PhD Thesis- PhD ID: PhD ID: JJTU, DEPARTMENT OF PHARMACEUTICAL SCIENCES Page 351

Transcription

1 PhD Thesis- 351

2 PhD Thesis- 1.0 PLATFORM TECHNOLOGY DESIGN CONCEPT FOR CARDIOVASCULAR DRUGS The objective of this research work was to establish a drug delivery technology platform for ph dependant drugs of cardiovascular category. Specifically, for drugs which has low solubility in alkaline ph. The design proposed was to coat tartaric acid beads with rate modulating polymers to achieve extended in-situ solubilisation for active. An outline of the design is depicted below All literature search indicated use of Fumaric acid to improve drug solubility due to its high retention property in the formulation, it was also indicated thatt faster release of soluble acid will deplete the reservoir and leading to low dissolution of active, in our research we targeted a highly soluble acid such as Tartaric acid and investigated different drugs such as dipyridamole & Carvedilol phosphate to modulate the release of active from the formulation in such a way that it ensured a profile similar to reference product, a commercial friendly manufacturing composition and process was established, in this way this research work will result into developme ent of generic cost effective formulations for patients in need, thus fulfilling the social cause. Figure XXX Structural representations of the proposed ER dipyridamole or Carvedilol phosphate pellets [Seal I & II designed to modulate release of Tartaric acid from formulation]

3 PhD Thesis- Fig. xx: SEM image demonstrating whole section of TAP-425 pellets Fig. xx: SEM image demonstrating whole section of TAP-425 pellets Fig. xx: SEM image demonstrating crosssection of TAP-425 pellets Seal coat I & II applied on these pellets are rate modulating coats, either of the one is composed of enteric polymers which will modulate release of tartaric acid from the formulation. As release and availability of Tartaric acid is critical for dipyridamole release, by modulating release of tartaric acid from the formulation by rate modulating polymers desired drug release profile is envisaged. The concept for this platform drug delivery technology is to use acidic core coated with hydrophilic or enteric polymers in such a way that would modulate the release of tartaric acid from the formulation sufficient enough to delay the availability of acid for the drug to form in situ salt or acidic local milieu. The proposed design have acidic core coated with rate controlling polymeric membrane, followed by drug layering and subsequent ER coat. This design shall be evaluated for multiple drugs of similar category where active has ph dependant release

4 PhD Thesis- Dissolution of tartaric acid from the bead was compared with dissolution of dipyridamole, the formulation was fine tuned to get profile similar to reference product so that a bioequivalence could be achieved. This concept has helped in two ways, one it helped to modulate the release of dipyridamole and also helped in controlling the interaction of dipyridamole with tartaric acid, thus preventing formation of dipyridamole tartaric acid adduct, product thus developed product was stable, scalable and commercially viable. This was concluded based on satisfactory development /scale up trials A detail investigation was carried out to understand binder effect. SEM surface morphology of drug layered pellets with 15% binder appears to have uniform, porous layer with smooth surface as shown below in SEM photograph. Fig. XX : SEM image demonstrating integrity of drug layered pellets Fig. XX : SEM image demonstrating whole section of drug layered pellets

5 PhD Thesis- Fig. XX: SEM image demonstrating cross-section drug layered pellets Fig. XX: SEM image demonstrating cross-section drug layered pellets From the surface response plot and polynomial equation obtained for the effect binder concentration and dispersion on the % assay it can be concluded that positive increase in the binder concentration is an indicative of there is significant increase in the Assay from 88.9% to 98.4% with increasing the concentration of binder form 5% to 15% with respect to API. Dispersion (%w/w) does not have significant effect on the Assay of the Dipyridamole Binder concentration with respect to Dipyridamole API and % dispersion of the drug suspension were found to be the critical factors for drug layering. Assay of the drug

6 PhD Thesis- layered pellets increases simultaneously with increase in the binder concentration and percentage dispersion. Surface response plot and positive coefficient of polynomial equation for binder concentration and dispersion concludes that binder concentration has more significant impact on the assay of drug than percent dispersion of drug suspension. Yield of the drug is increases simultaneously with increase in the binder concentration and percentage dispersion. Surface response plot and positive coefficient of polynomial equation for binder concentration and dispersion concludes that binder concentration has more significant impact on the yield of process than percent dispersion of drug suspension. Process efficacy of the drug layering is decreases with increase in the binder concentration and percentage dispersion. Surface response plot and negative coefficient of polynomial equation for binder concentration and dispersion concludes that binder concentration has more significant impact on the process efficacy of drug layering than percent dispersion of drug suspension During investigation of ER Coating, The ER coating level of 6% was sufficient enough to provide uniform surface with no evidence of rough or fractured surface. Fig. XX: SEM image demonstrating integrity of ER coated pellets Fig. XX: SEM image demonstrating whole section of ER coated pellets

