Enclosure I



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BRIEF RESUME OF THE INTENDED WORK:
ENCLOSURE – I
6.1 Need for the study:


More than 50% of the pharmaceutical products are administered orally for several reasons, of which better patient compliance and existence of highly developed technology are most important.

Many prescription and non-prescription beneficial agents are known to have extremely unpleasant tastes. In particular the macrolide antibiotics, especially erythromycin and Clarithromycin, have an extremely bitter taste, making oral administration of these actives difficult.

Administration of an orally having bitter and obnoxious tastes with acceptable level of palatability is a challenge to the pharmacist in the present world, especially in pediatric and geriatric formulation. Thus taste masking in the present day pharmaceutical industry has become a potential tool to improve patient compliance and commercial success of the product1.

Recent years have seen a tremendous progress in the technique of masking the unacceptable taste of an orally administered pharmaceuticals, such as filling in capsules, coating with water in soluble polymers or pH dependent water soluble polymer, adsorption on ion-exchange resin, micro encapsulation with various polymers complexing with cyclodextrin,chemical modification such as use of insoluble prodrugs , effervescent systems, salt formation, and use of excipient like flavors, sweeteners, gelatin, gelatinized starch and surfactants adding super disintegrants in the taste masked formulation2.

Pharmaceutical companies are commercially motivated to invest time, money and resources in developing palatable, pleasant tasting products because good tasting products:


  • Enhance patient compliance

  • Provide a competitive advantage when a therapeutic category is crowded with similar products e.g. anti-infective category etc.

  • Provide brand recognition to combat private-label competition.

Macrolide antibiotics have bitter taste and are particularly useful in treatment of common pediatric infections of the middle ear and upper respiratory tract, as well as certain forms of pneumonia which afflict the elderly. Children, older persons, and many other persons including disabled or incapacitated patients often have trouble swallowing tablets or capsules. In these situations, it is desirable to provide the drug either in a chewable solid form or a liquid form3.

The method carrying out need to be proved satisfactory with respect to taste masking and it can be useful on large scale with more efficient instruments.



ENCLOSURE – II

    1. Review of the literature:

  1. Rahul dabre et al ., prepared taste masked composition of Erythromycin because there is need to mask the taste of the bitter drugs in order to patients compliance, other the conventional method, newer techniques is to be exploited for the effective taste masking of drug.1

  2. Gattani SG et al., developed mouth dissolving tablets of Ondensetron hydrochloride using natural superdisintegrants along with Ac-Di-Sol, primogel, polyplasdone XL and they reported that Ac-Di-Sol was found to be more effective than others due its high swelling capacity.2

  3. Kirit Patel et al., prepared Azithromycin dehydrate mouth dissolving tablet using Kyron-T-134,which is an ion exchange resin available for taste masking of bitter drug such as Azithromycin, Clarithromycin, and Erythromycin. Kyron-T-314 works equally efficiently with hydrophilic and hydrophobic formulations, especially where other disintegrants are ineffective. Kyron-T-314 was compared with other disintegrants to determine its relative efficacy. Disintegration of tablet using Kyron-T-314 was found effective superdisintegrant as compared to other disintegrants is that it swells on getting hydrated but doesn't dissolve or have an adhesive tendency. 4

  4. Douglas et al., prepared taste masked formulations of Ranitidine with a synthetic cation resins for oral administration such as chewable or suckable tablets, granules and aqueous /non-aqueous suspensions. By carrying out resinate of drug with sulphonated styrene-divinylbenzene in sodium salt form (amberlite IRP 69), methacrylic acid–divinylbenzene resin in potassium salt form (amberlite IRP 88) and methacrylic acid-divinylbenzene resin in free ancid form (amberlite IRP 64). adsorbates formed from methacrylic acid-divinylbenzene resin in free acid form were reported to be taste masked and preferred for the formulation.5

  5. Lu MY et al., formulated Suspension of a polymer carrier system to reduce the bitterness of Erythromycin and Clarithromycin by absorption to carbopol(high molecular weight polyacrylic acid) ionic bonding of the amine macrolide to the polyacrylic acid, endogenous cations are replaced drug in GIT. Taste protection was encapsulated with polymer coating and concluded that hydroxypropyl methylcellulose phthalate (HP-55) provides the best combination of suspension stability, taste protection and bioavailability6 .

