INTRODUCTION - FORMULATION AND EVALUATION OF SUSTAINED RELEASE MATRIX TABLETS OF STAVUDINE

 

CHAPTER-1

INTRODUCTION

          The oral route of drug administration is the most important method of administering drugs for systemic effects. The parenteral route is not routinely used for self administration of medication. The topical route of administration has been newly employed to deliver drugs to the body for systemic effects. It is probable that at least 90% of all drugs used to produce systemic effects are administered by the oral route. When a new drug is discovered, one of the questions is the pharmaceutical company asks is whether or not the drug can be effectively administered for its intended effect by the oral route. If it cannot, the drug is primarily relegated to administration in a hospital setting or physician’s office. Solid oral dosage forms represent that the preferred class of product. The reasons for this preference are well known.

 

         There are numbers of potential limitations associated with conventional per-oral dosage forms². They are as follows:

 

i.       The concentration of drug in plasma and hence at the site of action, fluctuates over successive dosing intervals even at the steady state condition. Therefore it is not possible to maintain constant therapeutic concentration of drug at the site of action.

ii.      The fluctuations of steady state concentration of drug in plasma can subject the patient either to under medication or over medication.

iii.  For drugs with short biological half-lives (˂ 2 hrs), frequent doses would be required to maintain in steady state plasma concentration.

 

1.1 Rationale of controlled drug delivery system

          The basic rational for sustained/ controlled drug delivery systems is to alter the pharmacokinetics and pharmacodynamics of pharmacologically active moieties by using novel drug delivery systems or by modifying the molecular structure and or physiological parameter inherent in a selected route of administration.

 

i.       Reduction in fluctuation of drug blood levels about the mean.

ii.     Reduce the dosage frequency.

iii.  To improve patients compliance.

iv.   To insure safety and improve efficacy of drugs.

v.      More consistent and prolonged therapeutic effect.

vi.   Decreased incidence and intensity of adverse effects and toxicity.

vii. Better drug utilization.

 

1.2 Anatomy of stomach

          To comprehend the consideration taken in the design of the gas powered system and to evaluate their performance, the relevant anatomy as shown in above diagram and physiology of the GI tract must be fully understood. The GI tract is essentially a tube about 9 m long that run from mouth to the anus and includes throat (pharynx), oesophagus, stomach, small intestine, and larg intestine. The wall of GI tract has the same general structure through most of its length from the oesophagus to the anus, with some local variation for each region.

 

          The stomach is a j- shaped dilated portion of the alimentary tract situated in the epigastric, umbilical and left hypochondriac region of the abdominal cavity. Its size varies accourding to the amount distention: up to 1500 ml following a meal, after food has emptied, a ‘collapsed state is obtained with a resting volume of only 25-50 ml. The stomach is composed of the following parts: fundus, above the opening of the oesophagus into the stomach; body, the central part, and antrum. The pylorus is an anatomical sphincter situated between the most terminal antrum and the duodenum.

 

          The fundus and body store food temporarily, secrete digestive juice and propels chime, a milky mixture of food with gastric juice to the antrum. The antrum grinds and triturates food particles and regulates the secretion of hydrochloric acid as well as emptying of food.

 

          Fasting gastric PH is specially steady and approximate 2, but there are short periods of 7 ± 6 min characterized by higher values. Food buffers and neutralizes gastric acid, thus increasing the PH up to 6.5. After meal ingestions completed, the PH rapidly falls back below 5 and then gradually decline to fasting state values over a period of few hrs.

The pyloric sphincter has a diameter of 12.8 ± 7 mm in humans. The duodenal PH is 6.1; and its transit time is relatively short, less than 1 min. The small intestine has a large surface area, which is comparable to the area of basketball, 463 m². The PH of the small intestine is 6-7 and its transit time is 3 ± 1 hrs, is relatively constant and is unaffected by food. The colon has some absorption properties of water and ions, certain drug and especially peptide molecule are also absorbed.

