WO2023223349A1

WO2023223349A1 - Stabilized nitroglycerin micro granules preparation and process for preparation thereof

Info

Publication number: WO2023223349A1
Application number: PCT/IN2023/050457
Authority: WO
Inventors: Rajesh Agrawal; Vishal Gupta; Rakesh KHATTAR; Mukesh SINHA; Mithu Sen
Original assignee: Modi-Mundipharma Pvt. Ltd.,
Priority date: 2022-05-18
Filing date: 2023-05-15
Publication date: 2023-11-23

Abstract

Stabilized nitroglycerin micro granules preparation and process for preparation thereof The present invention is related to the preparation of a stable micro granules 5 formulation containing nitroglycerin for oral uptake, prepared by adsorption of nitroglycerin on a uniform sized hydrophilic - hydrophobic polymer matrix system which is admixed with non-ionic pH dependent viscolyzing and stabilizing agent and showing sustained release of drug for the management and prevention of angina pectoris. These adsorbed and admixture micro granules or an oral solid dosage form 10 containing these micro granules provides excellent stability and better content uniformity on storage in unit dose container or multi dose containers made of glass or plastic.

Description

FIELD OF THE INVENTION:

The present invention relates to the preparation of a novel, stable and sustained release micro granules. The invention specifically relates to a unit oral dosage form of nitroglycerin containing these micro granules for the management and prevention of angina pectoris.

BACKGROUND OF THE INVENTION:

Nitroglycerin also known as Glyceryltrinitrate (GTN) or 1, 2, 3-Propanetriol 1, 2, 3-trinitrate is a nitroglycerol where the hydrogen atoms of all three hydroxy groups of the glycerol moiety are replaced by nitro group. Nitroglycerin is highly potent, pale yellow viscous liquid, slightly soluble in water, at room temperature. It is extremely sensitive to shock and heat, also start decomposing at 50-60°C and explodes at 218°C when exist as pure substance form. For safety reasons, nitroglycerin is diluted to 2% by weight or preferably kept in triturate form; with the use of other substances as diluents or inert substance like lactose, dextrose, propylene glycol, or other inert excipients.

It is a highly potent coronary vasodilator to provide relief from anginal chest pain, by acting as a prodrug, releasing nitric oxide to open blood vessels and alleviating heart pain. It is clinically prescribed for prophylaxis or medical treatment of angina pectoris i.e., sudden heart-related chest pain which is caused by the reduced blood flow to heart muscles. Nitroglycerin act as vasodilator agent by dilating the arteries and veins; thus provides more blood flow to the heart muscles.

Nitroglycerin is converted into nitric oxide into smooth muscle and activates guanylyl cyclase, thereby increasing cyclic GMP concentration and resulting in smooth muscle relaxation. Dilatation of veins results in decreased venous return to the heart, thereby decreasing left ventricular volume by reducing the preload and decreasing myocardial oxygen requirements. Arteriolar relaxation reduces arteriolar resistance by reducing the afterload, hence decrease myocardial oxygen demands. In addition, nitroglycerin causes coronary artery dilatation, thereby improving myocardial blood distribution.

Various dosage forms of nitroglycerin are available for the treatment of angina pectoris. Nitroglycerin is generally used in the form of sublingual tablets, capsules, composite gradual release tablets, ointments, transdermal patches or intravenous infusion. Time of onset and duration of action for each form of nitroglycerin administration differs from the other, as sublingual tablet or spray of nitroglycerin has two-minute onset and twenty-five-minute duration of action; oral formulation has a thirty-five-minute onset and a duration of action of 4-8 hours; transdermal patch has an onset of thirty minutes and a duration of action of ten to twelve hours.

Clinical results revealed that the continuous exposure to nitrates has been shown to cause the body to stop responding normally to this medicine. Medical practitioner recommends that the patches should be removed at night, allowing the body a few hours to restore its responsiveness to nitrates, whereas sublingual preparations are widely used in the emergency situations. A controlled or sustained release oral dosage forms are also available aiming at maintaining a stable concentration of nitroglycerin in the plasma. Considering the importance of drug administration route, oral drug delivery way has been widely accepted for drug administration by virtue of its convenience to the patient.

Notwithstanding with the efficacy of nitroglycerin, it’s high volatility and mobility leads to the loss of drug to the environment during storage and use , leading to suboptimal dosage to the patient.

Thus, when tablets containing nitroglycerin and an excipient such as lactose are exposed to the atmosphere in a semi enclosed or open container, the loss of nitroglycerin results in a change in the nitroglycerin content of the tablets. Further, the mobility of nitroglycerin is manifested by the migration of the drug from one tablet to another when such tablets are in contact with each other in a closed container over an extended period. Apart from this, nitroglycerin is volatile at room temperature even when diluted with inert substance or when prepared as a solid commercially available medicinal product or oral dosage forms for drug delivery.

The stabilization of nitroglycerin in solid dosage form has been a challenge of scientific community for more than 40 years due to its instability and vaporization at atmospheric pressure. The vaporized nitroglycerin migrates from tablet to other tablets, to container or container components, when packed in single dose or especially in multi dose containers and stored typically for a long time. The migration from one tablet to another tablets, causes Content Uniformity (CU) problems. This causes variability of nitroglycerin content from one tablet to another tablet and thus may lead to negative therapeutic consequences. Nitroglycerin itself has poor chemical stability during storage. This leads to loss of potency and rapid degradation of the Active Pharmaceutical Ingredient (API) resulting in formation of dimmers; Di-nitroglycerin (DNG), Monomers; Mono-nitroglycerin (MNG) and several other unknown degradation products, responsible for drug-related adverse events, including the so called “nitrate-headache”.

