UNIVERSITY OF MEDICINE AND PHARMACY “GR. T. POPA” IAŞI

FACULTY OF PHARMACY

PhD student Pharm. ROXANA-GEORGIANA POTUR

CONTRIBUTIONS TO THE RESEARCH OF NEW FORMULATIONS OF ANTIDIABETIC AGENTS TABLETS

AND TO THEIR MANUFACTURING TECHNOLOGY

SUMMARY OF THESIS

Scientific guide: Prof. Dr. ELIZA GAFIŢANU

IAŞI 2011

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Rector Decision no 22508/18.10.2011 Public presentation date: 24.01.2012

The content of the thesis:

238 pages, from which: • 36 pages: STATE OF KNOWLEDGE; • 202 pages: EXPERIMENTAL PART, that includes:

146 figures; 132 tables; 201 refrences; in extenso published papers:

one paper in a CNCSIS B+ journal one paper in a ISI journal

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CONTENT

Abbreviations..........................................................................................................ix INTRODUCTION...................................................................................................1

I. STATE OF KNOWLEDGE………………………………………………...….4 II. EXPERIMENTAL PART……………………………………………………36 1. FORMULATION, PREPARATION AND QUALITY CONTROL OF IMMEDIATE RELEASE TABLETS WITH METFORMIN AND GLIBENCLAMIDE, OBTAINED BY FLUID BED TECHNOLOGY………37 1.1. STUDY OF THE INFLUENCE OF THE BINDER AND OF THE GRANULATION SOLVENT ON THE CHARACTHERISTICS OF THE GRANULES AND OF THE RESULTED TABLETS………………………...38 1.2. STUDY OF THE INFLUNCE OF THE FORMULATION FACTORS ON THE PHYSICAL CHARACTHERISTICS AND ON THE RELEASE OF METFORMIN HYDROCHLORIDE AND GLIBENCLAMIDE FROM IMMEDIATE RELEASE TABLETS…………………………………………..73 2. FORMULATION, PREPARATION AND QUALITY CONTROL OF THE MONOLITHIC AND BILAYERED PROLONGED RELEASE TABLETS WITH METFORMIN AND GLIBENCLAMIDE, OBTAINED BY FLUID BED WET GRANULATION…………………………………………...……..113 2.1. STUDY OF THE INFLUENCE OF HYDROPHILLIC POLYMERS ON THE FORMULATION AND ON THE DISSOLUTION OF METFORMIN HYDROCHLORIDE AND GLIBENCLAMIDE FROM PROLONGED RELEASE MONOLITHIC TABLETS………………………………..……..114 2.2. STUDY OF THE INFLUENCE OF HYDROPHILLIC POLYMERS ON THE FORMULATION AND ON THE DISSOLUTION OF METFORMIN HYDROCHLORIDE AND GLIBENCLAMIDE FROM PROLONGED RELEASE BILAYERED TABLETS…………………………………...…….155 3. STABILITY STUDY OF IMMEDIATE AND PROLONGED RELEASE TABLETS WITH METFORMIN HYDROCHLORIDE AND GLIBENCLAMIDE, OBTAINED BY FLUID BED WET GRANULATION………………………………………………………………186 3.1. STABILITY STUDY OF IMMEDIATE RELEASE TABLETS WITH METFORMIN HYDROCHLORIDE AND GLIBENCLAMIDE………….186 3.2. STABILITY STUDY OF PROLONGED RELEASE TABLETS WITH METFORMIN HYDROCHLORIDE AND GLIBENCLAMIDE…………..195 GENERAL CONCLUSIONS………………………………………………….203 SELECTED REFERENCES………………………………………………..…231 SCIENTIFICAL ACTIVITY ON THE TOPIC OF THE THESIS…………239

Abbreviations

PhEur European Pharmacopeia

USP-NF United States Pharmacopoeia National Formulary

HPMC hydroxypropylmethylcellulose

PLS partial least squares

CMCNa sodium carboxymethylcellulose

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INTRODUCTION.PURPOSE OF THE THESIS. MOTIVATION OF THEME SELECTION

The purpose of the thesis consisted in the formulation and in

the preparation of fixed-dose combination tablets for diabetes type II, a disease that is treated by polymedication, with low patient compliance.

