in the art upon reading the following detailed description of the preferred embodiments, in conjunction with the accompanying drawings, wherein like reference numerals have been used to designate like elements, and wherein:

[020] FIG. 1 is a diagram 100 depicting a pictorial representation of multi-component pharmaceutical single dosage form comprising tablet units/tablet sub-units before enrobing/enrobing/encapsulation, in accordance with one or more exemplary embodiments.

[021] FIG. 2 is a diagram 200 depicting a multi-component pharmaceutical single dosage form containing two tablet units, in accordance with one or more exemplary embodiments.

[022] FIG. 3 is a diagram 300 depicting a multi-component pharmaceutical single dosage form containing three tablet units, in accordance with one or more exemplary embodiments.

[023] FIG. 4 is a diagram 400 depicting a multi-component pharmaceutical single dosage form comprising enrobed tablets with pre-formed gelatin shells, in accordance with one or more exemplary embodiments. [024] FIG. 5 is a diagram 500 depicting a multi-component pharmaceutical single dosage form comprising encapsulated tablets with two tablet units, in accordance with one or more exemplary embodiments.

[025] FIG. 6 is a diagram 600 depicting a multi-component pharmaceutical single dosage form comprising enrobed tablets with two tablet units having empty space or placebo tablet unit, in accordance with one or more exemplary embodiments.

DETAILED DESCRIPTION

[026] It is to be understood that the present disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the drawings. The present disclosure is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

[027] The use of “including”,“comprising” or“having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. The terms“a” and“an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. Further, the use of terms“first”,“second”, and“third”, and the like, herein do not denote any order, quantity, or importance, but rather are used to distinguish one element from another.

[028] All publications herein are incorporated by reference to the same extent as that clearly to be included by reference if each individual publication or patent application, and individually indicated. The following description includes information that may be useful for understanding the present invention. This does not admitted that any of the information is prior art, or to be or being specifically related to the invention claimed herein or implicit any prior art publication is referred to as provided herein.

[029] The term tablet unit/tablet sub-units refer to the tablet units that comprise the muti- component single dosage form. The tablet sub-units or tablet units may be coated or uncoated as described herein. [030] The term "biphasic release" as used herein refers to two different phases of release of pharmaceutical or drug active or salts thereof from the composition, with or without a preceding lag time. The appearance of second phase of release may be detected with a sudden increase in the rate of release at the beginning of the second phase. This can be observed by a change in the slope of the cumulative drug release profile.

[031] The term "modified release pharmaceutical composition" as used hereinbefore and throughout the description includes dosage forms containing combination of components providing pharmaceutical or drug active or salts thereof (immediate release and/or extended release) from the multi-component pharmaceutical single dosage form.

[032] The term "controlled release" is intended to refer to non-immediate release of pharmaceutical or drug active or salts thereof from the formulation.

[033] The term "sustained release" is used in its conventional sense to refer to a formulation that provides for gradual release of pharmaceutical or drug active or salts thereof over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of pharmaceutical or drug active or salts thereof over an extended time period.

[034] The term "delayed release" is used in its conventional sense to refer to a formulation in which there is a time delay between oral administration of the formulation and the release of pharmaceutical or drug active or salts thereof. Delayed release may or may not involve gradual release of pharmaceutical or drug active or salts thereof over an extended period of time, and thus may or may not be sustained release. For example, delayed release formulations of pharmaceutical or drug active or salts thereof are enterically coated components.

[035] The modified release pharmaceutical composition or sustained release and immediate release components therein may be prepared by processes known to the person having ordinary skill in the art of pharmaceutical technology such as direct compression, wet or dry granulation, slugging, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion- spheronization, spray drying and solvent evaporation. [036] Suitable "rate controlling polymers" may include one or more of hydrophilic and hydrophobic polymers or mixtures thereof.

[037] Suitable hydrophilic polymers may include one or more of cehulosic polymers/copolymers or its derivatives including methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose; polyethylene oxides, polyethylene glycols, chitosan, gums, starch derivatives, polyurethanes, galactomannans, polysaccharides, polyalcohols, acrylic acid or acrylamide derivatives and the like. The preferred hydrophilic polymer is hydroxypropyl methylcellulose/ Hypromehose E5 or any commercially available grade thereof such as Methocel.