Indian Patent Application No 1517/MUM/2014 discloses an oral stable sublingual pharmaceutical composition of nitroglycerin comprising lactose, pregelatinized starch, croscarmellose sodium, colloidal silicon dioxide and calcium stearate. Invention relates to a pharmaceutical composition of nitroglycerin devoid of stabilizer which is stable against the migration of the drug from tablet to tablet when such tablets are in contact with each other or from tablet to container and container components stored in lOcc amber glass bottles.

The US patent application 6,110,597 discloses a stable nitroglycerin containing pharmaceutical composition, preferably a direct compressed tablet, comprising effective amounts of nitroglycerin, lactose, silica, starch, a stabilizer glyceryl monostearate in an amount of about 0.5 to 10 %, and a lubricant. Invention closely replicates the properties of nitroglycerin moulded sublingual tablets (e.g., adequate disintegration and sublingual absorption), while reducing the problems experienced with compressed tablets (e.g., friability and weight variations). The stable tablets are characterized by a decreased migration of nitroglycerin, decreased potency loss, excellent content uniformity when stored in bottle.

US 4,091,091 describes nitroglycerin containing pharmaceutical preparation and its methods for stabilizing sublingual pharmaceutical composition consisting essentially of nitroglycerin, polyvinylpyrrolidone and at least one conventional pharmacologically inert, non-toxic, water-soluble sublingual pharmaceutical excipient, wherein nitroglycerin is the sole pharmacologically active agent and polyvinylpyrrolidone is the sole stabilizer. These nitroglycerin tablets are stabilized against the migration of the active agent from tablet to tablet when such tablets are in contact with each other in a glass jar.

US 3,789,119 relates to improved sublingual pharmaceutical compositions of nitroglycerin and methods for producing those compositions. Preparation provides rapid release of nitroglycerin upon sublingual administration, and being thereby stabilized against the tendency of nitroglycerin to migrate significantly from tablet to tablet, from tablet to environment, and from tablet 'to container with resulting loss of original potency during storage in either glass or plastic container.

WO2012113564 discloses a stabilized solid pharmaceutical preparation of Glyceryl trinitrate for oromucosal or oral administration, characterized in that it contains at least one carrier material and a non-volatile carboxylic acid ester stabilizer (mono- and diglycerides, polyethoxylated glycerides, esters of lactic acid, D-alpha tocopheryl polyethylene glycol 1000 succinate and solid triglycerides) that reduces the volatility of the GNT.

US 4,073,931 disclose a nitroglycerin inclusion compound with cyclodextrin and composition containing same. The inclusion compound is obtained by contacting cyclodextrin with nitroglycerin in the presence of water. This inclusion compound is very stable as a quick effective drug for treating angina pectoris and easy in handling.

EP 0028526 Bl relates to a novel pharmaceutical preparation containing 2,4,6- tri nitroglycerin as active ingredient in a balanced biphasic hydrophilic-lipophilic composition. The pharmaceutical preparations of this invention facilitate the transdermal absorption of medicaments.

SK 19941524 discloses a pharmaceutical composition with diffusion -Osmotic controlled drug release. Preparation contains a one-layer tablet core having a polymeric film-coat, therapeutically active agent and hydrophilic polymer. It further contains, if desired, a two-layer tablet core comprising an active agent and hydrophilic polymer in the first layer of this core and a hydrophilic polymer in the second layer of this core. The composition is suitable for the preparation of tablets with a controlled drug-release and containing active agents like nitroglycerin etc.

GB 1125882 discloses a sustained release pharmaceutical composition comprises one or more medicaments adsorbed on colloidal magnesium aluminium silicate particles, some of the particles having one or more medicaments adsorbed thereon being provided with an enteric and/or retardant coating. The particles may be tableted or encapsulated.

US 4,629,621 discloses a sustained release composition for releasing a biologically active compound (nitroglycerin) into its surrounding environment. Here, pharmaceutically active compound is dispersed in a matrix which, when contacted with an aqueous liquid, erodes progressively and said matrix comprising a mixture of 5 to 95% by weight of a polyethylene glycol and 95 to 5% by weight of an erosion rate modifier amphiphilic compound. Dosage forms comprising the credible matrix are prepared by moulding, particularly by injection moulding.

US 4,235,870 discloses Slow release pharmaceutical compositions comprising a combination of a higher aliphatic alcohol and a hydrated hydroxy-alkyl cellulose in ratio of from 2:1 to 4:1 parts by weight and comprising from 20 to 40 percent by weight of the composition; the method for making the same, and their inclusion in pharmaceutical dosage forms intended for oral administration, to provide a slow release of a therapeutically active compound during a predetermined period of time, from five to ten hours after oral ingestion by humans and animals. EP 0,248,548 A2 discloses a solid controlled release pharmaceutical composition comprising an active ingredient incorporated in a controlled release matrix comprising a water soluble polydextrose. The controlled release matrix may also contain at least one of a digestible C₈-C₅₀ substituted or unsubstituted hydrocarbon, especially a C₁₂-C₃₆ fatty alcohol, and a polyalkylene glycol, especially polyethylene glycol.