 

1.3 Gastric emptying :

          The process of gastric emptying occurs during both fasted state and fed state however, the pattern of motility differs markedly in these two states. In the fasted state, it is characterized by an interdigestive series of electrical events, which propagate both through stomach as well as small intestine every 2-3 hrs. This activity is called as interdigestive myoelectric complex (MMC), and is often divided into four consecutive phases.

 

Phase I: It is a quiescent period lasting from 40-60 min. with rare constractions.

 

Phase II: It is a period of similar duration consisting of intermittent action potentials gradually increases an intensity and frequency as phase progresses.

 

Phase III: It is short period of intense, large regular contractions lasting from 4-6 min. as it serves to sweep undigested materials out of stomach and down in small intestine, it is termed as ‘housekeeper waves’. As the phase III of one cycle reaches the distal part of small intestine, the phase III of next cycle begins inn duodenum.

 

1.4 Factors affecting gastric emptying time

i.       Volume: The resting volume of stomach is about 25-52 ml. This volume is important for dissolution of dosage forms. As the volume is large, emptying is faster. Gastric emptying of small volumes like 100 ml or less is governed by migrating myoelectric complex (MMC) cycle whereas large volumes of liquids like 200 ml or more are emptied out immediately after administration . Fluids at body tempreture leave the stomach more rapidly than either warmer or colder fluids.

ii.     Hormonal effects: Stress conditions increases gastric emptying rate whereas depression slows down gastric emptying time. Generally females have slower gastric emptying rate than males. Age and obesity also affect gastric emptying.

iii.  Presence of food: Gastric emptying time differs in fasted state and in fed state. The calorific value of food affects the gastric emptying time.

iv.   Gastric secretions: Acids, pepsin, gastrin, mucus and other enzymes are the secretions of stomach. Normal adults produce a basal secretion up to  60 ml with approximately 4 mm mole of hydrogen ions every hrs.

Different types of Sustained release systems:

          There are several types of sustained release systems that are designed and catagorised accourding to their mechanisms they employ. These include diffusion controlled, dissolution controlled, erosion controlled, ion exchange controlled and transport control also known as Osmotic pump system.

Matrix systems

          Diffusion controlled systems also known as matrix systems are very popular for sustained  release formulations (Colombo et al. 2000). The can be divided up into different types of mechanisms by which they prolong drug release, these includes reservoir matrix systems, monolithic matrix systems and osmotic pump systems.

Reservoir matrix systems

          This system involves a membrane which controls the release of drugs from the matrix system. The drug will eventually diffuse through the membrane and its release is kept constant by the diffusion distance that the drug particles have to cover.

          Osmotic pump system contains osmotic  pressure. They containes a core tablet that is surrounded by semipermeable membrane coating which has an orifice. The core tablet has two layer to it, one containing the active ingredients/ drug known as active layer and the second containing osmotic agent which is also known as push layer. Water enters into the tablet through semipermeable membrane causing the drug to dissolve and suspend. The increase in the osmotic pressure causes the dissolve/ suspend the drug to be pumped out of delivery orifice. The rate of drug delivery can be changed by altering the size of delivery orifice and the thickness of the semipermeable membrane.

Monolithic matrix systems

These system involve the drugs to be encapsulated or dispersed in a matrix. These system can be employed by forming hydrophobic matrices and hydrophilic matrices to allow for control or prediction of drug release. They can be divided into soluble/ hydrophilic matrix systems which swell on hydration and dissolve to release the drugs and insoluble/ hydrophobic matrix system which release the drugs after being dissolved into the solvents.  

1.5 Drug release studies

          Drug release studies are performed using dissolution apparatus. Samples are withdrawn periodically from the dissolution medium with replacement, and then analyzed for their drug content after an appropriate dilution. Various modifications of the standard USP dissolution apparatus I and II have also been employed. In case of floating GRDDS, by attaching a small, loose piece of non-reacting material such as not more than a few turns of wire helix around the dosage form has also been tried. However, this can inhibit the three-dimensional swelling process of the dosage form and consequently affect the drug release from the formulation [45].

