Progress and Characterization of Pramipexole Extended-Release Tablets

Pramipexole dihydrochloride monohydrate is an antiparkinson’s agent which is known as dopamine D2 receptor agonist. It is structurally different from the ergot-derived drugs, e.g. bromocriptine or pergolide. Pramipexole is designated chemically as (S)-2-Amino-4, 5, 6, and 7- tetrahydro-6-(propylamino) benzothiazole and has the molecularformula C10H17N3S. It comes under class I of Biopharmaceutical Classification System. The purpose of this study was to develop and evaluate pramipexole dihydrochloride monohydrate extended release tablets by wet granulation method using different proportions of polymers and binder. Pre-formulation studies were done initially and the results were found to be within the limits. All the mentioned batches were prepared and granules were evaluated for pre-compression parameters such as loss on drying, bulk density, tapped density and compressibility index. Tablets were evaluated for weight variation,thickness, hardness, friability; disintegration time and assay were found to be within the limits. In vitro dissolutions were performed with 0.05M 6.8 PH phosphate buffer and effectof various polymerswere explored. Final selection of formulation was based on dissolution profile,from dissolution studies formulation 9 showed 80% drug release within 20 hours, so it will be compared with innovator. Similarity and difference factors which revealed that formulation (F 9) containing HPMC K 200, Eudragit L100 and binderare most successful as it exhibited in vitro drug release that matched with innovator product.In vitro drug release profilereveals that with increased concentration of Eudragit L 100. Accelerated stability studies were performed for the optimized batch which indicatedthat there were no changesin drug contentand in vitro dissolution.

1.1 Conception-

The challenge of targeting medicines specifically to the colonic region of the gastrointestinal tract is one that has been embraced by scientists over the once two decades.The colon has lately been accepted as a decreasingly important point for medicine delivery. Among all the routes of medicine administration that have been explored for the development of controlled release systems the oral route has in far achieved the utmost attention and success. It's to the ease of administration as well as to the fact that gastrointestinal physiology offers further inflexibility in lozenge form design than utmost other routes1.

The scientific framework needed for development of a successful oral controlled medicine deliveryconsists of an understanding the furrowing aspects-

The physicochemical characteristics ofthe medicine. Applicable GI deconstruction and physiology.

Lozenge form characteristics.

The factors to be considered in the design of colon-specific medicine delivery system deconstruction and physiology of colon pH in the colon

Gastrointestinalconveyance

Colonic micro foliage deconstruction and physiology of colon

The GI tract is divided into stomach, small intestine, and large intestine. The large intestine extending from ileocaecal junction to the anus is divided into three main corridors. These are the colon, the rectum and the anal conduit.The colon is divided into caecum, thrusting colon, depatic flexure,transverse colon, the splenic flexure, descending colon and the sigmoid colon. It's about1.5 m long, the transverse colon being the longest and most mobile part and has an average peripheryof about6.5 cm, although it varies in periphery from roughly 9 cm in the caecum to 2 cm in the sigmoidcolon.

4Morishita Metal.,56 has estimated the utility ofcolon targete01                                   acid) and EPA( eicosapentanoic acid) as a new diabetic specifics that promote natural glucagon- suchlike peptide- 1( GLP- 1) stashing. The end of this study was to estimate the goods of the long chain adipose- acids DHA and EPA on blood glucose situations, tube insulin and GLP- 1 attention. In addition, point- specific differences in these goods were determined using several intestinal parts, stomach,jejunum and colon.

Sanket D Gandhi etal.,57 has formulated and estimated the  colon targetedtablets of secnidazole for the treatment of amoebiasis. Thecolon as a point for medicine delivery offers distinct advantages on accountof a near neutral pH a much longer conveyance time, fairly low proteolytic enzyme exertion and a much lesser responsiveness to immersion enhancers. The formulated tablets were estimated for hardness, frangibility, weight variation, medicine content, in- vitro and stability study.

Kishor sahebrao salunkhe etal.,58 has formulated and estimated the dextrin matrix tablets of ibuprofen for colon specific medicine delivery.The formulated matrix tablets were estimated by differentIPQCtests, content uniformity and in- vitro medicine release study. The results of in- vitro study indicatethe matrix tabletscontaining dextrinas carrier and ethyl cellulose as binder are most suitableto deliver the medicine specifically in colonic region as compared tomatrix tablets of dextrin with other bindersystems.

