WO2019003062A1

WO2019003062A1 - Tamper-proof dosage form comprising pharmaceutically active agent

Info

Publication number: WO2019003062A1
Application number: PCT/IB2018/054579
Authority: WO
Inventors: Sivakumar Venkata BOBBA; Bhimrao Jadhav; Dhananjay Shinde
Original assignee: Zenvision Pharma LLP
Current assignee: Zenvision Pharma LLP
Priority date: 2017-06-29
Filing date: 2018-06-21
Publication date: 2019-01-03
Anticipated expiration: 2019-12-29

Abstract

The present disclosure relates to tamper-proof dosage form comprising oncological pharmaceutically active agent or other active ingredient which is susceptible to topical or nasal contact. The tamper-proof dosage form according to present invention resist crushing, cutting or chewing and prevents topical and inhalational contact of active ingredient which leads to no adverse clinical symptom.

Description

TAMPER-PROOF DOSAGE FORM COMPRISING PHARMACEUTICALLY

ACTIVE AGENT

FIELD OF THE INVENTION

The present invention relates to tamper-proof dosage form comprising pharmaceutically active agent.

BACKGROUND OF THE INVENTION

Oncological drugs can be lifesaving to a cancer patient, but unintentional exposure to these powerful agents may be harmful to the lives of healthcare professionals like pharmacists or nurses or the individual who are in association with these oncological drugs. The exposure of Oncological drugs is harmful to healthy cells and tissues.

Healthcare professionals like pharmacists, physicians, operating room personnel, Hospital staff such as shipping and receiving personnel, custodial workers, laundry workers and waste handlers or individual who are in association with oncological drugs may prone to inhalational or topical exposure to the oncological drugs during the course of their work which leads to adverse clinical symptom. Exposure of these oncological drugs can confer significant health risks and adverse clinical symptoms such as immediate nervous system effects, acute and long term reproductive effects (e.g., infertility and miscarriage), and a subsequent risk for hematologic malignancies. In addition to oncological drugs there are several other therapeutic categories of drugs which causes adverse clinical symptoms due to their topical or inhalational exposure and these includes analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, antidiabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, erectile-dysfunction- improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β-blockers, cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2-inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti- osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, and non-essential fatty acids.

Oncological drugs and certain other drugs in other therapeutic categories are prone to adverse clinical symptom due to their topical or inhalational exposure.

An oncological drug such as Dasatinib is a kinase inhibitor. Chemically dasatinib is N-(2- chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4pyrimidinyl] amino]-5- thiazolecarboxamide, monohydrate and its molecular weight is 488.01. Its empirical formula is C22H26CIN7O2S · H2O. Dasatinib is represented by compound of structural formula I

Formula I

Dasatinib is a white to off-white powder. Dasatinib is slightly soluble in ethanol, methanol and insoluble in water.

A Dasatinib tablet of Bristol Myers Squibb has been approved in USA as on Jun 28, 2006 under the trade name SPRYCEL^®. The product is available in the strength of 20MG, 50MG, 70MG, 80MG, 100MG &140MG. The product is indicated for the treatment of adults with "newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase", "chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib", "Philadelphia chromosome -positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy"

Imatinib is a small molecule kinase inhibitor. Chemically Imatinib mesylate is 4-[(4- Methyl 1 -piperazinyl)methyl] -N- [4-methyl-3 -[ [4-(3 -pyridinyl)-2-pyrimidinyl] amino] - phenyljbenzamide methanesulfonate and its molecular weight is 589.7. Its molecular formula is C29H31N7O · CH4SO3. Imatinib mesylate is represented by compound of structural formula II

Formula II

Imatinib mesylate is a white to off-white to brownish or yellowish tinged crystalline powder. It is soluble in aqueous buffers less than or equal to pH 5.5 but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers. In non-aqueous solvents, the drug substance is freely soluble to very slightly soluble in dimethyl sulfoxide, methanol, and ethanol, but is insoluble in n-octanol, acetone, and acetonitrile.

