WO2016120892A1

WO2016120892A1 - Abuse deterrent controlled release solid dosage form

Info

Publication number: WO2016120892A1
Application number: PCT/IN2016/050032
Authority: WO
Inventors: Nitin Bhalachandra DHARMADIKARI; Yashoraj R. Zala; Mohammed Majed KHAN
Original assignee: Sun Pharma Advanced Research Company Ltd.
Priority date: 2015-01-29
Filing date: 2016-01-29
Publication date: 2016-08-04

Abstract

An abuse deterrent multiparticulate solid dosage form comprising: • a first composition comprising coated cores, each coated core comprising a. a core comprising a drug susceptible to abuse and a crush resistant carrier having a first melting point b. a first coat surrounding the said core and comprising water soluble polymer, c. a second coat surrounding the first coat and optionally, a third coat, surrounding the second coat, the second and/or third coat comprising a water insoluble polymer, d. an outermost coat surrounding the inner concentric coats and consisting essentially of a reverse enteric polymer, and • a second composition comprising an alkalizer.

Description

TITLE

ABUSE DETERRENT CONTROLLED RELEASE SOLID DOSAGE FORM

BACKGROUND OF THE INVENTION

The United States is in the midst of an unprecedented prescription drug abuse epidemic as classified by the Centers for Disease Control and Prevention (CDC) and the World health organization (WHO). An estimated 52 million Americans use prescription drugs for nonmedical reasons at least once in their lifetimes - with some using prescription drugs for recreational purposes. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), more than 6.5 million people above the age of 11 used prescription drugs for non-medical reasons in 2013. The major drugs of abuse are opioids, tranquilizers, sedative -hypnotics which are highly potent drugs having a narrow therapeutic window. The abuse of these drugs leads to life threatening effects such as respiratory depression, or even death. The problem is further exacerbated in the case of controlled release dosage forms containing potent drugs susceptible to abuse, since controlled release preparations have a higher dose of drug incorporated into them. This makes a higher amount of drug available to the abuser through physical manipulation such as grating grinding, extraction with appropriate solvent, application of force, etc for abusing through inhalation, injection, swallowing and smoking. Thus there is a need in the art for an abuse resistant dosage form that resists all these modes of abuse. To address all the problems described above, the present inventors provide a oral abuse deterrent multiparticulate solid dosage form comprising coated cores which are difficult to be tampered by physical means and abused by oral, nasal, or parenteral routes. DESCRIPTION OF THE FIGURES

One specific embodiment of the present invention has been diagrammatically represented by way of Figure 1. Figure 1 illustrates embodiment of oral abuse deterrent multiparticulate solid dosage form of the present invention as a controlled release dosage form. The solid dosage form contains a first composition having a mixture of finite number of controlled release mini-tablets (referred to hereinafter as ER mini-tablets) and finite number of immediate release mini-tablet (referred to hereinafter as IR mini-tablets). Various components of the ER mini-tablet are as follows: • mini-tablets having a compressed core containing drug susceptible to abuse and crush resistant carrier (1),

• first coating of water soluble polymer (2)

• second coating of mixture of a water insoluble polymer and water soluble polymer (3)

• third coating of water insoluble polymer and a plasticizer (4)

• an outermost coat surrounding the inner concentric made up of reverse enteric polymer (5)

The IR mini-tablet and is it various components are referred to as

• drug susceptible to abuse and crush resistant carrier as mini-tablet (1)

• first coating of water soluble polymer (2)

Second composition comprises an alkalizer (6)

The first and second compositions are filled in capsule shell/sachet/pouch (7)

Figure 2 is a photograph of the coated mini-tablets of the multi-particulate abuse deterrent solid dosage form, according to one embodiment of the present invention.

Figure 3 is a photograph controlled release mini-tablet (1) which has been subjected to in vitro dissolution in 40 % v/v ethanolic solution at the end of twelve hours. The photograph reveals that the second coat (2) surrounding the first coat of water soluble polymer provides resistance to alcohol dissolution. The physical integrity of the coat is found to be almost maintained after subjecting to in-vitro dissolution. Further, the third coat surrounding the second coat is also found to remain intact and there are no signs of rupturing of this coating.

SUMMARY OF THE INVENTION

The present invention provides an oral abuse deterrent multiparticulate solid dosage form comprising:

• a first composition comprising coated cores, each coated core comprising

a. a core comprising a drug susceptible to abuse and a crush resistant carrier having a first melting point, b. a first coat surrounding the said core and comprising water soluble polymer that does not melt at or below the first melting point, c. a second coat surrounding the first coat and optionally, a third coat, surrounding the second coat, the second and/or third coat comprising a water insoluble polymer,

d. an outermost coat surrounding the inner concentric coats and consisting essentially of a reverse enteric polymer, and

• a second composition comprising an alkalizer.

DETAILED DESCRIPTION OF THE INVENTION

The term, "reverse enteric polymer" as used herein refers to a polymer that is soluble in acidic gastric fluids but is insoluble or alternatively swells or gels, at the pH of the small intestine.