[038] Suitable hydrophobic polymers include one or more of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, carnaubawax, hydrogenated vegetable oil, glycerol monostearate, stearylalcohol, glyceryl behenate, poly anhydrides, methylacrylates and the like.

[039] The polymers used can also be eroding or non-eroding or combination of both.

[040] The polymers, which may be used for bioadhesion, are described below. Natural polymers include but are not limited to proteins (e.g., hydrophilic proteins), such as pectin, zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, chitosan, oligosaccharides and polysaccharides such as cellulose, dextrans, tamarind seed polysaccharide, gellan, carrageenan, xanthan gum, gum Arabic; hyaluronic acid, polyhyaluronic acid, alginic acid, sodium alginate.

[041] When the bioadhesive polymer is a synthetic polymer, the synthetic polymer is typically selected from but are not limited to polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and methacrylic esters, polylactides, poly(butyric acid), poly(valeric acid), poly(lactide-co-glycolide), poly anhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), and blends and copolymers or mixtures thereof. [042] Other polymers suitable for use in the invention include, but are not limited to, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxybutylmethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, alkyl phthalate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate, cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(Iauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly (ethylene oxide), poly (ethylene terephthalate), polyvinyl acetate), polyvinyl chloride, polystyrene, polyvinyl pyrrolidone, and polyvinylphenol. Polylactides, polyglycolides and copolymers thereof, poly (ethylene terephthalate), poly (butyric acid), poly (valeric acid), poly(lactide-co- caprolactone), poly[lactide-coglycolide], polyanhydrides (e.g., poly(adipic anhydride)), poly orthoesters, blends and copolymers thereof. Another group of polymers suitable for use as bioadhesive polymers but not necessarily limited to polymers having a hydrophobic backbone with at least one hydrophobic group pendant from the backbone. Suitable hydrophobic groups are groups that are generally non-polar.

[043] Suitable "pharmaceutically acceptable binders" may include one or more of Methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, gum arabic, polymethacrylates, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, carrageenan, polyethylene oxide, waxes, pullulan, agar, tragacanth, veegum, pregelatinized starch, sodium alginate, gums, sugars such as sucrose, maltose, dextrose, lactose, amylase, synthetic resins and the like.

[044] The term "acidic and basic substances" as used herein are high molecular weight substances which exhibits acidity and basicity respectively when dissolved or suspended in water. The preferred high molecular weight acidic and basic substances are polymers. However, it will be appreciated to the person skilled in the art that any substance imparting said property can be used as long as it stabilizes the pharmaceutical composition. [045] The pharmaceutically acceptable excipients may include one or more fillers, lubricants, disintegrants, glidants, colorants, sweeteners, plasticizers and the like.

[046] Suitable fillers may include, but not limited to one or more of microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol, erythritol and the like.

[047] Suitable disintegrants may include, but not limited to one or more of croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone and the like.

[048] Suitable plasticizers may include, but not limited to one or more of glycerine fatty acid esters; triethyl citrate; propylene glycol; polyethylene glycol and the like.

[049] Suitable lubricants and glidants may include one or more of talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, Hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin; and the like Suitable plasticizers may include, but not limited to one or more of polyols such as glycerol, propylene glycol, polyethylene glycol (PEG), urea, or other known plasticizers such as triethyl citrate, dibutyl or dimethyl phthalate or water.

[050] Suitable examples of colorants include, but not limited to one or more of nonwater soluble lake pigments; neutral pigments; yellow ferric oxide; red ferric oxide; black iron oxide and the like.