Imatinib mesylate tablets of Novartis Pharmaceuticals Corp have been approved in USA as on Apr 18, 2003 under the trade name Gleevec®. The product is available in the strength of EQ 100MG base and EQ 400MG base. The product is indicated for the treatment of newly diagnosed Philadelphia positive chronic myeloid leukemia (Ph+ CML), Ph+ cml in blast crisis (BC), accelerated phase (AP) or chronic phase (CP) after interferon-alpha (IFN) therapy, adult patients with Ph+ acute lymphoblastic leukemia (ALL), pediatric patients with Ph+ acute lymphoblastic leukemia (ALL), myelodysplastic/myeloproliferative diseases (MDS/MPD), aggressive systemic mastocytosis (ASM), hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL), dermatofibrosarcoma protuberans (DFSP), Kit+ gastrointestinal stromal tumors (GIST) and adjuvant treatment of GIST.

U.S. Patent No. 8,894,988 discloses tamper resistant dosage forms of opioid analgesic, preferably Oxycodone, processes of manufacture, uses, and methods of treatment thereof.

U.S. Patent No. 8,420,056 discloses abuse-proofed dosage form of Tapentadol Hydrochloride, optionally together with physiologically acceptable auxiliary substances, at least one polyalkylene oxide, at least one synthetic or natural polymer and optionally at least one wax.

U.S. Patent No. 8,075,872 discloses abuse-proofed dosage form of oxycodone, oxymorphone, hydromorphone, morphine and Tapentadol Hydrochloride, optionally together with physiologically acceptable auxiliary substances, at least one polyalkylene oxide, at least one synthetic or natural polymer and optionally at least one wax.

The oncological active ingredients like Dasatinib, Sunitinib, Afatinib, Imatinib, Ponatinib, Ibrutinib, Axitinib, Lenvatinib, Bosutinib, Alectinib, Decitabine, Nilotinib, Lapatinib, Trametinib, Erlotinib, Osimertinib, Dabrafenib, Vandetanib, Crizotinib, Ceritinib and other certain active ingredient are susceptible to topical or nasal contact leads to adverse clinical symptom; therefore these should not be crushed, cut or chewed.

Oncological drug products and certain other active ingredients are susceptible for topical or inhalational contact. Topical and inhalational contact of such Oncological drug products and certain other active ingredients leads to systemic absorption of the same which leads to adverse clinical symptom. Due to their susceptibility for topical or inhalational contact these dosage form should not be crushed, cut or chewed. Therefore, these dosage forms should be swallowed whole. Thus, there is an unmet need in the art to provide tamper-proof dosage form comprising oncological active ingredient or certain other active ingredients which resist crushing, cutting or chewing and which prevents topical and inhalational contact of active ingredient

OBJECTS OF THE INVENTION

Accordingly, it is an object of the present invention to provide tamper-proof dosage form comprising Oncological active agent.

It is another object of the present invention to provide tamper-proof dosage form of certain other active ingredient which is susceptible to topical or nasal contact and leads to adverse clinical symptom.

It is another object of the present invention to provide tamper-proof dosage form comprising Oncological active agent and certain other active ingredient which resist crushing, cutting or chewing.

It is another object of the present invention to provide tamper-proof dosage form comprising oncological active agent and certain other active ingredient which prevents topical and inhalational contact of active ingredient; therefore prevents adverse clinical symptom

It is another object of the present invention to provide tamper-proof dosage form comprising oncological active agent which is efficacious and provides better patient compliance in the treatment of cancer. SUMMARY OF THE INVENTION

A first aspect of the present invention is to provide tamper-proof dosage form comprising oncological active agent or other certain active agent which causes adverse clinical symptoms when exposed through topical or inhalational route. In another aspect of the present invention is to provide tamper-proof dosage form comprising preferably oncological active agent. In another aspect of the present invention is to provide tamper-proof dosage form comprising oncological active agent and one or more pharmaceutically active excipient.

In another aspect of the present invention is to provide tamper-proof dosage form comprising oncological active ingredient in the form of tablet, capsule i.e. Hard gelatin capsule or Soft Gelatin Capsule, granule, pellet, beads, and sachet.

In another aspect of the present invention is to provide process of manufacturing the tamper-proof dosage form comprising oncological active ingredient.

In another aspect of the present invention is to provide the tamper-proof dosage form comprising oncological active ingredient for the treatment of cancer.

DETAIL DESCRIPTION OF THE INVENTION

The tamper-proof dosage form according to present invention means "a dosage form which prevents the topical or inhalational contact of active agent and also resists the crushing, cutting or chewing of the dosage form".

The active agent according to present invention means "oncological active agent or other therapeutic active agent which causes adverse clinical symptoms when exposed through topical or inhalational route".