There have been several attempts at reaching a stable nitroglycerin oral composition. However, the existing compositions do not specifically provide a solution for manufacturing of stable oral nitroglycerin micro granules or an oral solid dosage form or an oral preparation with low degradation, decreased loss of potency or inhibiting vaporization or migration of nitroglycerin from one dosage unit to another dosage unit or to container or container components, excellent content uniformity on storage in multi dose containers and also provides a sustained release of drug for a longer duration of action especially in hot and humid climatic conditions.

Further, none of disclosure provides a suitable solution for storage of dosage form in non-glass containers, particularly in plastic containers - for maintaining the stability and its sustained release characteristics.

Hence, there is need for an oral pharmaceutical composition for sustained release of nitroglycerin with low degradation profile, maintain potency with minimum vaporization of Active Pharmaceutical Ingredients and no migration of nitroglycerin from one dosage unit to another dosage unit or to container or container components, exhibiting excellent content uniformity on storage in unit- dose or multi-dose especially in non-glass containers.

In view of the above, the object of the present invention is to provide a stable, micro granule composition of nitroglycerin, which can be used as such or as a preparation of pharmaceutical dosage form containing these micro granules like tablets or capsules or sachets for the management of angina pectoris. Further objective of the present invention is to provide oral micro granules containing tablet or capsule or sachet dosage forms, which are characterized by very low, negligible or no nitroglycerin vaporization and excellent content uniformity when such tablets or capsules or sachets are in contact with each other or stored in multi dose glass or plastic polypropylene containers.

Yet another objective of the present invention is to provide oral micro granules containing tablet or capsule or sachet dosage forms, which are not susceptible for migration of nitroglycerin from tablet to another tablet or to container or container components on storage.

Another objective of the present invention is to provide stable oral micro granules or theses granules containing tablets or capsules or sachets dosage forms that retain an acceptable level of potency in line with label-claims in perfectly sealed container or in the presence of other material capable of absorbing nitroglycerin.

Yet another objective of the present invention is to provide stable oral micro granules containing tablets or capsules or sachets dosage forms, which have better chemical stability during shelf life, thus allowing long shelf-life particularly in a hot and humid climate conditions.

Still another objective of the present invention is to provide a sustained release oral dosage form of nitroglycerin to ensure better therapy outcome.

Another object of the subject matter is to provide a process for the preparation of sustained release nitroglycerin pharmaceutical composition which is cost effective.

Another objective of the present invention is to provide a sustained release oral dosage form of nitroglycerin with limited undesirable side effects like strong headache, nausea or vomiting due to the absence or very low level of degradation products as the monomer impurity. SUMMARY:

It is intended that all such features, and advantages be included within this description, be within the scope of the present invention. The following summary is provided to facilitate an understanding of some of the innovative features unique to the disclosed embodiment and is not intended to be a full description. A full appreciation of the various aspects of the embodiments disclosed herein can be gained by taking the entire specification, drawings, and abstract as a whole.

The present invention relates to manufacture of a novel, stable, sustained release nitroglycerin micro granules or oral solid unit dosage form of these micro granules primarily for the prevention and management of angina pectoris, which is prepared by adsorption of nitroglycerin on to a novel, uniform sized hydrophilic - hydrophobic polymer matrix system.

The present invention provides a micro granule or a dosage form containing these micro granules with improved stability and controlled vaporization of nitroglycerin by using uniform admixture of a non-ionic, pH-dependent viscolyzing and stabilizing agent with nitroglycerin containing hydrophilic - hydrophobic polymer matrix system, which is capable of maintaining optimum micro-environment at granular level, for inhibiting vaporization of nitroglycerin and assuring optimal product stability.

The present invention specifically provides nitroglycerin containing micro granules or an oral solid dosage form with excellent stability and better content uniformity on storage in multi dose containers, including plastic containers.

The adsorbed and uniform admixture micro granules or a dosage form containing these micro granules of nitroglycerin also have a very low degradation product formation on storage under hot and humid climate conditions.

The present invention also provides a sustained release oral solid unit dosage form of nitroglycerin, which contains highly stabilized, adsorbed and uniform admixture micro granules of nitroglycerin. The amounts of the ingredients in the final preparation are as depicted in Table 1 and 1A. Table 1: Composition of Micro Granules Preparation or micro granules containing dosage forms (Tablets/ Capsules/ Sachets):

Table 1A: Preferred Composition of Micro Granules Preparation or micro granules containing dosage forms (Tablets/ Capsules/ Sachets) along with optional ingredients:

The present invention also provides a process for manufacturing of stable micro granules of nitroglycerin which comprises the following steps:

Preparation of uniform size hydrophilic - hydrophobic balanced polymer matrix system wherein the polymer is used could be a; rate controlling polymer, hydrophilic polymer or hydrophobic polymer or a combination thereof; higher aliphatic alcohol.

Adsorption of nitroglycerin on hydrophilic - hydrophobic balanced polymer matrix system during uniform sizing of granules.

Admixing of non-ionic, pH dependent viscolyzing and stabilizing agent on adsorbed nitroglycerin hydrophilic - hydrophobic balanced uniform size polymer matrix system.