         

          An alternative method involves fully submerging the dosage form under a ring or mesh assembly. However, in case of swellable systems drug release is highly dependent on the full surface exposure, unhindered swelling and the drug solubility in water. Using the apparatus I, highly swellable tablets were found to be fully constricted by the basket within 5-7h. This prevented further independent movement and unimpeded swelling with a departure from linear release. Therefore, USP dissolution apparatus II, in many cases, was found to be satisfactory [46].

 

Factor affecting drug release

          It has been observed that the release rate of the drug from the matrix system depends on the type of matrix, characteristics of the polymer and the incorporated drug substance, matrix additives and other technological variables. Some of the factors are:-

 

Polymer characteristics

          Polymer is the fundamental component of hydrophilic matrix system, which controls the rate of drug release by formation, through hydration, of diffusion and erosion resistant gel layers.Various properties of polymer that affects the release rate are:

(i)                 Polymer viscosity: Polymers with different molecular weights and degrees of reticulation, exhibiting a range of viscous efficiencies, which affect the drug release, are available. It is well established that as the molecular weight or viscosity of the polymer increases, release rate of the drug from the formulation decreases. Further, it has been observed that there exists of a limiting viscosity i.e. the drug release rate no longer decrease when the viscosity grade increases above that. For HPMC, limiting viscosity is 15,000 cps.[47]

 

(ii)              Ratio of polymer drug in dosage forms: The proportion of polymer is usually employed as control variable of drug release rate .An inverse relationship was reported between polymer to drug ratio and release rate of drug.

 

(iii)              Polymer hydration: It is important to study the hydration/swelling process for polymers and polymeric combinations used because swelling of polymermight influence and control the drug release. An inverse relationship is reported between polymers “constant rate swelling” and “constant rate dissolution”.[48]

1.5 Introduction to infection and disease

          Disease and death have always attracted the attention of the human mind 1. Varo and Columella in the first century BC postulated that diseases were caused by invisible beings, inhaled or ingested. As microbes are invisible to the unaided eye, definitive knowledge about them had awaited the development of microscope. The credit for having first observed and described bacteria goes to Anton van Leeuwenhoek. Infectious diseases can be caused by bacteria, viruses, fungi, protozoa or parasitic worms.

          There are large numbers of anti infective drugs that are currently available in the market those are against 2

1. Viral infectious diseases- AIDS, Chickenpox, common cold etc.
2. Bacterial  infectious  diseases-  Tuberculosis,  Anthrax,  Cholera,
3. Parasitic infectious diseases- Amoebiasis, Trypansomiasis etc.
4. Fungal infectious diseases – Blastomycosis, Candidiasis etc.
5. Prior infectious diseases - Transmissible spongioform encephalopathy, Bovine spongioform encephalopathy.

 

          Bacterial  infections  are  treated  with  antibiotics  3.  There  are many antibiotics available, but they fall into three major groups based on their mode of action: inhibitors of bacterial nucleic acid synthesis; inhibitors of cell wall synthesis; and inhibitors of bacterial protein synthesis.

          Viral  infections are normally overcome by the patient’s immune system. However, the advent of HIV infections and AIDS has led to the development of several new antiviral drugs.

          In case of chronic infections long term drug therapy is required. In drugs having the shorter biological half life, it is required to take the drug more number of times per day. Long term exposure of anti infective drugs to the micro organisms and to the body tissue leads to the development of drug resistance, toxicity and some other adverse reactions.

          Controlled release of the anti infective drug will reduce the exposure of higher concentrations of the drug to the microorganisms. This will reduce the bacterial resistance, tissue toxicity and other adverse reactions.

1.6 Introduction to controlled drug delivery systems ⁴

          Ideally, a drug should arrive rapidly at the site of action (receptor) in the optimum concentration, remain for the desired time, be excluded from other sites, and be rapidly removed from the site when indicated. Generally, the time course of a dosage form (Pharmacokinetic) in man considered to be controlled by the chemical structure of the drug. Decreasing the rate of absorption and/or changing the dosage form provide a useful adjunct. When it is not feasible or desirable to modify the drug compound at molecular level, often sought is a product that will require less frequent administration to obtain the required biologic activity time profile; for example, a tablet that has the same clinical effect when administered every twelve hours. In another instance it may be desirable to decrease the absorption rate in order to obtain a more acceptable clinical response. The goal in designing sustained or controlled delivery systems is to reduce the frequency of dosing or to increase the effectiveness of the drug by localization at the site of action, reducing the dose required, or providing uniform drug delivery.