[051] Referring to FIG. 1 is a diagram 100, depicting a pictorial representation of multi- component pharmaceutical single dosage form comprising tablet units/tablet sub-units before banding/enrobing/encapsulation, in accordance with one or more exemplary embodiments. The multi-component single dosage form 100 comprises of tablet units/tablet sub-units 101. [052] Referring FIG. 2 is a diagram 200 depicting a multi-component pharmaceutical single dosage form containing two tablet units, in accordance with one or more exemplary embodiments. The multi-component single dosage form 200 comprises a gelatin film 202 and tablet sub-units 201. A dosage form of the invention is shown in the FIG. 2 wherein the ends of two tablet units are banded together using a pre-formed cylindrical gelatin shell layer, gelatin film or gelatin banding process. Similar banding is possible by using enrobing method wherein pre-formed cylindrical shells are prepared and tablets are placed into the shells in the machine.

[053] Referring FIG. 3 is a diagram 300 depicting a multi-component pharmaceutical single dosage form containing three tablet units, in accordance with one or more exemplary embodiments. A dosage form formed by such a method can be further taken for additional process to include additional tablet units similar to dosage form of the invention shown in the FIG. 3. In figure 3, 302 is the gelatin film and the tablet sub-units are represented by 301.

[054] Referring FIG. 4 is a diagram 400 depicting a multi-component pharmaceutical single dosage form comprising enrobed tablets with pre-formed gelatin shells, in accordance with one or more exemplary embodiments. In figure 4, 402 is the gelatin film and the enrobed tablet sub-units are represented by 401.

[055] Referring FIG. 5 is a diagram 500 depicting a multi-component pharmaceutical single dosage form comprising encapsulated tablets with two tablet units, in accordance with one or more exemplary embodiments. In figure 5, 502 is the gelatin film and the encapsulated tablet sub-units are represented by 501.

[056] Referring FIG. 6 is a diagram 600 depicting a multi-component pharmaceutical single dosage form comprising enrobed tablets with two tablet units having empty space or placebo tablet unit, in accordance with one or more exemplary embodiments. During the process of banding a placebo tablet can be included between two tablet units used as per the dosage form of the invention shown in the FIG 6. The placebo tablet between two tablet units is to ensure upon splitting the dosage form gives two equal halves of the dosage form without damaging the tablet units. While breaking the tablet the placebo tablet will be broken in such a way that two tablet units either side of the placebo tablet are not damaged. Further to facilitate breaking of the tablet color marking lines can be printed at the point of breaking/cutting for ease of identification and also preformed or drilled holes along the marking line can made to facilitate easier breaking of the tablet. During the process of banding an empty space can be maintained between two tablet units used as per the dosage form of the invention shown in the FIG 6. The empty space between two tablet units is to ensure upon splitting the dosage form gives two equal halves without damaging the tablet units. In figure 6, 602 is the gelatin film, the encapsulated tablet sub-units are represented by 601, 603a and 603b represent the breaking areas, 604 placebo tablet sub-units and 605 represent the empty spaces.

[057] A dosage form of the invention is shown in the FIG. 4 and FIG. 5 wherein both the tablets are either enrobed partially or completely encapsulated depending on the dosage form application requirement. Both the tablets used for the dosage form, may comprise of tablets with same formulation comprising same active ingredient, tablets with different formulation comprising same active ingredient, and tablets with different formulation comprising different active ingredient. The drawings and examples are provided for understanding the invention and however do not cover all possible examples.

[058] In an embodiment, film compositions used in the enrobing, banding and encapsulation process can be of traditional process used in the pharmaceutical manufacturing process but not limited to; A gelatin shell composition typically contains Gelatin, colorant, plasticizer and water. A F1PMC shell typically contains F1PMC and water.

[059] In an embodiment, for handling multiple tablet units for enrobing or banding or encapsulation process in the machine, the existing machines can be modified.

[060] In an embodiment, the tablet units for attaching are compressed in such a way that at least one flat surface is available for attaching of the tablet units. In the examples provided the cylindrical tablets are compressed with round deep concave upper punches and round Flat faced lower punches.

[061] In an embodiment, surfaces other than flat surface in subunits are considered suitable for attachment. Examples include tablet surfaces such as flat surface with depression at the centre. Tablet subunit with concave surface for attachment may be attached to a tablet subunit having convex surface with similar curvature that of concave surface. Similarly, various other surfaces of tablet subunits matching each other may be considered possible candidates for attachment.