7 PhD Thesis- Fig. XX: SEM image demonstrating cross- section of ER coated pellets Fig. XX: SEM image demonstrating cross section of ER coated pellets DESIGN CONFIRMATION Above research has provided clarity in use, application and delivery of tartaric acid in more effective way, thus the proposed design concept for this research work wherein tartaric acid was used as a in-situ solubliser to modulate the release of acid was confirmed. The release of tartaric acid was modulated by rate modulating polymers which were synergistically linked to outer ER polymer composition and weight gain to achieve required dissolution profile. Based on satisfactory use of this concept in development of dipyridamole extended release pellets, similar design concept was proposed for Carvedilol phosphate. Impact of hydrophilic and hydrophobic polymers in seal coating-i: Table No.XX Batch No.: 016D1 Apparatus: USP I Volume:900ml RPM: 100 Media Time % Dipyridamole Release % Pts. Cap1 Cap2 Cap3 Avg. Min. Max. RSD (hr.) 0.1N HCl ph 5.5 PO

8 PhD Thesis Table No.XX Batch No.: 016D1 Apparatus: USP I Volume:900ml RPM: 100 Media Time Tartaric acid Release % Avg. Min. Max. Pts. (hr.) Cap1 Cap2 Cap3 RSD 0.1N HCl ph 5.5 PO Fig XX XX Dissolution profile Dipyridamole Vs Tartaric acid Table No. XXX Batch No.: 017C3 Apparatus: USP I Volume:900ml RPM: 100 Media Time Pts. % Dipyridamole Release % Avg. Min. Max. (hr.) Cap1 Cap2 Cap3 RSD 0.01N HCl ph 5.5 PO Table No.XXX Batch No.: 017C3 Apparatus: USP I Volume:900ml RPM: 100 Media Time Tartaric acid Release % Avg. Min. Max. Pts. (hr.) Cap1 Cap2 Cap3 RSD 0.01N HCl

9 PhD Thesis- ph 5.5 PO Fig 110 Dissolution profile Dipyridamole vs Tartaric acid Observations and conclusion: From the above data it can be concluded that hydrophobic polymer in seal coating-i provides a controlled release of tartaric acid which enables a controlled drug release profile of dipyridamole. Tartaric acid adduct formation was also not observed in both polymers coating which concluded that % seal coating is sufficient enough to prevent tartaric acid adduct formation. Dissolution and related substance data was found to be satisfactory for batch no: 17C3, but as peeling effect was observed after seal coating-ii, to optimize the seal coating on tartaric acid following trial was taken SEAL COAT I OPTIMIZATION [HYDROPHILIC APPRAOCH] Dipyridamole Release in OGD Media: 12% Seal Coating Apparatus: USP I Media Time Pts. (hr) 0.01N HCL ph 5.5 Phosphate 2 3 Table No. XXX Batch No.: 070C Volume: 900ml RPM: 100 % Drug Release Avg. Min. Max. %RSD

10 PhD Thesis Dipyridamole Release in OGD Media: 20% Seal Coating Table No. XXX Batch No.: 071C Apparatus: USP I Volume: 900ml RPM: 100 Media Time % Drug Release Avg. Min. Max. %RSD Pts. (hr) N HCL ph 5.5 Phosphate Dipyridamole Release in OGD Media: 16% Seal Coating Table No. XX Batch No.: 060E Apparatus: USP I Volume: 900ml RPM: 100 Media Time % Drug Release Avg. Min. Max. %RSD Pts. (hr) N HCL ph 5.5 Phosphate Fig xxx Effect of seal coating % on dissolution of dipyridamole

11 PhD Thesis- Conclusion: 12% - 20% Hydrophilic Seal coat doesnot have impact on dissolution under similar conditions, it was also observed that drug relase was relatively faster at 12% seal coat in 0.01N HCl, while with 20% it was relatively slower, with 16% seal coat the profile/ release was comparable to refrence product and hence 16% target seal coat was selected. SEAL COAT II OPTIMIZATION [HYDROPHOBIC] Seal coat II was optimised at % level to understand impact of each coating level on the dissolution Dipyridamole Release in OGD Media: 0% Seal Coating II and 16% Seal Coating I Apparatus: USP I Media Time Pts. (hr) 0.01N HCL ph 5.5 Phosphate Table No.XXX Batch No.: 72D Volume: 900ml RPM: 100 % Drug Release Avg. Min. Max. %RSD Dipyridamole Release in OGD Media: 2% Seal Coating II and 16% Seal Coating I

12 PhD Thesis- Table No XXX Batch No.: 072A2 Apparatus: USP I Volume: 900ml RPM: 100 Media Time % Drug Release Avg. Min. Max. %RSD Pts. (hr) N HCL ph 5.5 Phosphate Dipyridamole Release in OGD Media: 6% Seal Coating II and 16% Seal Coating I Table No.XXX Batch No.: 072B2 Apparatus: USP I Volume: 900ml RPM: 100 Media Time % Drug Release Avg. Min. Max. %RSD Pts. (hr) N HCL ph Phosphate Dipyridamole Release in OGD Media: 4% Seal Coating II and 16% Seal Coating I Table No.XXX Batch No.: 060E Apparatus: USP I Volume: 900ml RPM: 100 Media Time % Drug Release Avg. Min. Max. %RSD Pts. (hr) N HCL ph 5.5 Phosphate Fig XX Effect of Seal Coating II on dissolution