The thesis was aimed towards the formulation of immediate release and prolonged release tablets with metformin and glibenclamide, two antidiabetic agents with complementary mechanisms of action. The study presented the following structure:

• Formulation, preparation and quality control of immediate release tablets with metformin and glibenclamide, obtained by fluid bed technology;

• Formulation, preparation and quality control of prolonged release monolithic and bilayered tablets with metfomin and glibenclamide, obtained by fluid bed technology;

• Stability study of immediate and prolonged release metformin-glibenclamide tablets, obtained by fluid bed technology.

The objectives, derived from the formulation of the the two active substances into one pharmaceutical form, consisted in:

• the improvement of the rheological properties of the active substances and their processing using a industrially applicable method;

• the manufacturing of tablets with pharmacotechnical properties, corresponding to the requirements of international pharmacopoeias (PhEur, USP-NF);

• prooving the in vitro efficacy, by insuring the conventional and prolonged release of both active substances, using methods that meet the requirements of international pharmacopoeias (PhEur, USP-NF);

• insuring stability of the actives in the pharmacutical form for a period of minimum 2 years of storage in standard conditions: commercial package –

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aluminium – PVC blister, cardboard box, similar to the other products from therapy;

• optimization of the pharmaceutical formulation by using modern methods of experimental design, derived from the concept of quality by design;

• identification of the release mechanism of the actives from the pharmaceutical form, by kinetic analysis of dissolution profiles of prolonged release tablets, using mathematical modelling.

The properties of the active substances (solubility and dose) determined the facilitation of glibenclamide dissolution from the tablet. The facts that were taken into consideration were the low terapeutical dose and the poor solubility of glibenclamide, which manifests low release from the tablet, because of the close vicinity to metformin (with high theraputical dose and high water solubility).

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II. EXPERIMENTAL PART

1. FORMULATION, PREPARATION AND QUALITY CONTROL OF IMMEDIATE RELEASE TABLETS WITH METFORMIN AND GLIBENCLAMIDE, OBTAINED BY

FLUID BED TECHNOLOGY

INTRODUCTION

The formulation study implyes testing and selecting the excipients and the method of preparation, in order to obtain physico-chemical corresponding tablets regarding their apparance, mechanical resistance, disintergation, dissolution and uniformity.

In order to indentify the influence of the formulation over the physico-chemical properties of the immediate release tablets with metformin-glibenclamide, the dose ratio taken into study was of 500/2.5 mg.

The research had two main purposes: the study of the influence of the binder and of the granulation solvent over the characteristics of the resulted tablets and the identification of the influence of some formulation factors on tablet properties and on the release of both active substances from the pharmaceutical form.

Tablets were produced by the fluid bed wet granulation of metformin, the majoritary component of the formulation, that exhibits poor rheological properties. Wet granulation of active substances and excipients was frequently used as a technological solution for correcting the rheology and the compressibility of powders [1].

The granules produced by fluid bed technology have the advantage of being processed in one equipment, by pulverizing a binder solution over the surface of the fluidized powder. The heat transfer is better, insuring an uniform temperature in the bed of powders, favorable for the granulation of highly thermic unstable substances [2].

Glibenclamide is geometrically dispersed into metformin granules, and is followed by the incorporation of the filler, disintegrant, binder, lubricant, the compression and the film coating.

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The quality control of the granules of metformin and of the resulted tablets consists in the testing of the specific pharmaco-technical parameters (for granules: the mean diameter of the granules, Haussner index, Carr index, flow rate ; for tablets: hardness, friability, disintegration, glibenclamide and metformin content and dissolution). The testing followed the requirements of the international pharmacopoeias (PhEur, USP-NF) [3,4]. The interconnection of the formulation factors (independent factors) that derive from the experimental formulation, with the quality parameters (dependent factors) produces the experimental plan. This is generated through the variation of the independent factors and the experimental determination of the dependent variables.

The formulation factors have a distinct role in the study of pharmaceutical forms, influencing the amplitude of the research, in order to attain favorable compositions for all medicines. By analysing their influence on the final product (granules/tablets), experimental design consists into an important tool for the determination of the function of the excipients in the pharmaceutical formulation [5].

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1.1. STUDY OF THE INFLUENCE OF THE BINDER AND OF THE GRANULATION SOLVENT ON THE

CHARACTHERISTICS OF THE GRANULES AND OF THE RESULTED TABLETS

The optimal formulation for the granules of metformin was

selected by experimenting fluid bed granulation technique, in order to obtain a directly compressible granulate, with good rheological and disintegration properties. The resulted tablets complied to the requierments of PhEur 7.0.