[062] In an embodiment, the tablet unit used in the present invention can be applied to various shapes and sizes. The various shapes with atleast one flat surface include but not limiting to Oblong shape, Oval shape, cylindrical shape.

[063] In an embodiment, the tablet units used for attaching contain at least one active pharmaceutical ingredient (drug) having therapeutic effect. Two or more active pharmaceutical ingredient may also be mixed in one tablet unit.

[064] In an embodiment, the placebo tablet unit for linking two tablet units will be devoid of active pharmaceutical ingredient. Two or more tablet units used for preparation of single dosage unit may be of same formulation comprising same active ingredient or tablets may be of different formulation comprising same active ingredient or tablets may be of different formulation comprising different active ingredient.

[065] In an embodiment, the tablet subunits may include any of the active ingredients given here not limiting to Anastrozole, Alendronate Sodium, Atorvastatin,

Aciclovir, Aspirin, Amitriptyline, Amoxicillin, Amlodipine Besylate, Albuterol, Alprazolam, Atenolol, Azithromycin, Allopurinol, Hydrochlorothiazide, Acyclovir, Amiodarone Hydrochloride, Atomoxetine Hydrochloride, Acetaminophen, Aripiprazole, Amoxicillin, Ambroxol, Atorvastatin, Bisoprolol, Bupropion, Baclofen, Bisoprolol Fumarate, Benztropine Mesylate, Benazepril Hydrochloride, Buspirone Hydrochloride, Cyclobenzaprine, Carvedilol, Clopidogrel Bisulfate, Carbidopa, Chlorthalidone, Carisoprodol, Clonazepam, Clavulanate Potassium, Citalopram, Cefuroxime, Clonidine, Cetirizine Hydrochloride, Chlorthalidone, Chlopromazine, Ciprofloxacin, Cefadroxil, Cefixime, Clarithromycin, Canagliflozin, Carbamazepine, Celecoxib, Ciprofloxacin, Cephalexin, Cefdinir, Codeine Phosphate, Clozapin, Candesartan, Chloroquine, Ceftriaxone, Cefotaxim, Captopril, Cyproheptadine, Desloratadine, Domperidone, Diclofenac, Diazepam, Duloxetine, Diltiazem Hydrochloride, Dexlansoprazole, Domperidone, Dextroamphetamine, Dexamethasone, Doxycycline, Diphenhydramine Hydrochloride, Donepezil Hydrochloride, Dapagliflozin, Diclofenac salts, Dabigatran Etexilate Mesylate, Desvenlafaxine, Divalproex Sodium, Dextromethorphan, Empagliflozin, Enalapril Maleate, Ergocalciferol, Ezetimibe, Escitalopram Oxalate, Ethinyl Estradiol, Erythromycin, Esomeprazole, Eszopiclone, Epinephrine Hydrochloride, Folic Acid, Ferrous Sulfate, Fluoxetine Hydrochloride, Finasteride, Famotidine, Fentanyl, Furosemide, Fenofibrate, Fluconazole, Fexofenadine, Guaifenesin, Gemfibrozil, Glyburide, Glipizide, Gabapentin, Glimepiride, Guaifenesin, Hydrocodone Bitartrate, Hydrochlorothiazide, Haloperidol, Hydralazine Hydrochloride, Hydroxychloroquine Sulfate, Hydromorphone Hydrochloride, Isoniazid, Itraconazole, Irbesartan, Ibuprofen, Isosorbide Mononitrate, Ketorolac, Fevocetirizine, Fevothyroxine, Fevofloxacin, Fisinopril, Fovastatin, Fevodopa, Foperamide, Fosartan Potassium, Fevetiracetam, Forazepam, Foratadine, Fabetalol, Famotrigine,