The term "dosage form" according to present invention can be alternatively used as "composition".

The tamper-proof dosage form comprising pharmaceutically active agent may be in the form of tablet, capsule i.e. hard gelatin capsule or soft gelatin capsule, granule, pellet, beads, and sachet. The tamper-proof dosage form in the form of tablet, granule, pellet or beads may contain coating.

The tamper-proof dosage form according to present invention preferably may be in the form of tablet.

The tamper-proof dosage form comprising pharmaceutically active agent may contain one or more pharmaceutically acceptable excipient. The one or more pharmaceutically acceptable excipient in the present tamper-proof dosage form may be selected from the group consisting of fillers or diluents, viscosity modifiers, solvent, disintegrants, binders, surfactant/solubilizer, Coating materials, Plasticizers, antioxidant, glidants, lubricants, Coloring agents or combination thereof. The examples of fillers or diluents include but not limited to microcrystalline cellulose, lactose, sucrose, glucose, mannitol, sorbitol, dicalcium phosphate, tricalcium phosphate or combination thereof.

The examples of viscosity modifiers include but not limited to polyalkylene oxide, microcrystalline cellulose, carboxymethylcellulose sodium, polyacrylic acid, locust bean flour, pectins, waxy maize starch, sodium alginate, guar flour, iota carrageen, karaya gum, gellan gum, galactomannan, tara bean flour, propylene glycol alginate, sodium hyaluronate, tragacanth, tara gum, polysaccharide welan gum, xanthan gum or combination thereof.

The polyalkylene oxide includes but not limited to polyethylene oxide, polymethylene oxide, polypropylene oxide or combination thereof.

The examples of solvent include but not limited to caprylic acid, capric acid, oleic acid, palmitic acid, glyceryl monooleate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl caprylate, caprate, propylene glycol monocaprate, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dilaurate, polyethylene glycol (PEG) -4 glyceryl caprylate, PEG-6 glyeryl linoleate, PGE-6 glyceryl linoleate, PEG-6 glyceryl oleate, caprylic/capric triglyceride, propylene glycol dicaprylate/dicaprate, soyabean oil and mixtures of two or more thereof The examples of disintegrants include but not limited to croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone or combination thereof.

The examples of binders include but not limited to polyalkylene oxide, polyethylene oxide, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, polyvinyl pyrrolidone, starch derivatives such as corn starch, potato starch, a-starch and dextrin or combination thereof.

The examples of surfactant/solubilizer include but not limited to sodium lauryl sulfate, Dimethylacetamide (DMA), Beeswax, Polyoxyl 35 castor oil (Cremophor EL), Dimethyl sulfoxide (DMSO), Oleic acid Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), Ethanol, Soy fatty acids, Polyoxyl 60 hydrogenated castor oil (Cremophor RH 60), Glycerin, d-a-tocopherol (Vitamin E), Polysorbate 20 (Tween 20), N-methyl-2- pyrrolidone (NMP), Corn oil, mono-di-tridiglycerides, Polysorbate 80 (Tween 80), PEG 300, PEG 400, Poloxamer 407, Propylene glycol, Medium chain (C8/C10) mono- and diglycerides, Long-chain triglycerides, d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), Solutol HS-15, Sorbitan monooleate (Span 20), Hydroxypropyl- -cyclodextrin, Sulfobutylether- -cyclodextrin (Captisol®), β-cyclodextrin, Phospholipids, Castor oil, Corn oil, Cottonseed oil, Olive oil, Peanut oil, PEG 300 caprylic/capric glycerides (Softigen 767), PEG 400 caprylic/capric glycerides (Labrasol), PEG 300 oleic glycerides (Labrafil M-1944CS), PEG 300 linoleic glycerides (Labrafil M-2125CS), Polyoxyl 8 stearate (PEG 400 monosterate), Polyoxyl 40 stearate (PEG 1750 monosterate), Hydrogenated soy phosphatidylcholine (HSPC), Safflower oil, Sesame oil, Peppermint oil, Distearoylphosphatidylglycerol (DSPG), Soybean oil, Hydrogenated soybean oil, L- a-dimyristoylphosphatidylcholine (DMPC), Hydrogenated vegetable oils, L-a- dimyristoylphosphatidylglycerol (DMPG), Medium-chain triglycerides, Caprylic/capric triglycerides derived from coconut oil or palm see oil or combination thereof. The examples of Coating materials include but not limited to Hydroxy propyl methyl cellulose (HPMC), Synthetic polymers, Shellac, Corn protein, Zein, Polysaccharides, Gelatin, Povidone, Ethyl cellulose or combination thereof. The examples of Plasticizers include but not limited to Castor oil, Diacetylated Monoglycerides, Polyethylene glycol, Polypropylene glycol, Triacetin or combination thereof.