Table 1: List of chemicals used with their grades and supplier names

Kishore G etal.,59has developed and estimated the colon targetedtablets of praziquantel and its β- cyclodextrin complex to treat schistosomiasis. They planned to ameliorate the solubility of praziquantel by forming addition complex with β- CD. Different phrasings were preparedby changing the attention of matrix carriers and β- CD. phrasings containing xanthum goo and guar goo showed maximum medicine release in colonic terrain.These phrasings were perplexed with β- CD. After complexation of praziquantel with β- CD, praziquantel dissolution is significantly increased in colonic terrain.
 

The end of the present exploration work was to develop matrix tablets of Metformin HCL targeted to colon.

The delivery of medicines to colon for systemic action ora original effect is precious in a variety of circumstances. These include the topical treatment of conditions similar as ulcerative colitis, Chron’s complaint, perverse colon pattern, contagious complaint, colon cancer and the eventuality for the oral delivery of peptides and other labile medicines. Targetingof medicines to the colon via oral route can be achieved by different approaches including different expression system. For which the medicine release is controlled by differentpH conditions, conveyance time and microbialfoliage.

Metformin HCL is a BCS class- III (largely answerable- unwell passable) biguanide outgrowth that has been used worldwide for the treatment of type- II diabetes. In malignancy of its favorable clinical responsechronic remedy with Metformin HCL suffers from certain specific problems of which, the most prominent being the high cure (1.5-2.0 g/ day), partial life is about1.5-3.5 hours, low bioavailability (60) and high prevalence of GI side goods (30 cases). The situation is complicated further with drop in immersion of medicine with food that detainments tmax by over to 35 mins.

Colon targetedmedicine delivery systemsare developed to increasethe bioavailability of medicines since colon is composed of large quantum of lymphoid towel the medicineby passes the first- pass metabolism and enters into the systemicrotation. still Metformin HCL cannot cross the colonic epithelial subcaste since it belongs to BCS class- III. In order to increase the bioavailability of Metformin HCL saturation enhancers like succinic acid is used. therefore, it improvesbioavailability there by frequence of dosing is reduced, minimize the GI side goods and improves the patient compliance throughCDDS.

Chemical Name,1- dimethylbiguanide hydrochloride Empirical Formula C4H11N5. HCl

Molecular Weight165.62Melting point 2220C to 2260Corder Hypoglycemic agent

Cure0.5 to 3g daily in divided doses87pKa12.4

Description White, crystalline greasepaint, hygroscopic.

AntonymsCellulose, Hydroxy propyl methyl ether; HPMC; Propylene glycol Ether; Methocel; Pharmacoat, Methyl cellulose, Methyl hydroxypropyl cellulose.

Chemical Name Cellulose, 2- hyfroxypropyl methyl ether. Molecular Weight roughly,000

Category Coating agent, film-former, stabilizing agent, suspending agent,tablet binder and density- adding agent.

Apparent viscosity0.25-0.75 g/ cm3

Description Hydroxy propyl methyl celluloseis an odourless, tasteless, white or delicate-white coloured stringy or grainy

Solubility Soluble in cold water, undoable in chloroform, ethanol and ether, but answerable in fusions of ethanol or methanol and Dichloromethane.

Density

The density of the polymeris in the range from 75- 140 of the declared value.

Stabilityand storehouse It's a stable material althoughit's hygroscopic after drying. Increase in temperature reducesthe density of results. It undergoes a reversible responseto gel metamorphosis upon heatingand cooling independently. The greasepaint should be stored in a well-unrestricted vessel in a cool and dry place. 

 Incompatibility Extreme pHconditions, oxidizing accoutrements.

Experimental Studies 

Preformulation Studies

DescriptionVisual examination of medicine was done and description as per specification was checked.

Melting point

Melting point of medicine was determined by capillary system in triplet. The melting point was set up to be in the range of 222oC-226oC.

Solubility in different dissolution media

Redundant quantum of the medicine is added to 100 ml distilled water, 100 ml phosphatebuffer pH7.4(intestine), 100 ml phosphate buffer pH6.8(colon). After adding maximum quantum of the medicine shake each volumetric beaker in a shaker for further than 12 hrs for maximum achromatism of the result. also 5 ml of result was removed from each beaker and dilution was made as needed. Absorbance was taken at 233 nm in UV-Visible spectrophotometer.