The influence of three formulation factors on the properties of the granules and of the tablets was determined, by their variation on several levels. All the investigated factors (binder - copovidone Plasdone® S630/hydroxipropylcelullose - Klucel® EF; quantity of binder – 2 to 4%; quantity of granulation solvent - 500-1000 ml for a pilot batch) presented significant degrees of influence.

The most important action over the experimental field was manifested by the binder, followed by the quantity of granulation solvent. Regarding the dimension of the granules, the quantity of binder presented a major influence, followed by the one manifested by the type of binder and the quantity of the solvent.

The formulations with Plasdone® S630 resulted in smaller diameter granules and in larger granulometric distribution, when compared to the formulations with Klucel® EF. The increase in the quantities of binder and granulation solvent produces larger granules of metformin.

The influence of the formulation factors on the rheological properties of the granules was quantified through the values of Hausser index, Carr index and the the flow rate. The rheology was not influenced by the type and the quantity of the binder and the quantity of the granulation solvent. The granulate obtained with Plasdone® S630 showed good and excellent flow and the one prepared with Klucel® EF presented excellent flow properties.

The pharmaco-technical properties of the tablets (hardness, fraibility, disintegration) were influenced mainly by the type of

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binder and fewer by the quantities of the binder and of the granulation solvent.

Tablets resulted from the granules obtained with Plasdone® S630 were charactherised by superior hardness, lower fraibility and good disintegration.

Tablets resulted from the granules with Klucel® EF presented lower hardness, fraibility and far too rapid dissolution properties.

The increase of binder and granulation solvent percentages resulted in the production of tablets with superior hardness, lower friability and greater dissolution time.

As a consequence, the use of copovidone as binder for fluid bed wet granulation produced granules with excellent flow properties and tablets with better hardness, fraibility and disintegration time.

By analysing the contour plot diagrams, the optimal formulation for the granules was identified: 3.3013% from the total mass of the granules Plasdone® S630 as binder, dissolved 730 ml of purified water, for a pilot batch.

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1.2. STUDY OF THE INFLUNCE OF THE FORMULATION FACTORS ON THE PHYSICAL CHARACTHERISTICS AND ON THE RELEASE OF METFORMIN HYDROCHLORIDE AND GLIBENCLAMIDE FROM IMMEDIATE RELEASE

TABLETS

This research resulted in obtaining immediate release tablets with 500 mg metformin hydrocloride and 2.5 mg glibenclamide, by fluid bet granulation of the majoritary component and by geometrically dispersion of the minoritary active ingredient from the pharmaceutical form.

The study was intended to produce the most favorable composition that results in the quality of the finished produc, formulated as tablets with antidiabetic agents. For this purpose, several combinations of the active substances with different proportions of excipients were analysed, in order to insure the required release of the therapeutical agents from the pharmaceutical form.

The influence on tablet properties of five formulation factors (type of glibenclamide, filler, quantity of disintegrant, quantity of extragranular binder and average weight of the tablet) was studied.

The release rate of glibenclamide and metformin hydrochloride was improved succesively with the increase of the quantity of disintegrant, decrease of the filler proportion, the introduction of the extragranulary added binder and with the use of the micronized glibenclamide in the formulation.

The fraibility of the tablets significantly decreased when microcrystalline cellulose was used as a filler and when the binder was added extragranulary.

Tablet hardness presented reverse proportional variation with fraibility values, the hardness increasing when using microcrystalline cellulose instead of lactitol monohydrate and when adding the binder extragranulary. The hardness decreased with the increase of the quantity of disintegrant and of the weight of the tablet.

The disintegration of the tablets increased when using microcrystalline cellulose as filler and when majoring the average weight of the pharmaceutical form.

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The release of metformin hydrochloride from the tablets was favored by the increase of the percent of disintegrant from the formulation and was inhibited by the increase of the average weight of the pharmaceutical form and with the extragranulary addition of the binder.

Glibenclamide dissolution was promoted by the use of lactitol monohydrate, the increase of the percent of disintegrant, the addition of extragranulary binder and of micronized glibenclamide.

The selection of the final formulation was performed after data fitting and evaluation of the experimentation results. The main selection criteria consisted in the similarity of the active substances dissolution profiles, compared to those corresponding to Glucovance® (Merck Sante, France). The final formulation contained micronized glibenclamide, microcrystalline cellulose as filler, 3% extragranulary added binder and 4% superdisintegrant.