According to the present invention the drug susceptible to abuse includes but is not limited to highly potent drugs such as opioids like oxycodone, hydrocodone, oxymorphone alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tapentadol, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof. The present invention also includes tranquilisers sedatives and hypnotics such as alprazolam, bromazepam, chlordiazepoxied, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, pharmaceutically acceptable salts thereof, and mixtures thereof within its scope. Generally a single dose of the drug susceptible to abuse ranges from 1 to 200 mg. In one embodiment the drug susceptible to abuse is tramadol hydrochloride in an amount of 43 mg. The drug susceptible to abuse is present in the range of 1 to 35% by weight of the core. In a preferred embodiment, the drug susceptible to abuse is present in the range of 1 to 35%, more preferably 5 to 20% by weight of the core.

A non-limiting list of suitable crush resistant carriers which may be selected for inclusion in the core includes thermoplastic material such as polyalkylene oxide. In one embodiment, the crush resistant carrier is polyethylene oxide. The term "polyalkylene oxide" is defined for purposes of the present invention is a polyethylene oxide having a molecular weight of at least 100,000 based on rheological measurements, and preferably having a molecular weight of at least 100,000.The lower molecular weight polyalkylene oxides are usually referred to as polyethylene glycols. The polyalkylene oxides having higher molecular weight of 10, 00,000 or above may be used in the core for achieving a controlled release profile. In one specific embodiment the polyalkylene oxide usedjias a molecular weight in the range of 1 ,00,000 to 10,00,000. However it is also possible to use a higher molecular weight polyalkylene oxide but in lower amounts in the core to achieve an immediate release profile. The crush resistant carrier used in the core is characterized by a first melting point/temperature. In one embodiment when the crush resistant carrier is polyethylene oxide it has a first melting point/temperature of around 60° to 62 °C. The crush resistant carrier used is present in the range of of 1 to 90% by weight of the core, more preferably in the range of 40 to 90 % by weight of core. In one embodiment the polyalkylene oxide used is polyethylene oxide having a molecular weight of 3,00,000 and present in a concentration of 70-85% by weight of the core. The water soluble polymer used in the first coating surrounding the core does not melt at or below the first melting point and includes, but is not limited to hydroxypropylmethyl cellulose, polyvinyl alcohol, methylcellulose, and mixtures thereof among others... In one embodiment when the first coating surrounding the core comprising the water soluble polymer is a polyvinyl alcohol based coating The water soluble polymer is present in a range of 0.1 % to 7% by weight of the core, more preferably in the range of 1 % to 5% by weight of the core.

According to the present invention, the first composition having the core coated with the first coat is further coated with a second coat surrounding the first coat and optionally, a third coat, surrounding the second coat. The second and/or third coat is composed of water insoluble polymer either alone or in combination with a water soluble excipient. In the preferred embodiments the second coat and or third coat of water insoluble polymer provides a controlled release of the drug over a period of 8 to 24 hours. The second or the third coating may be made up of any pharmaceutically acceptable hydrophobic or hydrophilic controlled release material. In specific embodiments, the water insoluble polymer owing to its insoluble nature in hydrophilic solvents such as water, ethanol, provides resistance to release of the drug from the solid dosage form in water or hydro-alcoholic solutions containing 1 to 40% of ethanol.

Suitable examples of the water insoluble polymers include, but are not limited to, ethyl cellulose, cellulose acetate, cellulose butyrates, polyacrylates such as Eudragit RS and RL, that are insoluble in nature and the like and mixtures thereof. Examples of the water soluble excipients optionally used in the second or third coating, may be water soluble polymers, examples of which include, but are not limited to, gums, acrylic resins, guar gum, polyethylene glycol, certain water soluble grades of hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like. Particularly, grades of cellulose derivatives that have a very low viscosity and are water soluble in nature, are used. In a specific embodiment, the second or third coating is made up of a combination of ethyl cellulose and guar gum, polyvinyl alcohol, cellulose derivatives that are insoluble in medium containing upto 40 % ethanol. In this embodiment the water soluble polymer is ethyl cellulose combined with a water soluble gum- guar gum and a plasticizer. In one embodiment the coated core of the abuse deterrent multi-particulate solid dosage form coated with the first water soluble polymer coat and second water insoluble coat is further coated with a third controlled release coat of water insoluble polymer. In one embodiment wherein the core coated with a first coating of water soluble polymer is further coated with a second coat having a mixture of water insoluble polymer and water soluble polymer to a weight gain of 4 % to 20 % by weight of the core. In a particular embodiment, the core coated with the first and second coating is further coated with a third coating of cellulose acetate and polyethylene glycol to get a weight gain of 8 to 20% by weight of the core.

The coated core having a first, second and optionally a third coating surrounding it, is further coated with an outermost coat surrounding the inner concentric coats which is made up of a reverse enteric polymer. The third coat consists essentially of the reverse enteric polymer. The term consisting essentially of means the absence of another polymer which will change the nature of the coating particularly the ability of reverse enteric polymer to dissolve freely in the gastric fluids. Examples of reverse enteric polymer are found in polymers that have a group capable of accepting the hydrogen ion from an acid below the critical pH and thus becoming soluble in acid environment.

The reverse enteric polymer used in the present disclosure is selected from polymers that are prepared by polymerizing a mixture of the hydrophobic and basic monomer or a mixture of the hydrophobic, hydrophilic and basic monomer wherein the basic monomer may be selected from the group consisting of dimethyl amino ethyl acrylate, diethyl amino ethyl ethacrylate, diethyl amino ethyl acrylate, piperidine ethyl methacrylate and 2-tert-butyl amino ethyl methacrylate.