          Oral route is the most popular route of drug administration and is universally acceptable route. Indeed, for sustained release systems, oral route of administration has received most of the attention with respect to research, physiological and drug constraints as well as to design and testing products. This is because of the fact that there is more feasibility in dosage form design for oral route than for parentral or any other route.

          New drug entities have increased with concomitant recognition of the therapeutic advantages of sustained release drug delivery. Greater attention has been focused on development of sustained  released  drug  delivery  systems.  Sustained  released  constitutes  any dosage form that provides medication over an extended period of time. Sustained release drug products are designed for different routes of administration based on physicochemical, pharmacological and pharmacokinetic properties of the drug and upon the properties of the materials used in the dosage form 5.

1.6.1 Classification of  oral sustained release drug delivery systems: Based on techniques used in formulation⁶

          Matrix tablets, Microencapsulation, Enteric coated beads or spheres in capsules, Ion exchange resin preparations and Osmotic pumps.

Based on release mechanism⁷

          Dissolution controlled release systems, Diffusion controlled release systems, Diffusion and dissolution controlled release systems, Ion exchange resins, pH - independent formulations and Osmotically controlled release systems.

1.7 Human immunodeficiency virus (HIV) and Acquired  Immunodeficiency syndrome (AIDS)

          HIV defined as the human immunodeficiency virus type 1 (HIV-1), the well known human pathogen and the main causative agent of AIDS infecting more than 40 million people⁸. Till today there is no vaccine or permanent cure for HIV and AIDS. Anti retroviral drugs show effective treatment for the disease. The drug resistance strains of virus show greater impact and more treatment options. This further showed more impact on the identification and development of new drugs with improved safety and efficacy. The basic biological property of HIV-1 is rapid evolvement and greater genetic diversity⁹. There are two factors that are responsible for HIV-1 to generate this genetic variability. (1) The error-prone nature of the HIV-1 polymerase and the rapid replication of HIV-1⁹. The HIV recombination also increases the drug resistance strains during reverse transcription^10,11. The quasi-species in viral population have more number of drug resistant strains12. Suboptimal concentration of the antiretroviral drugs leads to the drug resistant strains. In vitro study of the suboptimal drug concentrations tool to study the drug resistance strains and this data is useful to study the strains developed in in-vivo^13,14.

          The most effective treatment for the HIV is highly active antiretroviral therapy (HAART) in which three or four drugs were combined and administered to the HIV patient¹³, 14. In HAART, combination of reverse transcriptase and protease inhibitors were used for the effective HIV therapy and it takes years long for the suppression of viral load 15, 16. This can lead to the development of the resistant viral strains. The basic idea of the drug resistance strains is useful for the development of new drugs and new formulations.

          The steps involved in the replication of HIV -1 virus is (1) Entry (2) Integration (3) Mutation. These three steps are the main focus for the scientists for the development of the new drugs. The knowledge on the development of the HIV cycle is valuable in conforming the drugs safety, efficacy, identifying the new drug targets and predicting the resistance in the patients¹⁷. Figure 1.1 shows the HIV life cycle in the cell. The following table shows the list of different antiretroviral drugs that are currently used in the treatment of HIV infection.

Table 1.1 List of antiretroviral drugs currently in the market

 

Name of the drug	Classsification	Elimination Half life (Hrs)
Zidovudine	NRTI	1.1
Lamivudine	NRTI	3–6
Didanosine	NRTI	1.3–1.6
Zalcitabine	NRTI	1–3
Stavudine	NRTI	1–1.6
Emtricitabin	NRTI	10
Tenofovir	NtRTI	17
Nevirapine	NNRTI	25–30
Efavirenz	NNRTI	40–50
Delavirdine	NNRTI	5.8
Etravirine	NNRTI	30-40
Amprenavir	PI	7-10
Indinivir	PI	1.2-2
Saquinavir	PI	1.5-2
Nelfinavir	PI	3.5-5
Ritonavir	PI	3-5
Atazanavir	PI	7
Darunavir	PI	15
Enfuvirtide	FI	3.8
Maraviroc	FI	14-18
Raltegravir	II	9