DETAILED DESCRIPTION OF INVENTION:

A novel oral stable sustained release micro granules as an oral dosage form containing nitroglycerin has been achieved by the present invention for the management and prevention of angina pectoris.

These micro granules are prepared by adsorption of nitroglycerin on a uniform sized hydrophilic - hydrophobic polymer matrix system. Further, invention improves stability and controls vaporization of nitroglycerin by preparing uniform admixture of a non-ionic, pH- dependent viscolyzing and stabilizing agent with nitroglycerin containing hydrophilic - hydrophobic polymer matrix system, which is capable of maintaining optimum microenvironment at a granular level, for inhibiting migration of nitroglycerin.

The terms preparation, compositions and formulations are used interchangeably and synonymously in the specification to describe the product of the present invention.

The stabilized nitroglycerin micro granules preparation for sustained release oral solid pharmaceutical dosage form preferably comprises nitroglycerin is a diluted triturate, in an amount of 2%w/w to 10%w/w, at least one carrier material, at least one rate controlling polymer, at least one non-ionic pH dependent viscolyzing and stabilizing agent, at least one lubricant or Glidant and optionally a combination of other pharmaceutically active ingredients.

The rate-controlling polymer is either a hydrophilic or a hydrophobic or a combination thereof; particularly suitable polymer that erode in aqueous media and results in slow or sustained diffusion of drug. The amount of polymer in the preparation of micro granules with respect to nitroglycerin depends upon the rate of drug release required, the type, the viscosity and the molecular weight of the polymer. Examples of suitable rate-controlling polymers include hydroxyl propyl methylcellulose, hydroxyl ethyl cellulose, ethyl cellulose, methyl cellulose and higher aliphatic alcohol; vinyl acetate copolymers; polysaccharides, such as xanthan gum, alginates, guar gum; starch and starch based polymers; polyethylene oxide, methacrylic acid copolymers; maleic anhydride; methyl vinyl ether copolymers and derivatives and a combination thereof. The concentration ranges are provided in Table 2.

Table 2

Specification for degradation product (Impurity) level in dosage form containing Micro granules of Nitroglycerin of the invention is shown in below Table 2A:

Table 2A

The non-ionic pH dependent, viscolyzing and stabilizing agent preferably polyacrylic acid, carboxy polymethylene and carbomers preferably carbopol is present in a concentration range from 3 to 10 mg per unit dose.

The stable sustained release oral solid pharmaceutical dosage form of the invention has the vaporization and the migration of the nitroglycerin inhibited such that the content uniformity among the unit dosage form is under precise control such that the Relative Standard Deviation is not more than 5%, when the dosage form is stored in the multi dose containers. The dosage form has improved stability in glass container as well as polypropylene multi dose containers, when stored under accelerated conditions or hot and humid climatic conditions.

The pharmaceutical dosage form has a sustained drug release profile of 60%, preferably 40% drug is release after 1 hour time interval, during in- vitro drug release test. The Tablet or Capsules dosage forms have a sustained drug release profile of 20% drug release in 1st hour; and 50% cumulative drug release in 4th hours; and 70% cumulative drug release in 8th hours; and 80% cumulative drug release in 10th hours.

Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

The present invention discloses a process for the preparation of the sustained release nitroglycerin composition. The process of the invention includes the following steps: i. Granulating the diluent and rate controlling polymer, hydrophilic polymer or hydrophobic polymer or a combination thereof with aqueous or non-aqueous solvent, ii. Drying, uniform sizing, inclusion of higher aliphatic alcohol and formulating said hydrophilic - hydrophobic balanced polymer matrix system, iii. Cooling and adsorption of nitroglycerin on said hydrophilic - hydrophobic balanced polymer matrix composition under the process of uniform sizing, iv. Admixing of non-ionic, pH-dependent viscolyzing and stabilizing agent on adsorbed nitroglycerin hydrophilic - hydrophobic balanced uniform size polymer matrix system, v. formulating said matrix composition by mixing the same with conventional excipients: at least one lubricant, at least one glidant, or a combination with other pharmaceutically active ingredients to obtain a stable sustained release nitroglycerin oral solid dosage form.

The invention of the present application provides for stable sustained release oral solid pharmaceutical dosage where the vaporization and the migration of the nitroglycerin is inhibited such that the content uniformity among the unit dosage form is under precise control such that the Relative Standard Deviation is not more than 5%, when the dosage form is stored in the multi dose containers. The pharmaceutical dosage form has improved stability in addition to glass container, most preferably in polypropylene multi dose containers, when stored under accelerated conditions or hot and humid climatic conditions. The pharmaceutical dosage form has a sustained drug release profile of 60%, preferably 40% drug is release after 1 hour time interval, during in- vitro drug release test. The Tablet or Capsules have a sustained drug release profile of 20% drug release in 1st hour, and 50% cumulative drug release in 4th hour; and 70% cumulative drug release in 8th hours; and 80% cumulative drug release in 10th hour.

EXAMPLES

The experiments conducted are exemplified herein for sake of explanation and understanding without limitation.