Finagliptin, Fansoprazole, Foperamide, Metronidazole, Methylphenidate, Meloxicam, Metoclopramide Hydrochloride, Mirtazapine, Metoprolol, Metformin Hydrochloride, Memantine Hydrochloride, Metformin Hydrochloride, Mesalamine, Methimazole, Minocycline Hydrochloride, Montelukast, Methotrexate, Methylprednisolone, Mometasone, Moxifloxacin, Mefenamic acid, Mebendazole, Metamizole, Miconazole, Meclizine Hydrochloride, Nebivolol, Nifedipine Hydrochloride, Nortriptyline Hydrochloride, Naproxen, Nadolol, Niacin, Nitrofurantoin, Norethindrone, Norgestimate Estradiol, Naphazoline Hydrochloride, Norfloxacin, Omeprazole, Oxcarbazepine, Oxybutynin, Oseltamivir Phosphate, Olmesartan, Ondansetron, Oxycodone, Olanzapine, Oxymetzoline, Ofloxacin, Pantoprazole Sodium, Pravastatin Sodium, Pramipexole Dihydrochloride, Phenytoin, Propranolol Hydrochloride, Prednisolone, Pregabalin, Paroxetine, Prochlorperazine, Pioglitazone, Promethazine Hydrochloride, Pseudoephedrine Hydrochloride, Prazosin Hydrochloride, Prednisone, Piroxicam, Prednisolone, Propranolol, Pyrazinamide, Quetiapine Fumarate, Quinapril, Ropinirole Hydrochloride, Rizatriptan Benzoate, Ranolazine, Rosuvastatin Calcium, Risperidone, Ranitidine, Ramipril, Rabeprazole Sodium, Rivaroxaban, Raloxifene Hydrochloride, Rifampicin, Salbutamol, Sumatriptan, Sitagliptin Phosphate, Spironolactone, Solifenacin Succinate, Sildenafil, Simvastatin, Sulfamethoxazole, Sertraline Hydrochloride, Salmeterol, Sitagliptin Phosphate, Sotalol Hydrochloride, Tizanidine, Timolol, Tolterodine Tartrate, Topiramate, Telmisartan, Trazodone Hydrochloride, Timolol Maleate, Temazepam, Tadalafil, Tramadol Hydrochloride, Tamsulosin Hydrochloride, Testosterone, Tamoxifen Citrate, Triprolidine, Theophyline, Tranexamic acid, Trimetazidine, Valsartan, Vilazodone, Hydrochloride, Venlafaxine Hydrochloride, Verapamil Hydrochloride, Valacyclovir, Warfarin, Xinafoate, Zolpidem Tartrate. [066] In an embodiment, the tablet unit for the attachment may be prepared with pharmaceutical excipients. Pharmaceutical excipients such as diluents may include not limiting to calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, silicified microcrystalline, cellulose acetate, sugar, dextrates, dextrin, dextrose, fructose, glyceryl palmitostearate, hydrogenated vegetable oil type I, isomalt, kaolin, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, microcrystalline cellulose, polydextrose, sorbitol, starch, starch pregelatinized, sucrose, xylitol.

[067] In an embodiment, binders may include not limiting to acacia, carbomers, gelatin, guar gum, dextrin, hydroxypropyl starch, liquid glucose, magnesium aluminium silicate, sodium alginate, zein, Povidone, co povidone, Hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose.

[068] In an embodiment, disintegrants may include not limiting to Low substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, starches, croscarmellose sodium, crospovidone, pregelatined starch, sodium starch glycolate.

[069] In an embodiment, lubricants may include not limiting to Magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, polyethyelene glycols.

[070] In an embodiment, the tablet units may additionally contain other excipients such as colours, glidants, anti-adherents etc.

[071] In an embodiment, the tablet units for attachments may be in the form of coated or uncoated tablets. The coated tablets may comprise of, not limiting to film coated tablets, enteric coated tablets, modified release coated tablets or sugar coated tablets.