The examples of antioxidant include but not limited to a-tocopherol, butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate or combination thereof.

The examples of glidants include but not limited to talc, magnesium stearate, starch, colloidal silicon dioxide or combination thereof. The examples of lubricants include but not limited to talc, silica, fats, magnesium stearate or stearic acid or combination thereof.

The examples of Coloring agents include but not limited to FD and C, D and C dyes and lakes or combination thereof.

The tamper-proof dosage form of the present invention may be in the form of immediate release or extended release or delayed release dosage form.

The tamper-proof dosage form comprising active agent may be selected from oncology, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, antimigraine agents, anti-muscarinic agents, erectile-dysfunction-improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β-blockers, cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2-inUibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti- obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, and non-essential fatty acids.

The tamper-proof dosage form comprising active agent may be preferably in the class of oncology. The oncological active agent according to present invention may be selected from but not limited to Dasatinib, Sunitinib, Afatinib, Imatinib, Ponatinib, Ibrutinib, Axitinib, Lenvatinib, Bosutinib, Alectinib, Decitabine, Nilotinib, Lapatinib, Trametinib, Erlotinib, Osimertinib, Dabrafenib, Vandetanib, Crizotinib, Ceritinib, Everolimus, Etoposide, Paclitaxel, Irinotecan, Docetaxel, Vincristine, Carboplatin, Cisplatin, Oxaliplatin, Bevacizumab, Cetuximab, Trastuzumab, Denosumab, Rituximab, Zoledronate, Abiraterone, Anastrozole, Bicalutamide, Exemestane, Goserelin, Medroxyprogesterone, Octreotide, Tamoxifen, Bendamustine, Carmustine, Chlorambucil, Lomustine, Melphalan, Procarbazine, Streptozocin, Fludarabine, Raltitrexed, Actinomycin D / Dactinomycin, Doxorubicin, Mitoxantrone, Eribulin, Topotecan, Vinblastine, Vinorelbine, Sorafenib, Trastuzumab emtansine, Temsirolimus, Vemurafenib, Ibandronic acid, Pamidronate, Bexarotene, Buserelin, Cyproterone, Degarelix, Folinic acid, Fulvestrant, Lanreotide, Lenalidomide, Letrozole, Leuprorelin, Megestrol, Mesna and Thalidomide. The oncological active agent according to present invention preferably may be selected from Dasatinib, Sunitinib, Afatinib, Imatinib, Ponatinib, Ibrutinib, Axitinib, Lenvatinib, Bosutinib, Alectinib, Decitabine, Nilotinib, Lapatinib, Trametinib, Erlotinib, Osimertinib, Dabrafenib, Vandetanib, Crizotinib, everolimus and Ceritinib. In another aspect of the present invention is to provide process of manufacturing the tamper-proof dosage form comprising active ingredient. The concentration of active ingredients and excipients were optimized during the manufacturing process of tamper-proof dosage form. The concentration of oncological active ingredients preferably dasatinib or imatinib or salt thereof has optimized. The tamper-proof dosage form according to present invention may contain any suitable amount of Imatinib, Dasatinib or salt thereof by weight of the composition. The concentration of Imatinib or salt thereof may ranges from about lOmg to lOOOmg by weight of composition; preferably may ranges from about 50mg to 800mg; more preferably 50mg, lOOmg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg. The concentration of Dasatinib or salt thereof may ranges from about 2mg to 500mg, preferably may ranges from about 5mg to 400mg; more preferably lOmg, 20mg, 50mg, 70mg, 80mg, lOOmg, 120mg, 140mg, 160mg, 180mg, 200mg, 220mg, 240mg, 260mg, 280mg, 300mg, 320mg, 340mg, 360mg, 380mg, 400mg.