EXPERIMENT 1

PREPARATION OF STABLE MICRO GRANULES OF NITROGLYCERIN

Carrier and release control polymer are mixed, granulated with purified water in a rapid mixer granulator, dried in fluid bed dryer at 60°C and suitably sized through 0.8 mm screen fitted in oscillating granulator or suitable equipment. The dried and sized granules are further layered by inclusion of molten higher aliphatic alcohol in a rapid mixer granulator by maintaining the temperature of granules and allowed to cool or conditioned at lower temperature around 20°C. The conditioning granules are further adsorbed with drug during specifically sizing through 1.4 mm screen and. then 0.8 mm screen fitted in oscillating granulator or suitable equipment. This polymer-drug adsorbed granule is further admixed with viscolyzing & stabilizing agent, preferably Carbomer. The stabilized micro granules are then optionally lubricated with Color Erythrosine Lake, lubricants like magnesium Stearate & Glidant like purified talc in low shear blender for at least 15 minutes. These micro granules of nitroglycerin are having less than 30%w/w granules below 425μm and between 15% w/w to 35%w/w granules below 180μm in size.

In process quality control parameters used in the process are listed in Table 3 below. All quality limits are for all in process stages. The shelf-life specification has wider ranges based upon observed stability data.

Table 3

EXPERIMENT 2

MICRO GRANULES COMPOSITION OF NITROGLYCERIN AND

INITIAL IN-VITRO DRUG RELEASE

Various formulations were prepared in the experiments of the invention. The compositions for example F-1to F -15 are as per following different levels of key ingredients quantity as shown in Table 4. The micro granules in formulations F1 to F13 were prepared as per the process parameters mentioned in Example 1 and have strength of 6.4 mg/dosage unit. The F14 and F15 formulations were prepared for comparison having coarse granules and fine granules respectively instead of micro granules. Furthermore, Formulation F-10 was also for sake of comparison with respect to the presence of pH controlling viscolyzing and stabilizing agent being absent in said formulation.

The formulations F-1 to F-9 and F-11 to F-13 having varied ingredients concentration, but within the defined ranges as per Table 1A and micro granules particle size distribution as desired are obtained. These formulations with varied composition also show satisfactory In-vitro drug release results as can be seen in below Table 4.

Table4

EXPERIMENT 3

MICRO GRANULES PREPARATION of Examples F-1 to F-13:

Lactose Monohydrate and Hydroxyethyl cellulose are mixed, granulated with purified water in a rapid mixer granulator, dried in fluid bed dryer at 60°C and suitably sized through 0.8 mm screen fitted in oscillating granulator or suitable equipment. The dried and sized granules are further layered by inclusion of molten higher aliphatic alcohol in a rapid mixer granulator by maintaining the temperature of granules and allowed to cool or conditioned at lower temperature around 20°C. The conditioning granules are further adsorbed with drug during specifically sizing through 1.4 mm screen and then 0.8 mm screen fitted in oscillating granulator or suitable equipment. This polymer-drug adsorbed granule is further admixed with viscolyzing & stabilizing agent, Carbomer ( Except in example F-10) . The stabilized micro granules are then finally lubricated with Color Erythrosine Lake, lubricants like magnesium Stearate &Glidant like purified talc in low shear blender for at least 15 minutes and compressed into tablets using rotary tablet compression machine and tooling. Example F-10 lubricated granule is also filled in suitable size hard gelatin Capsule shells or Quadruplet Laminate foil; having following structure: Polyglassine Paper (41gsm)/ LDPE (17gsm)/Alu. (12μ)/LDPE (35 gsm).

These micro granules of nitroglycerin are having less than 30%w/w granules below 425μm and between 15%w/w to 35%w/w granules below 180μm in size.

EXPERIMENT 4

COARSE GRANULES PREPARATION of Example F-14:

Lactose Monohydrate and Hydroxyethyl cellulose are mixed, granulated with purified water in a rapid mixer granulator, dried in fluid bed dryer at 60°C and suitably sized through 2.4 mm screen fitted, in oscillating granulator or suitable equipment. The dried and sized granules are further layered by inclusion of molten higher aliphatic alcohol in a rapid mixer granulator by maintaining the temperature of granules and allowed to cool or conditioned at lower temperature around 20°C. The conditioning granules are further adsorbed with drug during specifically sizing through 2.4 mm screen fitted in oscillating granulator or suitable equipment. This polymer-drug adsorbed granule is further admixed with viscolyzing & stabilizing agent, Carbomer. The stabilized micro granules are then finally lubricated with Color Erythrosine Lake, lubricants like magnesium Stearate & Glidant like purified talc in low shear blender for at least 15 minutes and compressed into tablets using rotary tablet compression machine and tooling. These lubricated granules are also filled in suitable size hard gelatin Capsule shells or Quadruplet Laminate foil; having following structure: Polyglassine Paper (41gsm)/ LDPE (17gsm)/Alu. (12μ)/LDPE (35 gsm).

These coarse granules of nitroglycerin are not having at least 30%w/w granules below 425μm in size.