[072] In an embodiment, the coating of tablet may include polymer or non-polymer excipients. The polymer and non-polymer excipients in the coating films may include not limiting to Povidone, Co-povidone, Hydroxypropylmethyl cellulose, Hydroxypropyl cellulose, Gelatin, acacia, alginate, alginic acid, ethyl cellulose, Hydroxypropyl methyl cellulose phthalate, Methylcellulose, Methacrylic acid, polyethylene oxide, Sodium carboxymethyl cellulose, lactose, talc, starch, pregelatinized starch. [073] In an embodiment, a preformed film or film by banding process may be used for attaching two or more tablet units. The preformed film or film by banding process may comprise of polymer or non-polymer excipients. The examples of polymer or non-polymer excipients for the film may include not limiting to Povidone, Co-povidone, cellulose derivatives such as Hydroxypropylmethyl cellulose, Hydroxypropyl cellulose, ethyl cellulose, Hydroxypropyl methyl cellulose phthalate, Methylcellulose, Sodium carboxymethyl cellulose, Gelatin, acacia, alginate and alginate salts, alginic acid, Methacrylate salts, Methacrylic acid, polyethylene oxide.

[074] In an embodiment, the film may also comprise of organic plasticizers. Organic plasticizers may include not limiting to Polyethylene glycols, propylene glycol, glycerine, acetyl tributyl citrate, acetyltriethyl citrate, benyl benzoate, diethylphthalate, dibutyl sebacate, dimethyl phthalate, glycerin monostearate, stearic acid, sorbitol, tributyl citrate, triethanolamine, triacetic, Povidone.

[075] The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention

[076] Mostly, all the tablet units are compressed in such a way that at least one flat surface is available for attaching of the tablet units. In the examples provided the cylindrical tablets are compressed with round deep concave upper punches and round Flat faced lower punches. The tablet units for attachments may be in the form of uncoated tablets, film coated tablets, enteric coated tablets and modified release coated tablets. The compressed tablets are optionally coated.

[077] In an embodiment, the multi-component pharmaceutical single dosage form in which at least one of the film coated tablet sub-units with preformed films comprise of atleast one excipient such as gelatin, Hydroxypropyl methylcellulose, Povidone, Co-povidone, Hydroxypropylmethyl cellulose, Hydroxypropyl cellulose, Gelatin, acacia, alginate, alginic acid, ethyl cellulose, Hydroxypropyl methyl cellulose phthalate, Methylcellulose, Methacrylic acid, polyethylene oxide or Sodium carboxymethyl cellulose.

[078] In an embodiment, a multi-component pharmaceutical single dosage form comprising: a plurality of tablet sub-units being selected from an uncoated, a film coated, a placebo, a delayed release coated (enteric coated), a modified release coated or combinations thereof, wherein ends of the plurality of tablet sub-units are held together with a film.

[079] In an embodiment, the film is in the form of a linker or a closure cap or enclosure film.

[080] In an embodiment, the film is applied to the dosage form by way of banding or enrobing or encapsulation process

[081] In an embodiment, the ends of the plurality of tablet sub-units are covered with a film.

[082] In an embodiment, the film is selected from a preformed gelatin shell layer or a preformed Hydroxypropyl methylcellulose (HPMC) shell layer.

[083] In an embodiment, multi-component pharmaceutical single dosage form comprises two tablet sub-units or tablet units, wherein one tablet unit/sub-unit is coated and the other tablet unit/sub-unit is uncoated.

[084] In an embodiment, the films comprise of atleast one excipient such as Povidone, Co povidone, Hydroxypropyl cellulose, Gelatin, acacia, alginate, alginic acid, ethyl cellulose, Hydroxypropyl methyl cellulose phthalate, Methylcellulose, Methacrylic acid, polyethylene oxide or Sodium carboxymethyl cellulose.

[085] In an embodiment, a multi-component pharmaceutical single dosage form comprising: a plurality of pre-formed cylindrical shells encompassing a plurality of tablet sub-units being selected from an uncoated, a film coated, a placebo, a delayed release coated (enteric coated), a modified release coated or combinations thereof.

[086] In an embodiment, preformed cylindrical shells are selected from gelatin or HPMC. [087] In an embodiment, a process of preparing a multi-component pharmaceutical single dosage form comprising:

Step a) placing the tablet units in a way that a plurality of flat surfaces of the tablet sub-units are facing each other;

Step b) applying a gelatin film solution to both the tablets using a roller;

Step c) drying the gelatin film to remove the moisture from the gelatin film; and Step d) step a, step b, step c are repeated to attach more number of tablet sub-units.