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2. FORMULATION, PREPARATION AND QUALITY CONTROL OF THE MONOLITHIC AND BILAYERED

PROLONGED RELEASE TABLETS WITH METFORMIN AND GLIBENCLAMIDE, OBTAINED BY FLUID BED WET

GRANULATION

INTRODUCTION

The aim of the study consisted in prolonging the action of both active substances and in identifying the formulation solution for including in one tablet, both antidiabetic agents (with complementary modes of action).

The research was performed in the recent field of the preparation, manufacture and therapy use of a prolonged release fixed dose combination pharmaceutical form that contains 500 mg/2.5 mg metformin/glibenclamide.

The study consisted in the thorough selection of the excipients for the tablets that can prolong the release of the antidiabetic agents for a period of 12 hours. The pharmaceutical form must insure 100% dissolution of both actives at the end time point.

Metformin and glibenclamide exhibit different solubility properties, implying formulation difficulties in obtaining their prolonged release. There are two possibilites of incorporation of the therapeutical agents: both in the one lubricated mixture, followed by single compression (monolithic tablets) and each in a separate lubricated mixture, followed by double compresion (bilayered tablets).

The pharmaceutical form that contains metformin and glibenclamide in a homogenous physical mixture with an appropiate hydrophillic matrix former for prolonged release is a monolithical tablet.

The purpose of the first part of the study consisted in the determination of the influence of the hydrophillic polymers on the formulation of prolonged release monolithic tablets with metformin and glibenclamide.

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The matrix former was selected taking into consideration active substances’ solubilities, having as criteria the molecular weight and the viscosity of their hydrated form [6, 7].

The objective of the second part of the study was the identification of the hydrophillic polymers on the formulation of prolonged release bilayered tablets with metformin and glibenclamide. The aim was to identify the specific polymer for each active substance that can prolong over a period of 12 hours the release form the two layers.

The immediate and the prolonged release tablets were investigated for their mechanism of release of the active substances, by mathematical modelling.

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2.1. STUDY OF THE INFLUENCE OF HYDROPHILLIC POLYMERS ON THE FORMULATION AND ON THE

DISSOLUTION OF METFORMIN HYDROCHLORIDE AND GLIBENCLAMIDE FROM PROLONGED RELEASE

MONOLITHIC TABLETS

Cellulose ethers are water soluble polymers, frequently used for the formulation of hydrophillic matrix systems. Hydroxypropylmethylcellulose (hypromellose, HPMC) is a nonionic polymer that produces the hydration and gelation of the matrix, as a pH value independent process. In the case of matrices that incorporate active substances with pH-dependent solubility (weak acids, weak bases), the release happens as a function of the disolution media pH value. Formulation of the weak acids/bases of the matrix systems induces a decrease in the release, when the tablet crosses the gastrointestinal tract, due to the constant increase of pH value.

Metformin hydrochloride is a weak acid that needs for stabilization a weak base polymeric agent, that produces a pH independent release. Sodium carboxymethylcellulose (sodium carmellose, CMCNa), known for its gelling capacity, has a high molecular weight, that induces a prolonged retention time of the ative substance in the pharmaceutical form.

Formulation of a dual polymeric system, with a stabilizing agent, has the advantage of the decrease of individual variability when it is administred to patients. The hydrated pharmaceutical form is not rigid and is easily dispersed by the normal peristaltism of the gastrontestinal tract.

The selection of the matrix former was made also as a function of glibenclamide’s properties: high lipophilly and low solubility in water.

The aim of the first part of the research into the formulation of prolonged release tablets was the identification of the influence of the hydrophillic polymers on the physical characteristics of the monolithic tablets and on the release of both active substances from the pharmaceutical form.

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The release rate of glibenclamide and metformin hydrochloride was succesively modulated, by using matris formers of different viscosities and a stabilizing agent, in several proportions.

The formulation study was performed making use of the experimental design technique, by varying independent factors (HPMC type, HPMC:CMCNa ratio) and resulting in a number of experimental determinations. The influence of the variables on the properties of the monolithic tablets (fraibility, hardness, metformin and glibenclamide dissolved at different time points) was studied.

The release kinetics of metformin and glibenclamide from the pharmaceutical form was identified by mathematical modelling. The selection criteria from concurent mathematical models was the Akaike index (the lowest value indicated the best model).

When the apparent viscosity was increased, hypromellose produced higher values of tablet hardness, low fraibility and the decrease of the release of active substances (metformin/glibenclamide).

The increase of HPMC:CMCNa ratio manifested into the increase of tablet hardness, the lowering of tablet fraibility and the decrease of the amount of active substances released from the pharmaceutical formulation.