An example of a preferred reverse enteric polymer used is a methyl methacrylate butyl methacrylate-dimethyl aminoethyl methacrylate copolymer which is a cationic copolymer synthesized from dimethyl aminoethyl methacrylate and neutral methacrylic acid esters, more particularly as is commercially available under the trade name Eudragit™ E which is soluble below an acidic pH such as pH 5 and swellable and permeable above about a higher pH such as above 5.0. It is depicted by the following structure.

The repeating unit in the polymer has the following structure: where R represents C¾ and C4H9 groups and the polymer has a molecular weight about 1,50,000. They may exist in different physical forms. The Eudragit™ E 100 product is granular, the Eudragit™ E 12.5 product is a 12.5% solution of E 100 in isopropanol and acetone, and the Eudragit EPO product is a fine powder made from E 100. Various grades of this polymer are commercially available from Evonik, Germany. Other suitable examples of reverse enteric polymers may be found in the art. It is beneficial to use polymers which are soluble only at pH 5.5 or below, that are additionally also impermeable since this further helps control the dissolution rate. In more preferred embodiments of the present invention the reverse enteric polymer is selected from a polymer that is soluble below about pH 5 but insoluble above about pH 5.5. For example, US20050137372 disclosed similar polymers prepared by polymerizing a mixture of the hydrophobic and basic monomer or a mixture of the hydrophobic, hydrophilic and basic monomer wherein the basic monomer may be selected from the group consisting of dimethyl amino ethyl acrylate, diethyl amino ethyl ethacrylate, diethyl amino ethyl acrylate, piperidine ethyl methacrylate and 2-tert-butyl amino ethyl methacrylate. Several other polymers having basic functional groups and thus the desired pH dependent solubility behavior can be used according to the present invention. Poly(lysine) (PL), poly(ethylenimine) (PEI) and chitosan are examples of such polymers. The reverse enteric polymer used in the present invention may be used in the form of a dispersion or in a powder form.

It is thus within skill in the art to use existing polymers with the appropriate basic ionizable groups or to synthesize new such polymers by incorporating monomers having basic ionizable groups and any such polymer may be used according to the scope of the present invention.

Suitable examples of the reverse enteric polymer that is soluble at an acidic but is insoluble at a second higher pH value, include, but are not limited to, methyl methacrylate and diethylaminoethyl methacrylate and the like. Any other reverse enteric polymer having such properties is encompassed within the scope of this embodiment of the present invention. In one specific preferred embodiment, the reverse enteric polymer that can be utilized in the present invention is a copolymer comprising amino and/or alkylamino and/or dialkyl amino groups such as copolymers comprising methyl methacrylate and diethylaminoethyl methacrylate such as commercially available as Kollicoat^® Smartseal 30 D from BASF. The polymer has a molecular weight of about 200,000 and a glass transition temperature of 57 to 63° C. In one preferred embodiment, the reverse enteric polymer of the outermost coating, is selected from methyl methacrylate butyl methacrylate-dimethylaminoethyl methacrylate copolymer (eg. Eudragit^® E PO) or methyl methacrylate and diethylaminoethyl methacrylate copolymer (Kollicoat^® smartseal) and the like and mixtures thereof. Reverse enteric polymers are soluble in acidic pH (pH < 5) and insoluble at basic pH (pH > 5). According to the nature of the reverse enteric polymer used in the outermost coat of the abuse deterrent multi-particulate solid dosage form, the polymer may be soluble at acidic pH of less than 5 and insoluble at pH above 5.5 or swellable and permeable above pH 5. The amount of reverse enteric polymer in the present invention varies from 0.5% to about 30% by weight of the coated core, preferably about 2 % to about 30 % by weight of the coated core , more preferably about 5 % to about 20 % by weight of the coated core.

The second composition of the oral abuse deterrent multiparticulate solid dosage form of the present invention contains one or more alkalizer. The term "alkalizer" as used herein refers to physiologically acceptable substances that neutralize acid. Examples of alkalizer include, but are not limited to calcium carbonate, disodium hydrogen phosphate, trisodium orthophosphate, sodium hydroxide, sodium carbonate, potassium hydroxide, sodium bicarbonate, dipotasium carbonate, tromethamine, aluminum trihydroxide, magnesium dihydroxide, aluminium oxide, magnesium oxide and mixture thereof. The coated core described above are mixed with an alkalizer. Alkalizer is selected from carbonates, bicarbonates, alkaline earth metal salts and organic base. In one preferred embodiment, the alkalizer is a mixture of sodium bicarbonate and magnesium oxide. The amount of alkalizer is such that when a single unit of the abuse deterrent multi-particulate solid dosage form of the present invention is administered the pH of the gastric fluids will not rise to or above the pH of small intestinal fluids (generally 3 to 5). Therefore the reverse enteric polymer coat will dissolve and allow release through the coated core. However the object of the invention is also to prevent multiple pill abuse and thus when multiple pills are taken by the abuser the amount of alkalizer will be a multiple of the number of pills ingested and the pH will rise to above the pH of small intestinal fluids rendering the reverse enteric polymer coat to be retained because the reverse enteric polymer will either be insoluble or swell or gel on the surface of the coated cores and the drug release will be hindered substantially. A person of skill in the art will be able to calculate an amount of alkalizer to be used. For example if the target is that when 3 units of the dosage form are ingested the drug release should be inhibited, then the amount of alkalizer should be sufficient to neutralize of partially neutralize the acid in the stomach. For example if gastric fluids correspond to 1000 ml of 0.01 N HC1 or 100 ml of 0.1N HCL then there would be in either of the two cases 10 milliequivalents of the acid in the gastric fluids. Therefore atleast 10 milliequivalent of alkalizer distributed in three units would be sufficient to achieve the objective. Therefore the person of skill in the art may use atleast 3.33 milliequivalents or more in a single unit to achieve the objective. A person of skill in the art will test the same in a population of patients and may revise the amount of alkalizer to be used to achieve the objective in-vivo.