[088] Formula and procedure for preparation of tablet units:

In an embodiment, various manufacturing procedures such as direct compression, wet granulation or dry granulation approaches can be adopted for preparation of tablet units for attachment.

[089] Example 1: Direct compression method

[090] The following steps are involved herein:

1. Sifted Antidiabetic drug, lactose monohydrate (Direct compressible).

2. Sifted Povidone K-30 and maize starch and added to step -1 and mixed manually then transferred to blender and blending was done for 20 min.

3. Sifted Magnesium stearate and transferred into blender and lubricated it for 5 min.

4. Lubricate granules were compressed in the tablet press using 7.00 mm round Flat bevel edged plain lower punch and 7.00 mm round plain concave upper punch.

5. Coating solution of Opadry pink were prepared in water using mechanical stirrer. 6. Core tablets were placed in coating pan and the coating solution was sprayed onto the tablets.

[091] Example 2: Wet granulation method

# Solvent used for granulation process and removed in drying process

[092] The following steps are involved herein:

1. Sifted Antidiabetic drug, lactose monohydrate. Sifted materials were mixed in Rapid mixer granulator for 10 minutes.

2. Dissolved Povidone K 30 in a mixture of Isopropyl alcohol and Purified water. Povidone solution was added to step 1 and granulated.

3. Step 2 contents were dried till LOD (Loss on drying) at 105°C is Less than 2 % w/w.

4. Sifted Maize starch and Magnesium stearate.

5. Contents of Step 3 and Step 4 were transferred into blender and mixed for 5 min.

6. Lubricate granules were compressed in the tablet press using 7.00 mm round Flat bevel edged plain lower punch and 7.00 mm round plain concave upper punch.

7. Coating solution of Opadry pink were prepared in water using mechanical stirrer.8. Core tablets from step 6 were placed in coating pan and the coating solution was sprayed onto the tablets.

[093] The banding or enrobing or encapsulation film may comprise of polymer or non polymer excipients. The examples of polymer or non-polymer excipients for the film may include not limiting to Povidone, Co-povidone, cellulose derivatives such as Hydroxypropylmethyl cellulose, Hydroxypropyl cellulose, ethyl cellulose, Hydroxypropyl methyl cellulose phthalate, Methylcellulose, Sodium carboxymethyl cellulose, Gelatin, acacia, alginate and alginate salts, alginic acid, Methacrylate salts, Methacrylic acid , polyethylene oxide.

[094] The film may also comprise of organic plasticizers. Organic plasticizers may include not limiting to Polyethylene glycols, propylene glycol, glycerine, acetyl tributyl citrate, acetyltriethyl citrate, benyl benzoate, diethylphthalate, dibutyl sebacate, dimethyl phthalate, glycerin monostearate, stearic acid, sorbitol, tributyl citrate, triethanolamine, triacetic, Povidone.

[095] The application of film on to the tablet units may be carried out with different approaches such as banding with banding solution, enrobing of preformed gelatin shell or encapsulation of film. In banding process, the banding solution is applied to edges of two tablet units simultaneously. Examples of banding film compositions are given below

[096] Example A: Banding solution - HPMC solution

Hydroxypropylmethyl cellulose 16 gms

Ethanol 53 gms

Water 31 gms

Banding solution Temperature: Room temperature

[097] Example B: Banding solution - Gelatin solution

Gelatin 22 gms

Water 78 gms

Banding solution temperature: 50°C to 60°C [098] Banding of two or more tablets:

At a time two tablet units of Example 1 are taken; the tablet units are oriented in such a way that flat surface of the tablets are facing each other. The gelatin film solution is applied to both the tablets using a roller. The gelatin film is allowed to dry to remove the moisture from the film. After removal of the moisture the film will be regid and both the tablet units will behave as one tablet unit. The process may be repeated to attach more number of tablet units. To attach more than two tablet units the tablet unit in the middle should have two flat surfaces.