The lowering of the lewel of released metformin/glibenclamide was a consequence of a larger quantity of polymer with high apparent viscosity. This happens as a cause of the prolonged time for the disintaglement of the polymeric chains from the surface of the tablet.

The release mechanism of metformin is based on Fickian diffusion, following the first order kinetics, that characterise highly soluble active substances. The release mechanism for glibenclamide is based on the capacity of diffusion and erosion of the polimer, following zero order kinetics, manifested by low solubility active substances [8, 9].

Regarding metformin release, from the tested types of hypromellose, favorable for the formulation were: Methocel® K4M, Methocel® K15M and Methocel® K100M. Benecel®K200PHCR inhibited the full release of metformin over a period of 12 hours, because of its higher apparent viscosity.

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Establishing the final formulation of monolithic tablets was not possible at this stage of the reasearch, because of the low level of glibenclamide released from the tested formulations. This is explained by the high molecular weight of HPMC matrix formers, that are favorable for metformin dissolution, but inhibit glibenclamide release.

In conclusion, new studies were needed for the increasing the dissolution rate of the low solubility active substance, mantaining at the same time the prolonged release of the highly soluble drug substance from the tablet formulation.

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2.2. STUDY OF THE INFLUENCE OF HYDROPHILLIC POLYMERS ON THE FORMULATION AND ON THE

DISSOLUTION OF METFORMIN HYDROCHLORIDE AND GLIBENCLAMIDE FROM PROLONGED RELEASE

BILAYERED TABLETS

As a result of the research from chapter 2.1, a new method of incorporation of both active substances in the prolonged release tablets was used.

Bilayered tablets can be formulated with specific polymers for each active substance with different solubility, that can exhibit sufficient for the therapeutical effect.

The core-in-cup tablet was preffered to conventional parallel bilayered tablets, because of a greater contact area and adeshion forces between the layers, preventing their detachment. The core-in-cup type of tablet is characterised by partial incorporation of the core into the coating layer, the superior surface of the core being completely exposed to the dissolution media. The preparation implies a double compression process, similar to dry sugar coating compression.

The aim of the study was the identification of the hydrophillic polymer influence on the formulation of prolonged release bilayered tablets with metformin and glibenclamide. The purpose of the research consisted in the determination of the specific polymers for insuring the 12 hours release of the active substances.

The formulation study was performed by using the experimental design technique.

The release kinetics of metformin and glibenclamide from the pharmaceutical form was identified by mathematical modelling. The selection criteria from concurent mathematical models was the Akaike index (the lowest value indicated the best model).

The release rate of glibenclamide and metformin was succesively adjusted by using matrix formers with different apparent viscosities and a stabilizing agent, in several ratios.

The hardness and the fraibility of the tablets reflect a double compression process manifested in the specified limits, with a finished product that meets the requirements.

Metformin release was insured by the formulation of the cup layer with 35% high viscosity hypromellose (100000 cP, Methocel® K100M) and 3.55% sodium carmellose.

The influence on glibenclamide release of two formulation factors was studied: the type and the quantity of hipromellose in the core of the tablet. The factors were varied, generating a significant range of experiments.

The release of glibenclamide from the hydrophillic matrix was stimulated by low viscosity hypromellose (2.4-7 cP) and inhibited by hyprmellose types that have the viscosity in the range of 12-120 cP. The increase of the quantity of HPMC also inhibits the rate of glibenclamide dissolution.

The final formulation of the core contained 65% low viscosity hypromellose (12 – 18 cP) Mantrocel® E15LV, producing a prolonged dissolution profile of glibenclamide over a period of 12h.

In this study, the release kinetics of both active substances from the bilayered tablets was investigated. The release mechanism of metformin is based on Fickian diffusion, following the first order kinetics, that characterise highly soluble active substances. The release mechanism for glibenclamide is based on the diffusion capacity and erosion of the polimer, following zero order kinetics, manifested by low solubility active substances

As a result of this research, core-in-cup bilayered tablets were obtained, in order to insure the formulation of metformin and glibenclamide in separate compartments of the pharmaceutical form (fig. 1). The main advantage of this system consists in the selection of the specific polymer - matrix former for the active substances with different properties.