The tamper-proof dosage form according to present invention contain any suitable amount of one or more pharmaceutically acceptable excipient like fillers or diluents, viscosity modifiers, solvent, disintegrants, binders, surfactant/solubilizer, Coating materials, Plasticizers, antioxidant, glidants, lubricants, Coloring agents or combination thereof. The amount of fillers or diluents present in the composition may ranges from about 1% to 85%; preferably about 5% to 80%; more preferably about 5% to 75%. The amount of viscosity modifiers and binder present in the composition may ranges from about 0.5% to 50%; preferably about 1% to 40%; more preferably about 1% to 30% by weight of composition.

The amount of disintegrants present in the composition may ranges from about 1% to 40%; preferably about 5% to 30; more preferably about 5% to 20% by weight of composition. The amount of antioxidant present in the composition may ranges from about 0.05% to 5%; preferably about 0.01% to 2.5%; more preferably about 0.01% to 1% by weight of composition. The amount of glidants present in the composition may ranges from about 0.05% to 10%; preferably about 0.1% to 3.5%; more preferably about 0.1% to 2% by weight of composition. The amount of lubricant present in the composition may ranges from about 0.05% to 10%; preferably about 0.1% to 3.5%; more preferably about 0.1% to 2% by weight of composition.

The binder or viscosity modifiers according to present invention plays vital role in making tamper-proof dosage form. Preferably polyalkylene oxide according to present invention plays vital role in making tamper-proof dosage form. At least one polymer selected from the group comprising polyalkylene oxides, preferably polymethylene oxide, polyethylene oxide, polypropylene oxide; polyethylene, polypropylene may be used. The polyethylene oxide is available with different molecular weight. The polyalkylene oxide according to present invention is at least 50,000 g/mol or above; preferably at least 100000 g/mol upto 15000000 g/mol. The polyalkylene oxide used according to present invention may contain optionally antioxidant. The polyalkylene oxide is commercially available under various trade names. The commercially available polyalkylene oxides may be like Polyox™, POLYOX^™ WSR N-10 (100,000g/mol), POLYOX^™ WSR N-80 (200,000g/mol), POLYOX^™ WSR N-750 (300,000g/mol), WSR 205 (600,000g/mol), WSR 1105 (900,000g/mol), WSR N-12K (1,000,000 g/mol), WSR N-60K (2,000,000 g/mol), WSR-301 (4000000 g/mol), WSR Coagulant (5000000 g/mol), WSR-303 (7,000,000 g/mol), WSR-308 (8,000,000 g/mol) and like. The amount of polyalkylene oxides may ranges from 5-85% by weight of composition. The use of polyalkylene oxides with at least 50,000 g/mol makes tablets tamper-proof which resist crushing, cutting or chewing.

The tamper-proof dosage form comprising active ingredient of the present invention can be manufactured by process such as direct compression, dry granulation, roller compaction, wet granulation and hot melt extrusion.

The tamper-proof dosage form comprising active ingredient of the present invention may involve process of curing. The curing process according to present invention additionally provides tamper-proof ness to dosage form

The manufactured tamper-proof dosage form according to present invention was exposed to curing. In polymerization, curing is a term in polymer chemistry and process engineering that refers to the toughening or hardening of a polymer material by cross- linking of polymer chains, brought about by electron beams, heat or chemical additives.

The manufactured tamper-proof tablets were exposed to heat in the hot air oven as curing process and parameters like polyethylene oxide molecular weight, curing time, curing temperature, curing method were optimized. The molecular weight of polyethylene oxide used may be of at least 50000g/mol; the curing time is between 10 to 120 minute preferably 60 to 120 minute; curing temperature is between 60 to 80°C; preferably 70°C. The manufactured tamper-proof tablets of oncological active agent like imatinib and dasatinib were exposed to heat in hot air oven at 70°C for 2 hours. It was found that hardness i.e. crushing strength of tablets was found be more when compared with tablet before curing. Thus curing process had substantially increased the hardness of the tablets according to present invention and made them plastic and brittle resistance. The increase in hardness and imparting plastic property by curing process was due to polymer softening/melting, bridge formation, fusion of polymer particle to form fused polymer matrix. However, bridge formation and fusion of polymer particles was more effective at high temperature than at low temperature due to melting of polymer; therefore, dosage form of the present invention resist crushing, cutting or chewing and prevents topical, inhalational exposure to the active agent.