[099] Enrobing of two or more tablet units using preformed gelatin shell:

At a time two tablet units are attached together. A preformed gelatin shell in the form of cylindrical shape is taken. The flat surface side of one tablet unit of Example 1 is inserted into the gelatin shell or any other shell. The insertion is carried out till it reaches pre-defined length of the gelatin shell. Further the flat surface side of another tablet unit of Example 1 is inserted in to the other side of the gelatin shell. The gelatin shell or any other shell is allowed to adhere to the tablet surface. After adherence of the shell to tablet surface the two tablet units will behave as one tablet unit. The process may be repeated to attach more number of tablet units. To attach more than two tablet units the tablet unit in the middle should have two flat surfaces.

[0100] Over encapsulation of tablet units:

Two tablet units are taken and fed in between two gelatin films together. The excess gelatin film is trimmed and removed by the die and simultaneously the two gelatin films are sealed. The over encapsulated tablet unit is allowed dry for removing the moisture from the gelatin film.

[0101] Reference throughout this specification to“one embodiment”,“an embodiment”, or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, appearances of the phrases“in one embodiment”,“in an embodiment” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment. [0102] The present disclosure has been described in terms of certain preferred embodiments and illustrations thereof, other embodiments and modifications to preferred embodiments may be possible that are within the principles and spirit of the invention. The above descriptions and figures are therefore to be regarded as illustrative and not restrictive. Thus the scope of the present disclosure is defined by the appended claims and includes both combinations and sub combinations of the various features described herein above as well as variations and modifications thereof, which would occur to persons skilled in the art upon reading the foregoing description.

Claims

CLAIMS I Claim:

1. A multi-component pharmaceutical single dosage form comprising: a plurality of tablet sub-units being selected from an uncoated, a film coated, a placebo, a delayed release coated (enteric coated), a modified release coated or combinations thereof, wherein ends of the plurality of tablet sub-units are held together with a film.

2. The multi-component pharmaceutical single dosage form as claimed in claim 1, wherein the film is in the form of a linker or a closure cap or enclosure film.

3. The multi component pharmaceutical single dosage form as claimed in claim 1, wherein the film is applied to the dosage form by way of banding or enrobing or encapsulation process

4. The multi-component pharmaceutical single dosage form as claimed in claim 1, wherein the ends of the plurality of tablet sub-units are covered with a film.

5. The multi-component pharmaceutical single dosage form as claimed in claim 1, wherein the film is selected from a preformed gelatin shell layer or a preformed Hydroxypropyl methylcellulose (HPMC) shell layer.

6. The multi-component pharmaceutical single dosage form as claimed in claim 1, wherein the multi-component pharmaceutical single dosage form comprises two tablet sub-units or tablet units, wherein one tablet unit/sub-unit is coated and the other tablet unit/sub-unit is uncoated.

7. The multi-component pharmaceutical single dosage form as claimed in claim 1 in the films comprise of atleast one excipient such as Povidone, Co-povidone, Hydroxypropyl cellulose, Gelatin, acacia, alginate, alginic acid, ethyl cellulose, Hydroxypropyl methyl cellulose phthalate, Methylcellulose, Methacrylic acid, polyethylene oxide or Sodium carboxymethyl cellulose.

8. A multi-component pharmaceutical single dosage form comprising: a plurality of pre-formed cylindrical shells encompassing a plurality of tablet sub-units being selected from an uncoated, a film coated, a placebo, a delayed release coated (enteric coated), a modified release coated or combinations thereof.

9. The multi-component pharmaceutical single dosage form as claimed in claim 8, wherein the preformed cylindrical shells are selected from gelatin or HPMC.

10. A process of preparing a multi-component pharmaceutical single dosage form comprising:

Step a) placing the tablet units in a way that a plurality of flat surfaces of the tablet sub-units are facing each other;

Step b) applying a gelatin film solution to both the tablets using a roller;

Step c) drying the gelatin film to remove the moisture from the gelatin film; and Step d) step a, step b, step c are repeated to attach more number of tablet sub-units.