Figure 1. Core-in-cup bilayered tablet

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3. STABILITY STUDY OF IMMEDIATE AND PROLONGED RELEASE TABLETS WITH METFORMIN

HYDROCHLORIDE AND GLIBENCLAMIDE, OBTAINED BY FLUID BED WET GRANULATION

INTRODUCTION Insuring chemical stability of the active substances in the

pharmaceutical form is one of the main purposes of the formulation process. It reflects the appropriate conservation of the medicine over the whole shelf-life period. The instability of the pharmaceutical form is characterised by the physico-chemical degradation of the active substance and its transformation into potential toxic compounds [10]. The stability studies are very important in the formulation of new medicinal products, because it offers critical information with refference to active substances’ behaviour in certain environemental conditions such as temperature, humidity and light [11]. For oral solid drug products, when the package does not permit the exposure to light, the photostability studies are not necessary.

The stability protocol must be developed with great care in order to become an efficient instrument for the determination of the drug quality. The stability study design factors are: packaging (bulk/individual), type of packaging material, storage conditions, analysis time points and the dose of active substance included in the pharmaceutical form [12].

The purpose of the research consisted in the determination of the influence of the final tablets composition, packaging material and storage conditions on the stability of metformin-glibenclamide immediate and prolonged release tablets.

The study was structured on three sections: normal, intermediary and accelerated storage conditions.

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3.1. STABILITY STUDY OF IMMEDIATE RELEASE TABLETS WITH METFORMIN HYDROCHLORIDE AND

GLIBENCLAMIDE

This chapter illustrates the stability study of immediate release tablets with 500 mg metformin and 2.5 mg glibenclamide.

The aim of the research consisted in the determination of the influence of the final tablet composition, packaging material and storage conditions on the stability of both antidiabetic agents in the conventional release pharmaceutical form.

The results of the 6 month accelerated stability study met the requirements and illustrate the possibility of shelf-life estimation to a period of 2 years in normal conditions.

The description of the tablets was identical over the testing period and met the quality requirements from the specification: round pink, biconvex coated tablets, with uniform and compact structure and intact edges.

Metformin hydrochloride and glibenclamide content met the requirements of the specification: ±5% deviation from the labelled quantity, for the three storage conditions.

The related substances of metformin hydrochloride and glibenclamide complied to the specification and to PhEur 7.0 requirements. The impurities generated in the product by the accelerated stability conditions were higher than than those from intermediary and normal conditions, but still in the specification limits. The dissolution criteria for the tablets was of a minimum of 85% dissolved at 30 minutes, for the whole testing period. The average weight and the uniformity of mass of the tablets met the requirements of the specification.

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3.2. STABILITY STUDY OF PROLONGED RELEASE TABLETS WITH METFORMIN HYDROCHLORIDE AND

GLIBENCLAMIDE

This chapter presents the stability study of prolonged release tablets with 500 mg metformin and 2.5 mg glibenclamide.

The aim of the research consisted in the determination of the influence of the final tablet composition, packaging material and storage conditions on the stability of both antidiabetic agents in the prolonged release tablets.

The results of the 6 month accelerated stability study met the requirements and illustrate the possibility of estimation of the shelf-life to a period of 2 years in normal conditions.

The description of the tablets was identical over the testing period and met the quality requirementss from the specification: white bilayered tablets with compact structure and intact edges.

Metformin hydrochloride and glibenclamide content met the requirements of the specification: ±5% deviation from the labelled quantity, for the three storage conditions.

The related substances of metformin hydrochloride and glibenclamide complied to the specification and to PhEur 7.0 requirements. The impurities generated in the product by the accelerated stability conditions were higher than than those from intermediary and normal conditions, but still in the specification limits.

The dissolution criteria for the tablets met the requirements of the specification, for the whole testing period. The average weight and the uniformity of mass of the tablets met the requirements of the specification.

The stability study illustrated the quality of the medicinal product for the shelf-life and administration period.

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GENERAL CONCLUSIONS

ORIGINAL CONTRIBUTIONS

The studies presented in this thesis conclude with the following original contributions:

• The thesis approached the topic of glycometabolic control in patients with type II diabetes, through the administration of fixed dose combination tablets, with antidiabetic agents that exhibit complementary modes of action. Because of the many cases in which monotherapy presents lack of succes, when compared to insulinotherapy, the study elaborated for this thesis showed a modern approach, focalized on the combined therapy of diabetes. By using the new technologies of processing the active and inactive ingredients in the pharmaceutical industry, immediate and prolonged release combination tablets were obtained.

• The research was conducted in the direction of tablet manufacturing by fluid bed granulation of metformin, in order to improve the rheology and the compressibility properties of the majoritary component of the formulation. The minoritary active ingredient (glibenclamide) was geometrically dispersed in the tablet. The elaboration of the manufacturing method was aimed towards the possibility of applying it at an industrial scale, for the production of important quantities of medicinal products, that can be used in therapy.