13 PhD Thesis- In over all the platform technology developed helped to create a stable, scalable & bioequivalent product to Aggrenox. It was hypothesized to apply the same concept for other basic drug of similar category of cardiovascular as enumerated below. OVER ALL CONCLUSIONS AND OBSERVATIONS: A seal coating and ER coating level appears to provide desired dissolution profile as observed in above comparisons, the seal coat helps to control the release of tartaric acid from the formulation that might help in turn to solubilise the active in the formulation. Hence modulation of drug release is possible by modulating the seal coating % and type of coating as enumerated above 2.0 CONCEPT APPROVAL BY EXTENDING THE CONCEPT CARVEDILOL PHOSPHATE AS MODEL DRUG TO To confirm the feasibility of this concept a another drug from cardiovascular category, having almost similar solubility characteristic was selected such as Carvedilol phosphate, which when ested in similar concept such as tartaric acid core coated with rate modulating polymers followed by drug layering and extended release coating resulted in to acceptable & comparable drug release profile to Coreg CR. This confirmed the acceptability of platform technology concept After numerous trials following compositions were arrived upon and were exposed to dissolution studies as enumerated below Table No.XX

14 PhD Thesis- OGD dissolution in USP II, RPM:100, Vol:900ml, Media 0.1NHcl for 24 hrs Batch No CORE G CR CORE G CR 80mg 1ZP mg 1ZP C2 50E 53E Core -- Tartaric Acid Pellets [TAP 425] seal coated with MRP1 (10%) Core mg/cap:200mg Batch Size NA 300 gm 500gm 300 gm Coati ng Detail NA 8% ER coated, MRPI:MRPII:MRPIII (50:25:25),DR coat of MRPIV 25% s 25% 25% Assay Time point F2 NA NA 1ZP ZP ZP ZP ZP ZP Table No.XXX Time in {Hr} Coreg CR- 38C2 Tartaric acid 1ZP

15 PhD Thesis- Fig XXXX Correlation of TA release with CP release Use of acidic solubliser coated with modified release coating can help to improve the drug dissolution as shown above. This confirms the application of this platform drug delivery concept to Carvedilol phosphate In overall a Tartaric acid bead coated with modified release coating system can be developed successfully for cardiovascular drugs, where solubility is ph dependant. The modified release coated beads in turn provide extended microclimatic ph within local milieu, thus facilitating extended solubility in unfavorable ph In overall a cost effective, commercially viable generic formulation for Aspirin/Dipyridamole ER Capsules and Carvedilol phosphate ER Capsules is developed ASPIRIN IR PELLET FORMULATION Aspirin is highly susceptible to degradation, hence commercially only tablet and enteric coated formulations are available, in this research work attempt has been done to develop a immediate release IR pellet formulation of Aspirin, the design of the product is enumerated below.

16 PhD Thesis- Fig XXX Aspirin IR Pellets design structure Product thus developed is stable, scalable and commercially viable, based on all development trials. The product thus developed can be mixed synergistically with dipyridamole or any other suitable drug 4.0 STABILITY: A detail evaluation of stability is provided in relevant section. The product thus developed is stable 5.0 SCALE UP: Scale up of the product was carried out in Pam Glatt 125 Lts. The details of the same is being captured in the relevant section, thus manufacturing of the product is commercially viable 6.0 BIOEQUIVALNCE: Aspirin/Modified releasee dipyridamole thus developed was dosed in healthy human volunteers to compare it with reference product Aggrenox. The product passed BE test criteria of CI [80-125] Based on these observations a platform technology development & scale up is concluded to accommodate ph dependant actives in a formulation wherein acid release is controlled to some extent to provide local acidic microenvironment, which shall help the drug to get solublised when exposed to unfavourable alkaline ph. This proof of concept can be extended to various drugs which have ph dependant solubility

17 PhD Thesis- 7.0 LIMITATIONS OF THE RESEARCH WORK The major limitation of this technology is to source rounded tartaric acid pellets as depicted above in SEM, we sourced these pellets from Pharmatrans Switzerland, another limitation could be stability of active in presence of acid, in most of the cases direct contact of drug with acid need to be minimised or avoided. 8.0 FUTURE RECOMMENDATIONS & SCOPE OF THE TECHNOLOGY This platform technology is being successfully applied to basic drugs which are soluble in presence of acid. In future detail in-vivo investigation of multiple drugs can be done to check impact of acidic solubliser in the system. This technology can be applied to achieve in situ solubilisation of active within the formulation, which then allows the solublised active to be diffused out from the system.