The core of the first composition of the abuse deterrent multi-particulate solid dosage form of the present invention, can be in the form of granules, pellets, spheroids, mini-tablets. These cores may be filled into a capsule, sachet or pouch or may also be compressed into a larger tablet such as dispersible tablet.

In one specific embodiment, the cores are in the form of compressed core mini-tablets. The term 'compressed core mini-tablet' as used herein means a tablet core is formed using a compression force, for example, in a compression press to manufacture a tablet. The term 'mini' as used herein means the size or the dimension of the tablet is more than 1 millimeter and not more than 3.00 millimeter in any of the dimensions. A finite number of mini-tablets may be filled into capsule shells or sachets or pouches or may also be compressed into a tablet to form the multiparticulate solid dosage form.

According to one preferred embodiment of the invention, the core of the first composition is a compressed core mini-tablet. It may be prepared by compressing the blend of either granules, or directly compressing the powder using punches having specific diameter of the tip, ranging from more than 1 mm to about 3 mm, preferably 2 to 2.5 mm. According to the invention further coatings are applied onto the compressed core mini-tablets to obtain the coated mini-tablets. Advantageously, the compressed core mini-tablets of the specific embodiment of the present invention, provide a well-defined uniform surface area and the coating applied is thus, very uniform. Since the surface area is lower compared to particles such as granules, pellets which are not subjected to compression forces, such particles can carry lower amount of coating weight gain compared to the mini-tablets. The compressed core mini-tablets or coated mini-tablets may be of varying shapes such as sphere or cylinder or square or any other suitable shape. Shapes with an aspect ratio of about 1 are preferred as they provide improved flow properties. In one embodiment, the particle size is such that the aspect ratio is about 1, for instance a spherical pellet. When the coated mini-tablets are required to be taken by sprinkling on an edible carrier such as soft food or drink, the solid dosage form can be either in the form of capsule, sachet or pouch. When the solid dosage form can be swallowed, it is designed to be a capsule filled with finite number of coated mini-tablets. When the coated mini tablet is intended to be sprinkled, the coated mini tablet has a size less than 2.5 mm. In one specific embodiment, the size of the coated mini tablet is in the range of 1.8 to 2.5 mm. Another advantage of the use of coated mini-tablets is the ability to modify the dose of the drug as per requirement by varying the number of mini- tablets filled into the capsule/sachet/pouch. For example, to arrive at a total dose of 'x' mg of drug in a single dosage form like a capsule, x coated mini-tablets, each containing 1 mg of drug would be required. Other alternatives may be selected for example, x/2 coated mini- tablets, each containing 2 mgs of the drug. On the other hand if a lower strength of the drug is desired in the dosage form lesser number of coated mini-tablets along with other excipients may be used.

In one embodiment, the abuse deterrent multiparticulate solid dosage form contains a first composition having a mixture of the coated minitablet that are controlled release in nature (ER coated mini-tablets), minitablet that are immediate release in nature (IR coated mini- tablets) and a second composition having an alkalizer, all either filled into either a capsules made up of gelatin or cellulose derivatives such as hydroxypropyl methyl cellulose or filled into pouch or sachet or may also be compressed into a larger tablet which may be dispersible in nature.

According to one preferred embodiment, the present invention provides an oral abuse deterrent multiparticulate solid dosage form comprising:

• a first composition comprising coated minitablets, each coated minitablet comprising

a. a compressed core minitablet comprising a drug susceptible to abuse and a crush resistant carrier having a first melting point.

b. a first coat surrounding the said compressed core minitablet and comprising water soluble polymer that does not melt at or below the first melting point,

c. a second coat surrounding the first coat and optionally, a third coat, surrounding the second coat, the second and/or third coat comprising a water insoluble polymer,

• a second composition comprising an alkalizer.

wherein the coated minitablet provide release of the drug in an controlled manner over a period of 8 hours or 24 hours. In this specific embodiment, the crush resistant carrier is polyalkylene oxide having the molecular weight ranging from 1,00,000 to 10,00,000 and its amount ranges from about 40 % to 90 % by weight of the compressed core minitablet. The compressed core mini-tablet may be coated with the first coating of water soluble polymer at a weight gain of 0.1 to 4 % by weight of the core. These coated mini-tablets are then further coated with a second coating composition which may be a mixture of water insoluble polymer and water soluble polymer at a weight gain of 4 % to 20 % by weight of the core. When the solid dosage form is tailored to release the drug for a period of 12 hours the insoluble polymer may be coated to a weight gain of 4 to 8 % by weight of the core. Whereas for more prolonged duration of release, higher amount of the coating may be applied. Further, these coated mini-tablets are further coated with another third coating of water insoluble coating to a weight gain of 5 to 25 % by weight of the core. In one specific embodiment, the third coat is made up of cellulose acetate and polyethylene glycol applied to weight gain of 8 % to 20 % by weight of the compressed core mini-tablet.