• The treatment of type II diabetes implies polimedication, due to its complexity and numerous complications. In the context of increasing the number of units administred to the patient, the reduction of the amount of recommended tablets for one treatment becomes very important for increasing the compliance. Having this actual problem as a starting point, a new prolonged release formulation with metformin and glibenclamide was studied for the release of active substances over a period of 12 hours. The research becomes a part of the world trend of obtaining a hydrophillic matrix

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system that can incorporate both active substances, that exhibit antagonic physico-chemical properties.

• From the first part of the study resulted complying immediate release tablets, and from the second part, monolithic and bilayered matrix tablets. The bicompartimental pharmaceutical form was an inlay core-in-cup tablet, obtained by double compression, similar to dry sugar coating by compression. The active substances were incorporated in separate layeres, due to their different charateristics that need specific hydrophillic matrix formers.

• The tablets were tested for their stability over a period of 6 months of normal, intermediary and accelerated consitions. The results illustrated a shelf-life of minimum 2 years.

PERSPECTIVES OF THE RESEARCH

The thesis openes the following research perspectives: • The diversification of the formulation of medicinal

products intended for the treatment of type II diabetes; • The administration of prolonged release fixed dose

combination forms in polimedicated type II diabetes, increasing patient compliance;

• The incorporation into one pharmaceutical form of two antidiabetic substances with antagonic characteristics (solubility, dose);

• Industrial appliable method of manufacturing that can provide good yield production;

• Continuous interest for the optimization of an oral solid pharmaceutical form with antidiabetic agents that exhibit complementary modes of action in control.

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SELECTED REFERENCES

1. Qiu Y. Developing Solid Oral Dosage Forms Pharmaceutical Theory and Practice. Elsevier Science, 2009.

2. Levin M. Pharmaceutical Process Scale-Up. New York: Marcel Dekker, 2002. 3. Smith WF. Experimental design for formulation. Philadelphia: Society for

Industrial and Applied Mathematics; Alexandria, Va.: American Statistical Association, 2005.

4. *** European Pharmacopoeia 7.0, Strasbourg: Council of Europe: European Directorate for the Quality of Medicines and Healthcare, 2010.

5. ***United States Pharmacopoeia 32 National Formulary 27. Rockville, Md.: United States Pharmacopeial Convention, 2009.

6. Wen H, Park K. Oral Controlled Release Formulation Design and Drug Delivery: Theory to Practice. Hoboken, N.J.: Wiley, 2010.

7. Shargel L. Applied biopharmaceutics & pharmacokinetics. New York: McGraw Hill, 2009.

8. Kadri BJV. Mechanism of drug release from matrix tablets involving moving boundaries. Department of Pharmaceutical Sciences, University of Toronto, 2001.

9. Wen H, Park K. Oral Controlled Release Formulation Design and Drug Delivery: Theory to Practice. Hoboken, N.J.: Wiley, 2010.

10. Huynh-Ba K. Pharmaceutical Stability Testing to Support Global Markets. New York: Springer, 2009.

11. Evens RP. Drug and biological development: from molecule to product and beyond. New York; London: Springer, 2007.

12. Balakrishnan N. Methods and Applications of Statistics in the Life and Health Sciences. Hoboken: John Wiley and Sons, 2009.

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SCIENTIFICAL ACTIVITY ON THE TOPIC OF THE THESIS

PUBLICATION LIST

ISI INDEXED JOURNALS

Optimization by experimental design of an immediate-release tablet comprising metformin and glibenclamide Potur Roxana-Georgiana, Moisuc Lăcrămioara, Boiţă Tudor, Potur Mircea-Dan, Gafiţanu Eliza Farmacia Journal, Soc. Pharmaceutical Sciences Romania, Bucharest, 2011, 59 (5): 690-699.

CNCSIS (B+) INDEXED JOURNALS Formularea prin design experimental a comprimatelor cu cedare imediată care conţin asocierea metformin clorhidrat/glibenclamidă Potur Roxana-Georgiana, Gafiţanu Eliza Medical-Surgical Journal, Soc. Med. Nat. Science, 2010, 114 (4): 1219-1226.