EXPERIMENT 5

MICRO GRANULES ( FINE) PREPARATION of Example F-15:

Lactose Monohydrate and Hydroxyethyl cellulose are mixed, granulated with purified water in a rapid mixer granulator, dried in fluid bed dryer at 60°C and suitably sized through 0.6 mm screen fitted in oscillating granulator or suitable equipment. The dried and sized granules are further layered by inclusion of molten higher aliphatic alcohol in a rapid mixer granulator by maintaining the temperature of granules and allowed to cool or conditioned at lower temperature around 20°C. The conditioning granules are further adsorbed with drug during specifically sizing through 0.8 mm screen and then 0.4 mm screen fitted in oscillating granulator or suitable equipment. This polymer-drug adsorbed granule is further admixed with viscolyzing & stabilizing agent, Carbomer. The stabilized micro granules are then finally lubricated with Color Erythrosine Lake, lubricants like magnesium Stearate & Glidant like purified talc in low shear blender for at least 15 minutes and compressed into tablets using rotary tablet compression machine and tooling. These lubricated granules are also filled in suitable size hard gelatin Capsule shells or Quadruplet Laminate foil; having following structure: Polyglassine Paper (41gsm)/ LDPE (17gsm)/Alu. (12μ)ZLDPE (35 gsm).

These fine granules of nitroglycerin are not having between 15%w/w to 35%w/w granules are below 180μm in size.

EXPERIMENT 6

Analysis of uniformity of content in dosage units of all the formulations are as per United State Pharmacopoeia 2020 (USP 43- NF 38; Monograph of Nitroglycerin Sublingual Tablets)*.

For Initial In-Vitro drug Release and Uniformity of Content in Dosage Units tests, the following specs are indicated:

Table 5

EXPERIMENT 7

The formulation F-10 (Tablets Dosage form) is exemplified for composition without Viscolyzing & Stabilizing agent with same process parameters and the micro granules particle size distribution. As can be seen in Table 4, although the initial results are satisfactory but stability results under stress storage conditions are not satisfactory with respect to slow in-vitro release profile and higher Related Substances, as further seen in below Table 6:

Table 6: Formulation F10 analysis 6^th

EXPERIMENT 8

Comparison in vitro drug release and content uniformity of different dosage form prepared using different Granules sizes (coarse or Fine granules) with respect to the preparations from micro granules.

The formulations F-14 and F-15 (Tablets dosage form) are examples when the composition is within preferred ranges as per Table 1 A, but micro granules particle size distribution is varied, resulting in undesirable release time as seen in Table 7 below. Formulation F-14, having coarse granule size exhibits a retardation in the release pattern i.e. slow In-vitro drug release after 8th hour time point. Formula F- 15, having fine granule size exhibits a rapid release pattern i.e. it shows faster In- vitro drug release in initial hours which is not desired.

Table 7

EXPERIMENT 9

In vitro drug release and content uniformity comparison of Capsules dosage form prepared without viscolyzing agent and by varying the particle size of the granules. Capsules filled with different size granules of same formulations F10, F-14 and F15, were also prepared and compared. A preferred composition of micro granules containing nitroglycerin is presented in Table 11 in subsequent pages. (Refer formulation F16- F18). The in vitro drug release performance of formulation F10 were not satisfactory as can be seen in below Table 8.

Table 8

The capsule dosage form of Formulation F-10 composition without Viscolyzing & Stabilizing agent but with desired Micro granules particle size distribution did not show satisfactory initial (In vitro drug release) & at stress study conditions (High Related Substance). Surprisingly, a drastically changed release profile is observed which is indicative of erratic behaviour of the dosage form in absence of a viscolyzing and stabilizing agent. The Formulation F-14 composition micro granules particle size distribution having Coarse granules, shows higher content variation in dosage units. However, Formulation -F15, which is with fine granules is showing satisfactory results in capsule dosage form.

EXPERIMENT 10

In assay, related substance and content uniformity comparison of Sachet dosage form prepared without viscolyzing agent and by varying the particle size of the granules.

Sachets of containing different size granules of same formulations F10, F-14 and F15 were also prepared and compared. A preferred composition of micro granules containing nitroglycerin is presented in Table 12 in subsequent pages. (Refer formulation F16- F18). Formulation F-10 shows High Related Substance at stress study conditions (50°C for 15 days), and Formulation F-14 with Coarse granules show higher content variation in dosage units; RSD is 8.6%. However, Formulation -F15, which is with fine granules is showing satisfactory results in sachet dosage form.

Table 9

EXPERIMENT 11

Four of the Table 4 preferred compositions of tablet dosage form i.e. F-1, F-11 to F-13. However, Formulation -F10, which is without viscolyzing and stabilizing agent is showing higher impurity profile results in tablet dosage form at50°C after 15 days storage ( refer Table -06) .were subjected to accelerated stability storage conditions (40°C/75% Relative Humidity RH) in Polypropylene Bottles (30’ s pack). Their results with respect to all quality parameters, after 6 months storage, were observed to be satisfactory (See Table -10 below) [LOQ- Limit of Quantification]

Table 10

EXPERIMENT 12

Capsules filled with preferred micro granules composition [F-16 to F18]

The process followed was same as that of Formulation F-1 to F-13 before tablet preparation step. Then these micro granules are filled in suitable size hard gelatin (HG) Capsule shells. These capsules are further packed in Alu-Alu blister pack. The in vitro drug release performance of all three formulations is satisfactory as can be seen in Table 11 below.

Table 11

Table 11A

tress Stability studies were carried for above formulations of Micro Granules of Nitroglycerin containing capsule dosage form in 1x10’s Alu-Alu blister Pack. erformance of the preferred compositions in capsule dosage form was reproducible md robust. The release after 1 month / 50°C & after 2 month / 40°C/75%RH results was lso satisfactory. The data is presented in above Table 11A.

