Cool Solutions for Hot Flushes

Transcription

1 Cool Solutions for Hot Flushes The use of Coated Minitablets to achieve a Flexible Release Profile for Gabapentin Mark Powell Scientific Manager Quay Pharmaceuticals

2 Project Outline Gabapentin is an established anticonvulsant used in the treatment of epilepsy and post-therapeutic neuralgia The aim of the project was to develop a modified/extended release oral formulation for evaluation of a new indication Proof of concept and data for patent submission

3 Gabapentin Cools Hot Flushes University of Rochester researchers, who have been investigating new therapies for hot flushes for several years, report in the July (2006) Obstetrics and Gynaecology journal that the seizure drug gabapentin is as effective as oestrogen, which used to be the gold standard therapy for menopause symptoms. Oestrogen is no longer the preferred treatment because recent, large studies have shown that the hormone increases the risk of heart disease, stroke, breast cancer and Alzheimer's disease for some women. "Gabapentin does appear to be as effective as oestrogen," said lead author Sireesha Y. Reddy, M.D., assistant professor of Obstetrics and Gynaecology at the University of Rochester Medical Centre. "Until now its efficacy relative to oestrogen was unknown"...

4 Target Release Profile Gabapentin has an elimination half life of 5 hours to 7 hours Target duration of therapeutic action was up to 12 hours for twice daily administration A target duration for in vitro release of gabapentin was 4 hours to 6 hours In vivo/in vitro correlation was not established

5 Formulation Strategy Because of the possible need to tailor the release profile following PK/PD studies, it was decided to produce minitablet cores (16 mg, 3 mm Ø) that could be separately coated with gastro-resistant and extended release polymers A high (75 %) API loading was achieved using a wet granulation approach

6 Tablet Core Formulation Component Composition (% w/w) Gabapentin 75% Polyvinylpyrrolidone (binder) 2% Microcrystalline cellulose (diluent) Sodium starch glycollate (intragranular disintegrant) 20% 2% Magnesium stearate (lubricant) 1%

7 Coatings Two coating systems were used: Eudragit FS30D (methacrylic acid copolymer) as gastro-resistant coat Eudragit RL30D and RS30D (copolymers of acrylic and methacrylic acid esters functionalised with tetra alkyl ammonium groups) as extended release coat A HPMC barrier coat was applied to overcome gabapentin incompatibility with FS30D

8 Effect of RL:RS Ratio

9 Analysis? An analytical method was required to support excipient compatibility and dissolution studies Since information on the dissolution profile was required over c. 6 hours, the method needed to be sufficiently sensitive to detect low (few % dissolved) levels of gabapentin But

10 No Chromophore! H 2 N COOH Gabapentin

11 UV Absorbance.simple unconjugated chromophores give rise to such high-energy and therefore such shortwavelength absorption that they are of little use Williams & Fleming, Spectroscopic Methods in Organic Chemistry, 1989 Chromophore Transition λ max (nm) N n σ* c. 195 C O n σ* c. 190

12 Analytical Options Inject large volume, detect at 210 nm No real λ max Poor peak shape Poor specificity Other detection technique (e.g. RI, ELSD, electrochemical) Derivatise

13 Detection at 210 nm Example sodium glutamate 20 µl injection of 1.0 mg/ml solution System suitability injection precision 3% Slight fronting

14 Amino acid UV Spectra Comparison of amino acid and aromatic spectra (data from NIST Chemistry Web Book - Poor absorbance (ε = 125) and no λ max for glutamic acid Detector drift of ± 1nm gives c. 2 % error

15 Different Detector Options available at Quay: UV RI (poor sensitivity) MS (not ideal for large numbers of samples) CCAD evaluated promising, but limited linearity (c )

16 Derivatisation Pros Improves sensitivity/detectability Modifies problem functional groups Cons Can complicate impurity profile Can narrow the polarity range of compounds of interest Robust, reproducible reaction needed

17 Chromatogram DAD1 A, Sig=338,10 Ref=390,20 (D:\ARCHIV~1\2005\021205A\ D) mau 160 Both compounds 1.0 mg/ml Gabapentin Phenylalanine min

18 Variant 1 Immediate release - 5 % HPMC-coated minitablets in 0.1M HCL % Gabapentin Dissolved Time (min)

19 Variant 2 % Gabapentin Dissolved Modified Release - 10 % FS30D-coated minitablets in ph 7.6 buffer after 2 hours in 0.1 M HCl Time (min)

20 Variant 3 Extended Release - 15% RL/RS-coated minitablets in ph 7.6 buffer 120 % Gabapentin Dissolved Time (min)

21 Drug Product Profile 1 % Gabapentin Dissolved Capsule Combination 80% immediate, 10% modified & 10% extended release Time (min)

22 Drug Product Profile 2 % Gabapentin Dissolved Capsule Combination 20 % immediate, 40 % modified & 40 % extended release Time (min)

23 Conclusions Wide range of release profiles possible through selection of different minitablet ratios Analytical method performed well, especially at low level Patent granted!

24 Acknowledgements Mike Frodsham Baljit Sanghera Prof. John Collett

25 Questions