  6. Agarwal R et al., devloped adsorbates of Chloroquine phosphate (CQP) was prepared by using a polyacrylic acid ion-exchange resin. Taste evaluation of the adsorbates shows significant masking of the bitterness of the drug, complex formation was complete at pH 6.0. Stability studies at 37, 45 and 60oC indicated that the complex was stable at all conditions for 1 month. In vitro release studies revealed with optimizing complete drug elution from the complex. 7

  7. John PJ et al., prepared a taste-masked composition comprising polycarbophil and a macrolide antibiotic, Clarithromycin. The complex is further coated with an acid resistant polymer eudragit L100, releasing the drug in the intestine. For certain drugs the bioavailability may not be altered by the use of enteric coating, where the drug is released in the small intestine, but it shown for the drugs with a narrow absorption window was restricted to the upper gastric region, and hence use of enteric coating may alter the bioavailability.8

  8. Bhalero AV , formulated and evaluated Clonazepam fast dissolving tablets using superdisintegrants(cationic exchange resins) and solid dispersion technique by using PVP K-30 and combination of 5% w/w crosscaramellode sodium and 5% w/w sodium starch glycolate and they reported that so formulated tablets showed least dispersion time of 8seconds and faster dissolution rate.9

  9. Bajaj AN et al., prepared an oral controlled release suspension of Bromhexine using ion exchange resin technology. Prepared sorption of strong cation exchange resin and the drug were evaluated for pH, particle size analysis, sedimentation ratio, viscosity, drug content and Invitro drug release pattern. Complex was further retarded by microencapsulated with ethyl cellulose by solvent evaporation to further retard the release characteristics. Both the drug resinates complex and microencapsulated product were suspended in a palatable aqueous suspension base and was evaluated for controlled release characteristics.10

  10. Amin PD et al., utilized various techniques for taste masking of Roxithromycin viz granulation with eudragit E 100 and complexation with ion exchange resins. Of these, complexation with ion exchange resins. yielded complete taste masking. Evaluation was confirmed by differential scanning calorimetry. The taste masked complex was then formulated in to palatable mouth dissolve tablets. Taste evaluation of the tablets showed complete masking of the bitterness of the drug. In vitro release studies revealed complete drug elution from the complex after a period of 30 min in pH 1.2 buffer.11

  11. Itoh, prepared a rapidly-releasing and taste-masking pharmaceutical dosage form and a process for preparing such oral dosage form.12

  12. Yajima, provided a composition for oral administration by using spray congealing technique, which was excellent in masking the taste of an unpleasant tasting drug and in bioavailability.13

  13. Morella, prepared taste masked suspensions of microcapsules as a function of a polymer coating and the pH of a suspending medium, taste masked oral pharmaceutical composition including: drug with pH-dependent solubility; a polymer encapsulating active ingredient(polymer having a quaternary ammonium functionality) as a suspending medium, said medium adjusted to a predetermined pH at which the pharmaceutically active ingredient remains substantially insoluble; and wherein the pharmaceutically active ingredient is taste masked by the combination of the polymer and suspending medium, result obtained shows that suspension using polymer coating evaluates the pH at which drug complex elute is complete. 14

ENCLOSURE – III

6.3 Objectives of the study:

It is an object of the present invention to provide an oral composition which can deliver

a pharmaco-kinetically acceptable dosage of a beneficial agent, or to at least provide

the public with a useful choice and to provide a taste masked composition, which

effectively masks the taste of the drug without compromising the dissolution rate with

the aim :



  1. To prolong the availability, by releasing the drug from the complex for over 12 hours in the gastro intestinal tract.

2. To reduce toxicity by slowing drug adsorption.

3. To increase stability by protecting the drug from hydrolysis or other degradative

changes in the GIT tract.

4. To improve palatability.

5.To make availability of formulation in liquid and solid sustained release dosage

forms.


Fast dissolving dosage form

1. To improve administration for those who are non-cooperative.

2. To achieve quick disintegration and dissolution of dosage form.

3. To be swallowed without water.

4. To allow high drug loading,

5. To leave minimal or no residual on mouth and also provides better mouth feel.

6. To study the molecular properties of drug resin complex using FTIR Spectroscopy.

Suspension by taste masking-

1. To use an indigenous cation exchange resin which is solid and suitably

insolubilized high molecular weight polyelectrolyte that can exchange their mobile

ions of equal charge with the surrounding medium reversibly and stoichiometrically.

2. To evaluate the prepared drug resin complex for Particle size, % Swelling, Drug

loading efficiency and taste evaluation.

3. To study the drug release of macrolide antibiotics from drug resin complex.

4. To study the molecular properties of drug resin complex using FTIR Spectroscopy.

5. To improve the patient compliance of bitterly tasting Macrolide Antibiotics that are

extensively prescribed in liquid form.



MATERIALS AND METHODS:

Drug

:

Azithromycin







Erythromycin estolate etc.










Polymer

:

Cellulose acetate phthalate







Hydroxypropylmethylcellulose







Ethylcellulose







Polyethylene glycol







Stearic acid or Stearyl alcohol







Propylene glycol










Coating materials

:

Wincoat WT- Mp1002







Acrycoat L100







Acrycoat E30










Sweeteners

:

Aspartame







Mannitol







Lactose










Vegetable oil

:

Hydrogenated castor oil










Weak cationic exchange

:

Kyron-T114

Resins




Kyron-T40 Gel







Tulsion ADS-750







Tulsion ADS-300










Anti- oxidants

:

Butylated hydroxyl Anisole







Butylated hydroxyl toluene










Superdisintegrants

:

Crosspovidone, sodium starch glycolate, Crosscaramellose











METHODS

Taste masking by various techniques

1. Meltable coating techniques

-Drug embedded in wax/ vegetable oil etc.