The compressed core mini-tablet containing the drug may be obtained by various processes known in the art. For example, it is possible to obtain the compressed core mini-tablets by hot-melt extrusion, granulation, hot-melt granulation and then compressing into mini-tablets having a punch size in the range of 1 mm to 3 mm, preferably 2 to 2.5 mm. Preferably the compressed core minitablets are prepared by the process of direct compression in mini- punches in a single side rotary compression machine at a speed of 15-20 rpm. The compressed core mini-tablets may be prepared using a multi-tip D-tooling compression punches. In a specific embodiment, each punch is uniquely designed to have 14 compression tips, each tip being round concave with a diameter of 2 mm. The compressed core mini- tablets punched out are cylindrical in shape. As compared to usual granulate compositions, the mini-punches used give the advantage of being able to control the hardness of the minitablet. The hardness of the compressed core minitablet ranges from 0.5 Kilopond (kp) to 2 Kilopond (kp).In one embodiment, the dimensions of the particles are about 2 millimeters or less. Essentially the compressed core minitablets have a size above 1 mm. In one embodiment, the compressed core minitablets have a particle size distribution in the range of 1.8 to 2.5 mm. In another embodiment, the compressed core minitablets range in the size of 2 to 2.5 mm. In one embodiment when the abuse deterrent muliparticulate solid dosage form comprising coated minitablet coated with a first coating of polyvinyl alcohol and plasticizer, a second coating of ethyl cellulose guar gum and a third coating of cellulose acetate and polyethylene glycol was subjected to in vitro dissolution in 40 % v/v ethanolic solution upto a period of 12 hours it was found that the second coat surrounding the first coat of water soluble polymer provided resistance to alcohol dissolution. The physical integrity of the coat was found to be almost maintained after subjecting to in-vitro dissolution. Further, the third coat surrounding the second coat was also found to remain intact and there were no signs of rupturing of this coating. The oral abuse deterrent multiparticulate solid dosage form comprising coated cores is prepared by a process comprising steps of preparing a first composition comprising the steps of: a) preparing a core comprising mixture of the drug and crush resistant carrier having a first melting point

b) coating the cores of a) with the first coat of water soluble polymer that does not melt at or below the first melting point of the crush resistant carrier c) curing the coated cores of b), at about a temperature of the first melting point, for a period of about 1 hour to 2 hours in moving bed coating equipment,

d) applying a second coating of water insoluble polymer,

e) applying third coating of cellulose acetate and plasticizer,

f) applying a coating of reverse enteric polymer,

g) mixing the coated cores of first composition with a second composition comprising alkalizer and optionally, lubricants, disintegrants and filing into the capsule, pouch or sachet or may be compressed into a larger tablet.

In one preferred embodiment, the oral abuse deterrent multiparticulate solid dosage form is prepared by a process comprising steps of preparing a first composition, the process comprising the steps of: a) compressing the core comprising mixture of the drug and crush resistant carrier into compressed core minitablets having mean diameter of more than 1 mm to 2.5 mm,

b) coating the compressed core minitablets of a) with the first coat of water soluble polymer that does not melt at or below the first melting point, c) curing the coated minitablets of b), at about the temperature of of the first melting point of crush resistant carrier for a period of about 1 hour to 2 hours in a moving bed coating equipment,

d) applying a second coating of water insoluble polymer,

e) applying third coating of cellulose acetate and plasticizer,

f) applying a coating of reverse enteric polymer,

g) mixing the coated minitablets of first composition with a second composition comprising alkalizer and optionally, lubricants, disintegrants and filing into the capsule, or pouch or sachet or or may be compressed into a larger tablet.

In one aspect, the present invention provides a process of preparing the oral abuse deterrent multiparticulate solid dosage form, wherein the dosage form is prepared by a process comprising steps of preparing a first composition comprising: a) compressing the core comprising mixture of the drug and crush resistant carrier having a first melting point, into compressed core mini-tablets having mean diameter of more than 1 mm to 2.5 mm,

b) coating the compressed core mini-tablets of a) with the first coat of water soluble polymer that does not melt at or below the first melting point

c) curing the coated minitablets of b), at about the temperature of the first melting point of the crush resistant carrier for a period of about 1 hour to 2 hours in a moving bed coating equipment,

d) applying a second coating of water insoluble polymer

e) applying third coating of cellulose acetate and plasticizer

f) applying a coating of reverse enteric polymer

g) mixing the coated minitablet of first composition with

the second composition comprising alkalizer and optionally, lubricants, disintegrants and filing into the capsule, pouch or sachet.