EXPERIMENT 13

Nitroglycerin in Micro Granules of preferred composition (formulation F-16 to F-18) filled in Sachets dosage form Micro Granules composition of NitroglycerinF-16 to F-18 were prepared in Sachets osage form as per Experiment 2 and then these micro granules are filled in suitable ize Quadra laminate Sachet foil. The Foil Type was Polyglassine Paper (41gsm)/ LDPE 17gsm)/Alu. (12μ)ZLDPE (35 gsm). The composition and stability results of said ormulations F-16 to F-18 was same and is shown in Table 12 and Table 12A espectively.

Table 12

Table 12A

Stress Stability studies were carried for above formulations of Micro Granules of Nitroglycerin containing Sachets dosage form for Sachet Packing in Quadra laminate Sachet foil. The assay and the impurity results were satisfactory after 15 Days and 1 Month at 50°C stress conditions in Sachets dosage form also.

EXPERIMENT 14

Micro Granules composition of Nitroglycerin in Tablet dosage form in 2.6 mg per tablet

Compositions for Example F-19 to F- 23 for Nitroglycerin Strength 2.6 mg per dosage unit were made for initial Analytical studies. Micro granules Manufacturing Method was as per Formulation trials F-1 to F-13 and the individual ingredient/material amounts were as follows in Table 13

Table 13

F-24 composition is without viscolyzing and stabilizing agent but Micro granules particle size distribution is within desired range and thus the initial analytical results and stability results of these formula F-19 to F-24 show clear distinction as shown in Table 14. The experimental results show that for all preferred Formulations (F - 19 to F-23) that all batches performance is satisfactory initially and after 6 months accelerated stability at 40°C/75% Relative Humidity (RH). However, the F-24 formulation Product manufactured without viscolyzing agent shows a drastic changes in the behaviours i.e. in vitro % drug release is erratic and rapid and there is an increase in the impurity profile of the drug product after 6 months accelerated stability at 40°C/75% Relative Humidity.

Table 14

w

⃰formulation F-24 is without viscolyzing and stabilizing agent EXPERIMENT 15

Micro Granules composition of Nitroglycerin in Capsule dosage form in 2.6 mg per capsule

The compositions of formulation F-26 with Strength 2.6 mg per dosage unit were prepared with Micro granules manufacturing method as per Formulation process of Experiment 2. Then these micro granules are filled in suitable size hard gelatin Capsule shells. Performance of the most preferred composition (Formulation F-26) in capsule dosage form, in 2.6 mg strength was found to be satisfactory (Table 15).

Table 15

EXPERIMENT 16

Micro granules preparation of 6.4 mg/ Capsule dosage unit nitroglycerin without Color which is only for aesthetic appearance, Talc, and Magnesium Stearate as a flow aid with Optimum Particle Size in Formulation F27 shown in Table 16.

Micro granules manufacturing method as per following process: Lactose Monohydrate and Hydroxyethyl cellulose are mixed, granulated with purified water in a rapid mixer granulator, dried in fluid bed dryer at 60°C and suitably sized through 0.8 mm screen fitted in oscillating granulator or suitable equipment. The dried and sized granules are further layered by inclusion of molten higher aliphatic alcohol in a rapid mixer granulator by maintaining the temperature of granules and allowed to cool or conditioned at lower temperature around 20°C. The conditioning granules are further adsorbed with drug during specifically sizing through 1.4 mm screen and then 0.8 mm screen fitted in oscillating granulator or suitable equipment. This polymer-drug adsorbed granule is further admixed with viscolyzing and stabilizing agent, Carbomer. These granules are filled in suitable size hard gelatin Capsule.

Table 16

As seen in Table 16, the F27 formulation without color, Talc & Magnesium Stearate provides satisfactory performance. EXPERIMENT 17

Micro granules preparation of 10 mg/ dosage unit nitroglycerin

Formulation F-25 in Tablet, Capsule & Sachets dosage forms were made and their initial Analytical Results are presented in Table 17. Micro granules manufacturing method was as per Formulation process of Experiment 2.

Theses micro granules are compressed into tablets using rotary tablet compression machine and using B- Type tooling. These lubricated granules are also filled in suitable size hard gelatin Capsule shells or

Quadruplet Laminate foil; having following structure: Polyglassine Paper (41gsm)/ LDPE (17gsm)/Alu. (12μ)/LDPE (35 gsm).

Table 17

EXPERIMENT 18

In Vitro drug release of micro granules preparations of Experiment 17, having 10 mg of nitroglycerine per dosage unit

In- Vitro dissolution testing of the 2 different dosage - tablets and capsules was carried out and the observed results are as per following Table 18.

Table 18

Formulation F-25 having higher strength Micro Granules composition of Nitroglycerin in two of the dosage forms viz. Tablet/Capsule shows satisfactory results with respect to following:

• Assay results are satisfactory,

• content uniformity results are satisfactory

• Impurity levels are within the acceptable ranges, and

• Dissolution of capsules and tablets are within the acceptance ranges.

In the specification, there has been disclosed preferred embodiments of the invention. Although specific terms are employed, they are used in a generic and descriptive sense only and not for purposes of limitation of the scope of the invention. Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore, contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.