The hammer test was performed to check the tamper-proof properties of the tablet according to present invention. The tablets samples such as in-house tablet of imatinib made with polyethylene oxide (Tamperproof), in-house tablet with similar composition to Gleevec tablets (imatinib) without polyethylene oxide in USA, commercially available imatinib tablet by Cipla company without polyethylene oxide obtained from India market were evaluated for hammer test in order to check the tamper-proof properties of the tablet. From the illustration of no. of stroke required [Table No. 1], it was found that in-house tablet manufactured with polyethylene oxide according to present invention provides more resistance to crushing and breaking since it requires more stroke of hammer when compared with in-house tablet with similar composition to Gleevec tablets (imatinib) in USA and commercially available imatinib tablet Cipla company. Even tablet according to present invention get only deform after more stroke.

The detail process of Hammer Test performed is mentioned below:

1) Kept tablet on flat black granite.

2) Applied manually hammer strokes on the tablet from the distance of 10 cm at a rate of 45-50 strokes/minute using Teflon hammer.

3) Recorded the number of strokes required to appear crack on the tablets

Observation Table (Hammer Test):

Table No. 1 :

Also the hardness or crushing strength of the tablet has been measured by using hardness tester (EBT-2PRL) by Electrolab. It was found that tablet according to present invention provides hardness of at least 250N and above; preferably hardness of the tablet according to present invention was found to be 250N to 600N; more preferably 250N to 500N. The tablet according to present invention provides resistance to crushing and breaking.

The tamper-proof dosage form of the present invention was evaluated for parameters like appearance, average weight, thickness, Disintegration Time and assay and were found to be satisfactory.

The tamper-proof dosage form of the present invention prevents topical, inhalational exposure of active agent to healthcare professionals like pharmacists, nurses, physicians, operating room personnel, hospital staff such as shipping and receiving personnel, custodial workers, laundry workers and waste handlers or individual who are in association with these active agents. The tamper-proof dosage form of the present invention prevents these individual from health risk and adverse clinical symptoms such as immediate nervous system effects, acute and long term reproductive effects (e.g., infertility and miscarriage), and a subsequent risk for hematologic malignancies

The tamper-proof dosage form comprising active ingredient of the present invention can be packaged in suitable air tight containers and moisture proof packs.

The tamper-proof dosage form of the present invention, due to their inventive properties may have more commercial success than the existing available dosage form in the relevant field.

EXAMPLES:

The following Examples are provided solely for illustrative purposes and are not meant to limit the invention in any way.

Example 1 :

Manufacturing Process:

1. Imatinib Mesylate, Micro-crystalline Cellulose, hydroxypropyl methyl cellulose, Polyethylene oxide Polymer, Crospovidone and colloidal silicon dioxide were sifted through ASTM #40 and mixed in blender.

2. Magnesium stearate was sifted through ASTM #60.

3. The blend of step 1 was lubricated with magnesium stearate of step 2.

4. The blend of step 3 was compressed into tablet using tablet compression machine.

5. Compressed tablets were kept for curing in hot air oven at 70°C for 2 hrs. to activate the polyethylene oxide polymer.

6. After 2 hr. tablets were withdrawn and cooled to room temperature.

Example 2:

Manufacturing Process:

1. Imatinib Mesylate, Microcrystalline Cellulose, hydroxypropyl methyl cellulose,

Polyethylene oxide Polymer, Croscarmellose Sodium and colloidal silicon dioxide were sifted through ASTM #40 and mixed in blender.

2. Magnesium stearate was sifted through ASTM #60.

3. The blend of step 1 was lubricated with magnesium stearate of step 2. 4. The blend of step 3 was compressed into tablet using tablet compression machine.

6. After 2 hr. tablets were withdrawn and cooled to room temperature.

7. Tables of step 6 were coated with Opadry white.

Example 3:

Manufacturing Process:

Polyethylene oxide Polymer, Crospovidone, Butylated hydroxy toluene and colloidal silicon dioxide were sifted through ASTM #40 and mixed in blender.

2. Magnesium stearate was sifted through ASTM #60.

3. The blend of step 1 was lubricated with magnesium stearate of step 2.

6. After 2 hr. tablets were withdrawn and cooled to room temperature. Example 4:

Manufacturing Process:

1. Imatinib Mesylate, Microcrystalline Cellulose, hydroxypropyl methyl cellulose, Polyethylene oxide Polymer, Crospovidone and colloidal silicon dioxide were sifted through ASTM #40 and mixed in blender.

2. Magnesium stearate was sifted through ASTM #60.

3. The blend of step 1 was lubricated with magnesium stearate of step 2.

6. After 2 hr. tablets were withdrawn and cooled to room temperature.

Example 5:

6.