In one embodiment, the core coated with the first coat of water soluble polymer surrounding the core is subjected to the process of curing. Without limiting the scope of the invention, the coated core of the present invention may be heated in moving bed coating equipment such as a pan coater or a fluid bed coater. The temperature of heating/curing or sintering is maintained such that the crush resistant core is cured at a temperature greater than or equal to the first melting point temperature of the crush resistant carrier.. In the preferred embodiment, the core coated with a first coating of a water soluble polyvinyl alcohol is cured at a temperature of around 70°C. In one specific embodiment the core coated with the first coating of a water soluble polymer is coated in a fluid bed coater at a temperature of for example, 72±2°C for a period of 90 minutes. The process of curing confers the required hardness to the core to acquire resistance to physical tampering such as grinding, crushing, grating or application of a force. Also the process of curing reduces the tackiness of the coated core.

It may be appreciated that the abuser is well versed with various techniques to extract the drugs susceptible to abuse. These techniques include, crushing of the solid dosage form with an intention to achieve maximum surface area for extracting the drug using suitable solvents such as alcohol which are available to the abuse, without any extra efforts. The oral abuse deterrent multiparticulate solid dosage form of the present invention was found to provide not only deterrence to multiple pill abuse but also showed deterrence to crushing, extraction using alcohol, deterrence to syringeability or injectability. Further, if the dosage form is also designed for controlling the release of the drug over a period of time, each unit dosage form would have higher amount of the drug compared to amount in the immediate release dosage form.

Further, the oral abuse deterrent multiparticulate solid dosage form of the present invention, has shown a good resistance to dose dumping in the presence of ethanol administration. This feature is very important in that dose dumping due to presence of alcohol in stomach, can cause release of the total dose at initial time point instead of releasing over a period of time, for which the dosage form is designed, such as 12 hours, 24 hours and so on. The dumping of the total dose of the drug can cause serious issues to the vital parts of the body and can lead to respiratory depression and possibly even death.

The multiparticulate solid dosage form of the present invention is tested for its abuse deterrent properties to various ways of abuse such as physical tampering such as grinding, grating flattening/indentation by application of force, crushing etc and further extraction into suitable solvents adopted by the abusers. The multiparticulate dosage form of the invention was tested for in-vitro dissolution in order to evaluate ability to provide resistance to multiple unit abuse. Extractability in 1 to 40% of hydroalcoholic solutions for resistance to extraction was tested. Resistance to grinding, crushing grating was tested by subjecting the cores to crushing in a coffee grinder and then subjecting to sieve analysis in descending mesh aperture sizes. The particles having a size less than 90 microns which are of the inhalable size and can be abused by nasal insufflation were determined. The crushed particles were also tested for syringibility and injectibility tests by extracting the drug in suitable solvent. This extract was tested for syringibility by allowing the extract to cool and settle at room temperature and volume of solution withdrawn for 1 minute into an insulin syringe was recorded. For the purpose of injectibility the particles crushed using a coffee grinder were extracted into suitable solvent and then the solution withdrawn in the syringe was quantified by analytical means such as HPLC.

The oral abuse deterrent multiparticulate solid dosage form of the present invention is found to provide adequate resistance to indentation by application of a force. It is also possible to determine the resistance to application of force by any other technique. In one instance, a texture analyser is used. In this technique, r the coated cores of the multiparticulate abuse resistant solid dosage form, were subjected to a force using the texture analyser. Force required to travel a particular distance at a fixed test speed is calculated Before starting the measurement, the coated core is placed vertically or along its length and aligned directly under the probe such that the descending probe penetrates the coated core in the center such that the force of the descending probe is applied perpendicular to the diameter and in line with the thickness of the coated core. The probe of the texture analyser initially travels at a pre-test speed of 1 mm/sec towards the coated core. When the probe contacts the coated core the trigger force set is reached and then the probe travels at a test speed of 0.08 mm/second for a distance of 1.5 mm. The instrument measures the force required to move the probe for a distance of 1.5 mm at the specified speed of 0.08mm/second after coming in contact with the coated core. It is also possible to determine the time, instead of the force applied.

The examples that follow do not limit the scope of the invention and are merely used as illustrations.

EXAMPLE 1

Table 1(A): First composition in the form of controlled release coated mini-tablet

Table 1 (B): first composition having an immediate release

mini-tablets

Table 1(C): Abuse deterrent multi-particulate solid dosage form

The component I and component II of the first composition, prepared as per above table 1A and IB, were mixed with the alkalizer of the second composition and filled into capsules. Drug susceptible to abuse, in instant case, Tramadol hydrochloride, crush resistant carrier, polyethylene oxide were blended together, lubricated with magnesium stearate and compressed into mini-tablets using a punch diameter of 1 mm to 2.5 mm, into cylindrical shaped mini-tablets. The cores were compressed into mini-tablets to achieve a hardness of 0.5 Kpond to 2 Kpond. The compressed core mini-tablets were then coated with first coating of water soluble polymer such as polyvinyl alcohol. The coated mini-tablets were subjected to a process of curing by heating the coated mini-tablets in a moving bed coating equipment at a temperature of the first melting point of the crush resistant carrier. In one specific embodiment, the coated minitablet were heated a temperature of about 70 C for a period of about 1 hour to 2 hours in a coating pan or fluid bed coater.