Claims

WE CLAIM

1. A stabilized nitroglycerin micro granules preparation for sustained release oral solid pharmaceutical dosage form comprising

Nitroglycerin is a diluted triturate, in an amount of 2%w/w to 10%w/w, at least one carrier material, at least one release controlling polymer, characterized in at least one non-ionic pH dependent viscolyzing and stabilizing agent, optionally at least one lubricant or Glidant and optionally a combination of other pharmaceutically active ingredients. wherein the preparation has at least 30%w/w granules of micro granules of nitroglycerin are below 425μm size and 15%w/w to 35%w/w granules are below 180μm size.

2. The stabilized nitroglycerin micro granules preparation as claimed in claim 1, wherein said carrier material is selected from lactose, dextrose, propylene glycol or other inert substance.

3. The stabilized nitroglycerin micro granules preparation as claimed in claim

1, wherein said non-ionic pH dependent, viscolyzing and stabilizing agent is selected from polyacrylic acid, carboxypolymethylene and carbomers.

4. The stabilized nitroglycerin micro granules preparation as claimed in claim 1, wherein said release controlling polymer is either a hydrophilic cellulose preferably hydroxyl propyl cellulose, hydroxyl ethyl cellulose or hydroxyl propyl methyl cellulose or their combination.

5. The stabilized nitroglycerin micro granules preparation as claimed in claim 1, wherein said release controlling polymer is selected from the hydrophobic aliphatic alcohol (C8 - C18) in combination with hydrophilic cellulose preferably hydroxyl propyl cellulose, hydroxyl ethyl cellulose or hydroxyl propyl methyl cellulose or their combination.

6. The stabilized nitroglycerin micro granules preparation as claimed in claim 1, wherein said lubricant or glidant are material which are commonly used for pharmaceutical dosage form to aid and improve the flow properties of the micro granules.

7. The stabilized nitroglycerin micro granules preparation as claimed in claim 1 wherein said dosage form is selected from preferably sachets, capsule or tablet dosage form and is used for management and prevention of angina pectoris.

8. A process for manufacturing a stabilized nitroglycerin micro granules preparation as sustained release oral solid pharmaceutical dosage form comprising a. Granulation of carrier with rate controlling polymer; hydrophilic polymer or hydrophobic polymer or a combination thereof with aqueous or non-aqueous solvent, b. Drying, uniform sizing, inclusion of higher aliphatic alcohol and formulating said polymer matrix system, c. Cooling and adsorption of nitroglycerin on said polymer matrix composition under the process of uniform sizing of granules, having at least 20% particles below 425μm size, d. Admixing of non-ionic, pH-dependent, viscolyzing and stabilizing agent on adsorbed nitroglycerin polymer matrix granules, e. formulating said composition by mixing the same with conventional excipients: at least one lubricant, at least one glidant, or a combination with other pharmaceutically active ingredients, f. obtaining a stable sustained release micro granules of nitroglycerin having at least 30%w/w granules below 425μm size and between 15%w/w to 35%w/w granules are below 180μm size.

9. The process as claimed in claim 8, wherein the said micro granules of step (f) are further compressed into tablet or filled in either capsules or sachets to have the active ingredient concentration in the range of 2 to 10 mg per unit dose or more preferably in the range of 2.5 to 6.4 mg per unit dose.

10. The process as claimed in claim 8, wherein said micro granules are stable and degradation product formation in the granules is reduced to the level of total impurity limits of NMT 3% during the entire product shelf life.

11. The process as claimed in claim 8, wherein said micro granules are stable and degradation product formation in the granules is reduced such that the level of 1,3 Di Nitroglycerin& 1,2 Di Nitroglycerin is limited to below 1% level each during the entire product shelf life.

12. The process as claimed in claim 8, wherein said micro granules are stable and degradation product formation in the granules is reduced such that the level of 1-Mono Nitroglycerin& 2-Mono Nitroglycerin is limited to below 0.5% level, preferably below 0.3% during the entire product shelf life.

13. The stabilized nitroglycerin micro granules preparation as claimed in claim 1 and 8, wherein the content uniformity among the unit dosage form of the nitroglycerin is has Relative Standard Deviation not more than 5%, when the dosage form is stored in the multi dose containers.

14. The stabilized nitroglycerin micro granules preparation as claimed in claim 1 and 8, wherein the pharmaceutical dosage form have improved stability in addition to glass container, most preferably in polypropylene multi dose containers, when stored under accelerated conditions or hot and humid climatic conditions.

15. The stabilized nitroglycerin micro granules preparation as claimed in claim 1 and 8, the pharmaceutical dosage form has a sustained drug release profile of 60%, preferably 40% drug is release after 1 hour time interval, during in- vitro drug release test.

16. The stabilized nitroglycerin micro granules preparation as claimed in claim 1 and 8, wherein the pharmaceutical dosage form Tablet or capsules has a sustained drug release profile of 20% drug release in 1st hour; and 50% cumulative drug release in 4th hour; and 70% cumulative drug release in 8th hour; and 80% cumulative drug release in 10th hour.

17. The stabilized nitroglycerin micro granules preparation as claimed in claim 1-7 and 13-16 such as herein described in the specification along with examples.

18. The process for manufacturing a stabilized nitroglycerin micro granules preparation as sustained release oral solid pharmaceutical dosage form as claimed in claim 8-12 and 13-16, such as herein described in the specification along with examples.