2. Taste masking by weak cationic Exchange Resins

3. Spray coating techniques

-Micro emulsion technology, solvent evaporation, fluidized bed coating etc

4. Spray drier techniques

Formulation of taste masked macrolide antibiotics


  1. Fast dissolving Azithromycin tablets

  • It can be prepared by direct compression and other methods.

  1. Erythromycin dry suspension/Clarithromycin oral suspension

  • Dispersion production process etc.

ENCLOSURE – IV

7.1. Source of data:


  1. Library: Bharathi College of Pharmacy.




  1. E-library: Bharathi College of Pharmacy.


ENCLOSURE - V
7.2. Method of collection of data:

The data required for the study would be collected from the laboratory based work

planned as follows:

1. Evaluation of Drug Resin Complex

a) Particle size analysis and swelling study of resin

b) Taste Evaluation by subjective method

c) Drug Entrapment efficiency determination

d) Drug release from DRC

e) Molecular properties of drug resin complex

f) Content uniformity of spray coated material.

g) Estimation of spray dried material for drug content.

2. Prepared granules for Azithromycin fast dissolving tablets will be evaluated for

flow properties such as:


  1. Angle of repose

  1. Bulk density

  2. Carr’s consolidation ratio

  • Hausner’s ratio.Prepared fast dissolving tablets will be evaluated for

  1. Hardness

  2. Weight variation

  3. Friability

  4. In vitro dispersion time

  5. In vitro dissolution time

  6. Stability studies as per ICH guidelines

  7. Wetting time

  8. Estimation using UV- visible spectroscopy and other methods.

3. Prepared using taste masked Erythromycin sample for the preparation of

dry suspension.


  1. Evaluation of dry suspension

  2. Sedimentation volume and redispersibility of suspension

  3. Drug leaching into the Suspension

  4. Particle size analysis of suspension

  5. Viscosity of suspension

  6. Taste evaluation by subjective method

  7. Estimation of Erythromycin

  8. FTIR evaluation


ENCLOSURE – VI

7.3. Does the study require any investigation or intervention to be conducted on patients other humans or animals? If so, please mention briefly.

-NOT APPLICABLE-



7.4. Has ethical clearance been obtained from your institution in case of 7.3?

-NOT APPLICABLE-


ENCLOSURE – VII
LIST OF REFERENCES:

  1. Rahul dabre, Vishnubotla nagaprasad, Rajiv malik. Taste masked composition of Erythromycin and other there of, united states patent application publication. 2007; 1(A):514-523.

  2. Gattani SG, Shiyani BG, Kakade KN, Patil AB, Surana SJ. Formulation and evaluation of mouth dissolving tablet of Ondensetron hydrochloride by using superdisintegrants. Indian Drugs. 2009; 46(1):44-50.

  3. Goodman and Gillman’s. The pharmacological basis of therapeutics. The Mc. Graw hill companies. 2002; 9(E):1776.

  4. Kirit Patel, Deepan Patel, Vinod Raghuwanshi. Evaluation of Azitromycin dehydrate mouth dissolving tablet using Kyron-T-134. CPHI. 2008;1(V):182-184.

  5. Douglas. Drug adsorbates. United states patent num 5219563. 1993;142-144.

  6. Lu MY Borodkin S. A polymer carrier system for taste masking of macrolide antibiotics. Pharma res. 1991;1(1):706-712.

  7. Agarwal R, Mittal R, Singh A. Studies of ion-exchange resin complex of Chloroquine phosphate. Drug development Indian pharmaceuticals. 2006;6(A):773-776.

  8. John PJ. Taste masking pharmaceutical composition. Patent Application WO 02/092106. 2002;11.

  9. Bhalerao AV, Deshkar SS, Shirolkar SV, Gharge VG, Deshpande AD. Development and evaluation of Clonazepam fast dissolving tablets using Superdisintegrants and Soid dispersion technique. Research J. Pharm. and Tech. 2009;2(2):375-377.

  10. Bajaj AN, Sayed G. Oral controlled release Bromhexine ion exchange resinate suspension formulation. Indian drugs. 2000;(37):185-189.

  11. Amin PD. Patient compliant dose form for Roxithromycin. Ind J Pharm Sci. 2004;1(S):670- 673.

  12. Itoh, Rapidly releasing and taste-masking pharmaceutical dosage form. United states Patent 6221402. 2001;24.

  13. Yajima T. Particle design for taste masking using a spray congealing technique. Chem. Pharmaceutical Bulletin 1999;47(1):220-225.

  14. Morella, Taste masked liquid suspensions. US Patent 61973486 2001;12 .




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