The cured coated mini-tablets were further coated with a second coating of water insoluble polymer to a weight gain of 6 % to 20 % by weight of the core, followed by application of third coating of cellulose acetate and plasticizer to a weight gain of 8 % to 20 % by weight of the core. The two layered coated minitablet was then further coated with a reverse enteric polymer to a weight gain 5 to 15 % by weight of the core. These coated minitablets were mixed with the second composition comprising specified quantity of the alkalizer, lubricants, disintegrants and filled into the capsule. The capsules filled with the coated mini tablets were subjected to in-vitro dissolution in 900 ml of 0.01 N HCL using Type II USP apparatus. One unit per dissolution vessel and three units per dissolution vessel were tested to evaluate the ability of the dosage form for its in- vitro dissolution in order to evaluate ability to provide resistance to multiple unit abuse.

Table 2: Dissolution profile of the capsule of Example 1

Note: Each capsule contains Tramadol HCL 43 mg

It was observed that when single unit of solid dosage form of present invention was subjected to in-vitro dissolution in 900 ml of 0.01N HCL, the solid dosage form showed controlled drug release profile upto 12 hours. Further, when multiple pills were tested, such as three capsule units, the release was found to be inhibited, indicative of the dosage form being resistant to abuse by administration of multiple numbers of capsule units. EXAMPLE 2

Extractability study

The abuse resistant multiparticulate solid dosage form of example 1 was subjected to in vitro dissolution test in different dissolution media: a) 900 mL of O. IN HCl, b) 900 mL of 0.1N HCl with 5% alcohol and c) 900 mL of 0.1N HCl with 40% alcohol in a USP II paddle apparatus at 50 rpm for 120 minutes. The results of the dissolution test are as follows:

Table 3: In-vitro dissolution data of the capsule of example 1 in hydro-alcoholic media

From the results of Table 3, it is apparent that the abuse deterrent multi-particulate solid dosage form having coated minitablet of Example 1 when subjected to extraction studies in different hydroalcoholic solutions containing 5 to 40 % of alcohol, at the end of 120 minutes, there is no dumping of the drug, due to the presence of the alcohol in the dissolution medium. The abuse deterrent dosage form of the Example 1 showed inhibition to dose dumping in the presence of alcohol.

This data also indicates that the coated minitablet of Example 1 are resistant to extraction to alcohol. An abuser intending the crush the mini-tablets and extract with solvents like ethanol, would not be able to achieve the drug levels in the extracts.

EXAMPLE 3

Determination of extent of resistance to particle size reduction of Example 1 1. Demonstration of deterrence to nasal abuse

The coated minitablets of first composition of example 1, i.e component 1 or component 2 were evaluated for particle size reduction using a coffee grinder. For this, 1 gram of coated minitablet having diameter of about 2 mm were subjected to grinding in a coffee grinder having a rotating speed of 3600 rpm for 20 seconds. The resultant crushed mini-tablets were subjected to sieve analysis using series of sieves with descending mesh aperture sizes. The results of the sieve analysis are given in the table 4 below: Table 4: Results of the sieve analysis of the crushed mini-tablets subjected to coffee grinder

It may be noted that the upon subjecting to crushing, the coated mini-tablets provided a great level of resistance to particle size reduction, as only 0.68 % of the total particles had a average diameter of less than 90 microns. It is important to note than about 97 % of the crushed particles had an average particle size of more than 500 microns. This brings an important conclusion that the coated minitablet of the present invention provide resistance to nasal insufflation. This is because it is known than particles of size less than 100 microns are only deliverable to the lungs via nasal insufflation. In this case, the data indicates that only 0.68 percentage of particles are susceptible to abuse by nasal insufflation. 2. Demonstration of Deterrence to parenteral abuse

The coated minitablet of Example 1 of the present invention were subjected to the syringibility and injectibility tests to evaluate parenteral abuse deterrent properties of product.

The contents of two capsules of example 1, were evaluated for particle size reduction using a coffee grinder by rotating it in the coffee grinder having a rotating speed of 3600 rpm for 3 minutes at 30 seconds interval. The resultant crushed mini-tablets were subjected to following test:

Crushed powder equivalent to one dosage was weighed and transferred onto stainless steel spoon. 2 mL or 5 mL water was added to the powder on the spoon. Sample dispersion was heated for 1 minute with intermittent stirring with the help of syringe. After one minute heating, dispersion was allowed to cool and settle at room temperature for 30 minutes. The solution was withdrawn for 1 minute into a 1 mL insulin syringe through needle attached to it. The volume withdrawn in 1 minute was noted.

Syringeability test

The solution withdrawn in the syringe was transferred quantitatively into 50 mL volumetric flask. The syringe was rinsed with 0.1N Hydrochloric acid and the rinsing solution was transferred into the same volumetric flask. 15 ml of acetonitrile was added and diluted up to the mark with 0.1N hydrochloric acid and mixed well. 5.0 mL of supernatant solution was pipetted into a 25 mL volumetric flask and diluted up to the mark with the mobile phase and mixed. The resultant solution was filtered through a 0.45μ nylon filter by discarding first 5 mL and injected into HPLC for quantification.

Injectability test

The solution withdrawn in the syringe was transferred quantitatively into a 50 mL volumetric flask. 15 ml of Acetonitrile added and diluted with 0.1N hydrochloric acid. 5 mL of supernatant solution was pipetted into 25 mL volumetric flask and diluted with mobile phase. Resultant solution filtered through 0.45μ nylon filter, and injected in HPLC for quantification.