Preparation of1.2 pHphosphate buffer result

Place 250 ml of0.2 M potassium chlorideresult (14.911 g/ litre of distil water) in a 1 Litre volumetric beaker add425.0 ml of0.2 M hydrochloric acid and sufficient volume of distilledwater to produce1000 ml blend it well.

Preparation of6.8 pH phosphate buffer result

gm of monobasicpotassium phosphate was counted and adulterated up to 1000 ml to get stock result of monobasic potassium phosphate. 8gm Sodium hydroxide was counted and adulterated up to 1000 ml to get0.2 M sodium hydroxide result. 50 ml of the monobasic potassium phosphate result was taken from the stock result in a 200- ml volumetric beaker and22.4 ml of sodium hydroxide result from stock result of0.2 M sodium hydroxide resultwas added and also waterwas added to make up the volume.

1. Materials Used:

Results and Conversations

Standard estimation wind of Metformin HClin1.2 pH buffer

The absorbance was measured in a UV spectrophotometer at 233nm against1.2 pH buffer

7.1. Preformulation Studies

In the Preformulation studies, it was set up that the estimation of Pramipexole dihydrochloride monohydrate by UV Spectrophotometry system at λ maximum260 nm in distilled water showed reproducibility and this system was employed in the study. The correlation measure for the standard wind was set up to be0.9996, at the attentionrange, 10- 60 mcg/ ml and the retrogression equation generated was Y = 0.500 x-0.015x. medicine

– excipients comity studies were carried out and no change was observed medicine– Excipient comityStudies

As described in the methodology section the FT- IR studies were carried out for pure medicine alone and on with polymers. The results are epitomized as follows. An FT- IR diapason of pure Prampexole dihydrochloride monohydrate is shown in the Figure 3 and medicine and excipients comity are listed in the Table 6. also, FT- IR gamuts of Prampexole dihydrochloride monohydrate in combination with polymers are shown in numbers 4 to 8. These peaks weren't affected and prominently observed in FT- IR gamutsgiven in numbers 4 to 8. This indicates that there's no commerce between Prampexole dihydrochloride monohydrate and polymers and the medicinewas compatible with the expression factors.

Targeting of medicine to the colon is recognised to have several remedial advantages because colon is rich in lymphoid towel,uptake of antigensin to the mast cells of the colonicmucosa produce rapid-fire product of antibodies and therefore helps ineffective vaccinedelivery. The colonhas longer retention time and appearslargely responsive to an agent that enhancesthe immersion of inadequately absorbedmedicines. immersion of medicine motes from the colon like other regionsof GIT is a resultof a complex series of events. Successful colonic uptake of a medicine species bear both enzymatic stability and has to transport from the mucosal face to the venous and or lymphatic capillaries located in the sub mucosa. The colonic epithelial permeability is inadequate to allow for the transport rate needed for a remedial delivery. also theco-administration of an immersion enhancing agent offers a implicitmeans of over coming this hedge substantially through the use of chemicalenhancers like chelating agents, surfactant and dicarboxylic acids( succinic acid, lauricacid.etc)

The delivery of medicines to colon for systemic action ora original effect is precious in a variety of circumstances. These include the topical treatment of conditions similar as ulcerative colitis, Chron’s complaint, perverse colon pattern, contagious complaint, colon cancer and the eventuality for the oral delivery of peptides and other labile medicines. Targetingof medicines to the colonvia oral route can be achieved by different approaches including different expression system. For which the medicine release is controlled by differentpH conditions, conveyance time and microbial foliage.

Metformin HCL was chosen as a model medicine. It's a BCS class- III(largely answerable- unwell passable) biguanide outgrowth that has been used worldwide for the treatment of type- II diabetes. In malignancy of its favourable clinical response chronic remedy with Metformin HCL suffers from certain specific problems of which, the most prominent being the high cure (1.5-2.0 g/ day), partial life is about1.5-3.5 hours, low bioavailability (60) and high prevalence of GI side goods( 30 cases). The situation is complicated furtherwith drop in immersionof medicine with food that detainments t-max by over to 35 mins’