Pharmacokinetic modeling of glimepiride plasma concentration in healthy subjects Ioana-Maria Antonesi, Roxana Potur, D. M. Potur, Cristina Mihaela Ghiciuc, Cătălina Elena LupuşoruMedical-Surgical Journal, Soc. Med. Nat. Science, 2011, 115 (3): 949.

NATIONAL AND INTERNATIONAL CONFERENCE JOURNALS AND BOOKLETS

Formulation of a modified-release dosage form comprising metformin hydrochloride and glibenclamide for the treatment of type 2 diabetes Potur Roxana-Georgiana, Moisuc Lăcrămioara, Antonesi Ioana, Axinte Mihaela, Lionte Mihaela, Gafiţanu Eliza Panhellenic Pharmaceutical Congress, 15th edition, 13-15 May 2011, Athens, Greece. Optimization of the formulation by wet granulation of immediate-release tablets comprising metformin and glibenclamide Potur Roxana-Georgiana, Chiţac Cristina, Boiţă Tudor, Gafiţanu Eliza National Congress of Pharmacy Romania, Fourteenth Edition, 13-16 October 2010, Targu Mures, Romania.

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Robustness testing of a modified-release tablet formulatiom comprising metformin and glibenclamidei used for the treatment of type II diabetes Potur Roxana-Georgiana, Antonesi Ioana, Moisuc Lăcrămioara, Axinte Mihaela, Gafiţanu Eliza The first French-Romanian Colloquium of Medical Chemistry, University Alexandru Ioan Cuza, 7-8 October 2010, Iasi, Romania. Influence of the percent of superdisintegrant on the dissolution profile of tablets with glibenclamide and metformin hydrochloride, for the treatment of type II diabetes Potur Roxana-Georgiana, Băiţan Mariana, Moisuc Lăcrămioara, Chiţac Cristina, Gafiţanu Eliza.

Medical-Surgical Journal Supplement, Iasi. National seminar on drug design to use, 20 - 22 May 2009, University of Medicine and Pharmacy, Iasi, Romania. Formulation of an immediate–release dosage of metformin hydrochloride and glibenclamide used in the treatment of type II diabetes Potur Roxana-Georgiana, Băiţan Mariana, Moisuc Lăcrămioara, Chiţac Cristina, Gafiţanu Eliza Drug Metabolism and Pharmacokinetics Journal Supplement, Panhellenic Pharmaceutical Congress, 14th edition, 9-11 May 2009, Athens, Greece. Pharmacokinetic modeling of an antidiabetic sulfonylurea agent Antonesi Ioana Maria, Potur Roxana–Georgiana, Peşte Gabriela, Cristina Vlase, Ghiciuc Cristina, Lupusoru Catalina Elena Drug Metabolism and Pharmacokinetics Journal Supplement, Panhellenic Pharmaceutical Congress, 14th edition, 9-11 May 2009, Athens, Greece. Estimation of a steady state pharmacokinetic parameters after single dose administration of a generic sulfonylurea product Antonesi Ioana Maria, Potur Roxana–Georgiana, Ghiciuc Cristina, Lupusoru Catalina Elena The first French-Romanian Colloquium of Medical Chemistry, University Alexandru Ioan Cuza, 7-8 October 2010, Iasi, Romania.

Europass Curriculum vitae

Personal information

First name(s) / Surname(s) Potur Roxana-Georgiana

E-mail roxana.potur@yahoo.comroxana.potur@antibiotice.ro

Nationality Romanian

Date of birth 04.08.1983

Work experience

Dates 10.2007 - present

Occupation or position held PhD student in Pharmaceutical Technologye Main activities and responsibilities Researcher in the field of pharmaceutical formulation

Name and address of employer University of Medicine and Pharmacy “Gr. T. Popa”, Str.Universităţii nr.16, 700115 Iasi, Romania

Type of business or sector Scientifical research

Dates 10.2007 - present

Occupation or position held Pharmacist in Pharmaceutical Development Department Antibiotice RO

Main activities and responsibilities Formulation of tablets, capsules, semisolid products

Name and address of employer Antibiotice RO, Str. Valea Lupului nr. 1, Iaşi, Romania

Type of business or sector Pharmaceutical research

Personal skills and competences

Mother tongue(s) Romanian

Other language(s) English

Certificare Cambridge Advanced English

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Social skills and competences Work experience in the research and development of medicinal products Inovative Teamwork

Organisational skills and competences

Experience in the management of research projects

Technical skills and competences Scientifical research for the formulation, manufacturing, scale-up and registration of medicinal products

Computer skills and competences Microsoft Office, Statistical programming

Driving licence B category