The results for the Syringeability and Injectability test are as follows:

Table 5: Results

The syringibility and injectibility results indicate that the coated minitablets of the present invention provided complete resistance to syringibility and injectibility. Thus, the oral abuse deterrent multiparticulate solid dosage form of the present invention provides deterrence to abuse via parenteral route. As seen in above table, the drug solution could neither be syringed nor injected. EXAMPLE 4

Breaking strength

In order to determine whether the coated mini-tablets have resistance to deformation on application of a force, the coated minitablet of the first composition i.e component 1 or component 2 prepared as per the example 1 were subjected to application of force. Fort this, the coated minitablet having a cylindrical shape and average diameter of 2 to 2.5 mm, were subjected to application of force by placing the mini-tablets under a probe of the texture analyser. The instrument used is a texture analyser TA XT Plus with 50 kg load cell. Before starting the measurement the coated minitablet was placed vertically or along its length and aligned directly under the probe such that the descending probe penetrated the minitablet in the centre such that the force of the descending probe was applied perpendicular to the diameter and in line with the thickness of the minitablet. The probe of the texture analyser initially travelled at a pre-test speed of 1 mm/sec towards the coated minitablet. When the probe contacts the coated minitablet the trigger force set is reached and then the probe travels at a test speed of 0.08 mm/second for a distance of 1.5 mm. The instrument measured the force required to move the probe for a distance of 1.5 mm at the specified speed of 0.08mm/second after coming in contact with the mini-tablet. It was also possible to determine the time, instead of the force applied.

It was found that the coated minitablet deformed to a more compact shape and there was no crushing or splitting or powdering of the mini-tablets during the application of force.

This demonstrates that the coated minitablet of the oral abuse deterrent multiparticulate solid dosage form of the present invention are crush resistant and it is difficult for the abuser to tamper with the intention to extract the drug.

Claims

1. An oral abuse deterrent multiparticulate solid dosage form abuse deterrent

multiparticulate solid dosage form comprising:

• a first composition comprising coated cores, each coated core comprising

a. a core comprising a drug susceptible to abuse and a crush resistant carrier having a first melting point,

b. a first coat surrounding the said core and comprising water soluble polymer that does not melt at or below the first melting point,

• a second composition comprising an alkalizer.

2. An oral abuse deterrent multiparticulate solid dosage form abuse deterrent multiparticulate solid dosage form as claimed in claim 1 , wherein the core is in the form of compressed core mini-tablet and coated core is a coated mini-tablet.

3. An oral abuse deterrent multiparticulate solid dosage form abuse deterrent multiparticulate solid dosage form as claimed in claim 1, wherein the dosage form is a capsule, sachet, pouch or a tablet.

4. An oral abuse deterrent multiparticulate solid dosage form abuse deterrent multiparticulate solid dosage form as claimed in claim 1, wherein the water soluble polymer of the first coat is polyvinyl alcohol.

5. An oral abuse deterrent multiparticulate solid dosage form abuse deterrent multiparticulate solid dosage form as claimed in claim 1 , wherein the drug is released in a controlled manner over a period of 12 hours or 24 hours.

6. An oral abuse deterrent multiparticulate solid dosage form abuse deterrent multiparticulate solid dosage form as claimed in claim 1, wherein the crush resistant carrier is polyalkylene oxide and ranges from about 40 to 90 % by weight of the core.

7. An oral abuse deterrent multiparticulate solid dosage form abuse deterrent multiparticulate solid dosage form as claimed in claim 1 , wherein the polyalkylene oxide used has a molecular weight in the range of 1,00,000 to 10,00,000.

8. An oral abuse deterrent multiparticulate solid dosage form abuse deterrent multiparticulate solid dosage form as claimed in claim 1, wherein the second coat is a mixture of water insoluble polymer and water soluble polymer. An oral abuse deterrent multiparticulate solid dosage form abuse deterrent multiparticulate solid dosage form as claimed in claim 1, wherein the third coat comprises cellulose acetate and polyethylene glycol.

9. An oral abuse deterrent multiparticulate solid dosage form abuse deterrent multiparticulate solid dosage form as claimed in claim 1, wherein the reverse enteric polymer of the outermost coat is a copolymer based on methyl-methacrylate and diethyl- aminoethyl methacrylate or copolymer based on methyl methacrylate butyl methacrylate- dimethyl aminoethyl methacrylate.

10. An oral abuse deterrent multiparticulate solid dosage form abuse deterrent multiparticulate solid dosage form as claimed in claim 1, wherein the dosage form is prepared by a process comprising steps of preparing a first composition comprising: a) preparing a core comprising mixture of the drug and crush resistant carrier having a first melting point into cores.

b) coating the cores of a) with the first coat of water soluble polymer that does not melt at or below the first melting point of the crush resistant carrier

c) curing the coated cores of b), at a temperature of about the first melting point of the crush resistant carrier for a period of about 1 hour to 2 hours in a moving bed coating equipment,

d) applying a second coating of water insoluble polymer,

e) applying third coating of cellulose acetate and plasticizer.

f) applying a coating of reverse enteric polymer.

g) mixing the coated cores of first composition with a second composition comprising alkalizer and optionally, lubricants, disintegrants and filing into the capsule, pouch, sachet or a tablet.