Magnesium stearate 9.0

Tablet weight 900

7. Opadry white 27.0

8. Purified water q.s.

Coated tablet weight 927.0

Manufacturing Process:

1. Imatinib Mesylate, Microcrystalline Cellulose, hydroxypropyl methyl cellulose, Crospovidone and colloidal silicon dioxide were sifted through ASTM #40 and mixed in blender.

2. Magnesium stearate was sifted through ASTM #60.

3. The blend of step 1 was lubricated with magnesium stearate of step 2.

5. Tables of step 4 were coated with Opadry white.

Example 6:

Manufacturing Process:

1. Dasatinib, Microcrystalline Cellulose, hydroxypropyl methyl cellulose, Polyethylene oxide Polymer, Crospovidone and colloidal silicon dioxide were sifted through ASTM #40 and mixed in blender.

2. Magnesium stearate was sifted through ASTM #60. The blend of step 1 was lubricated with magnesium stearate of step 2.

The blend of step 3 was compressed into tablet using tablet compression machine. Compressed tablets were kept for curing in hot air oven at 70°C for 2 hrs. to activate the polyethylene oxide polymer.

After 2 hr. tablets were withdrawn and cooled to room temperature.

Claims

The tamper-proof dosage form comprising oncological active agent or other active ingredient which is susceptible to topical or nasal contact and leads to adverse clinical symptom.

The tamper-proof dosage form according to claim 1 further comprising polyalkylene oxide.

The tamper-proof dosage form according to claim 2, wherein polyalkylene oxide may be selected from polymethylene oxide, polyethylene oxide, polypropylene oxide; polyethylene, polypropylene and like.

The tamper-proof dosage form according to claim 2 and 3, wherein molecular weight of polyalkylene oxide is at least 50000g/mol.

The tamper-proof dosage form according to claim 1 wherein breaking strength ranges from 250N to 600N.

Tamper-proof dosage form according to claim 1, wherein oncological active agent or other active ingredient is selected from the group consisting of Dasatinib, Sunitinib, Afatinib, Imatinib, Ponatinib, Ibrutinib, Axitinib, Lenvatinib, Bosutinib, Alectinib, Decitabine, Nilotinib, Lapatinib, Trametinib, Erlotinib, Osimertinib, Dabrafenib, Vandetanib, Crizotinib, Ceritinib, Everolimus, Etoposide, Paclitaxel, Irinotecan, Docetaxel, Vincristine, Carboplatin, Cisplatin, Oxaliplatin, Bevacizumab, Cetuximab, Trastuzumab, Denosumab, Rituximab, Zoledronate, Abiraterone, Anastrozole, Bicalutamide, Exemestane, Goserelin, Medroxyprogesterone, Octreotide, Tamoxifen, Bendamustine, Carmustine, Chlorambucil, Lomustine, Melphalan, Procarbazine, Streptozocin, Fludarabine, Raltitrexed, Actinomycin D / Dactinomycin, Doxorubicin, Mitoxantrone, Eribulin, Topotecan, Vinblastine, Vinorelbine, Sorafenib, Trastuzumab emtansine, Temsirolimus, Vemurafenib, Ibandronic acid, Pamidronate, Bexarotene, Buserelin, Cyproterone, Degarelix, Folinic acid, Fulvestrant, Lanreotide, Lenalidomide, Letrozole, Leuprorelin, Megestrol, Mesna and Thalidomide.

Tamper-proof dosage form according to claim 1 and 6, wherein oncological active agent is preferably Dasatinib, Sunitinib, Afatinib, Imatinib, Ponatinib, Ibrutinib, Axitinib, Lenvatinib, Bosutinib, Alectinib, Decitabine, Nilotinib, Lapatinib, Trametinib, Erlotinib, Osimertinib, Dabrafenib, Vandetanib, Crizotinib, everolimus and Ceritinib; more preferably Dasatinib, Imatinib or salt thereof. The process of manufacturing the tamper-proof dosage form comprising the steps of

i) Admixing the oncological active agent or other active ingredient which is susceptible to topical or nasal contact with polyalkylene oxide

ii) Optionally mixing the same with one or more pharmaceutically acceptable excipient

iii) Compress it into the tablets

iv) Compressed tablets were exposed to curing at temperature of 70°C for 2 hours