 

NRTI, Nucleoside reverse transcriptase inhibitors

NtRTI, Nucleotide reverse transcriptase inhibitors

NNRTI, Non-nucleoside reverse transcriptase inhibitors

PI, Proteaseinhibitors

FI, Fusion inhibitors

          II, Integrase inhibitors

 

1.7.1 Drawbacks of conventional antiretroviral drugs

          At present there are so many antiretroviral drugs that are commercially available in the market as solid oral dosage forms such as tablets and capsules, liquid oral dosage forms such as solutions and suspensions. The oral dosage forms have several advantages like convenience, oral delivery of drugs have some disadvantages also such as first pass effect, absorption variation and enzymatic degradation of the drug in the GI tract. For example, the first antiretroviral drug approved for HIV treatment such as zidovudine shows rapid elimination half life of 1 hour and hepatic first pass metabolism and looses 40 % of the administered drug.

          In the conventional dosage forms the duration of the drug‟s pharmacological action is very short and limited because the Mean residence time of the drug depends on the elimination half life and there by the absorption of the drug 18. And also, many of the antiretroviral drugs show poor or low bioavailability due to various physicochemical factors such as dissolution, solubility and permeability (didanosine).

          The drug‟s performance in in-vivo manly depends on its physicochemical property such as drug stability and solubility. Research scientists today face so many formulation problems because of drug stability and GI tract liability. This can lead to the poor bioavailability and absorption. This can be overcome by the various studies on the drug physicochemical properties during preformulation study. For example, the bioavailability is rate limiting in Non NRTI due to their low water solubility. Thus the variation in oral bioavailability of many antiretroviral drugs may be a significant factor for failure of some drug regimens. Even though the drug is absorbed from the GI tract and enter in to the blood circulation, metabolism, elimination and transport of the drug will affect the drug to reach the target tissue/site. In order to make the successive therapy in AIDS, it is required to maintain the drug at constant and optimum concentration in the blood and also to the target tissue through out the treatment.

          Most of the antiretroviral drugs have shorter biological half life. However, because of their short biological half life these drugs needed to administer frequently. Hence with do not maintain the drug concentrations constantly for longer period of time.19. Due to the HIV‟s virustatic nature these drugs should be administered for the life of the patient. All most all antiretroviral drugs exhibit toxic effects such as hyperglycaemia, hepatotoxicity, hyperlipidemia, lactic acidosis, lipodystropy, osteonecrosis, osteoporosis, osteopenia, skin rashes, due to higher blood concentration of the drugs. In such conditions dose reduction and some times cessation of treatment because lactic acidosis may even be sometimes fatal. So the benefit and risk from the treatment is same with the use of these antiretroviral drugs but the treatment should be continued to increase the survival rate of the HIV infected person. And also with the continuation of the therapy resulted in frequent administration and there by increased the Pill burden. These problems can be overcome by design of novel drug delivery systems²⁰.

1.7.2 Need for novel and controlled drug delivery of anti  retrovirals

          To succeed in the HIV therapy for long term treatment with the anti HIV drugs, where the patients suffer from the problems associated with the plasma fluctuations, dose frequency; it is required to have an effective dosage form in the form of sustained and controlled release formulations to improve the therapeutic benefit and ideal therapy. With the help of the controlled and sustained drug delivery, effective plasma concentration was achieved without any fluctuations. It is also possible to avoid toxic plasma concentrations where it is a problem with conventional formulations and also possible to achieve effective therapy with low dosage of the drug, and to avoid the frequency of the dose administration.

          Percutaneous delivery of most antiretroviral drugs has been studied. The study indicates a challenging future of this route for antiretroviral drugs21-24. Novel delivery systems such like liposomes, microparticles and encapsulated erythrocytes are also under investigation. Liposomal drug delivery is one of the best deliveries to achieve the target and site specific drug delivery of various molecules. Scientists focused on the liposomal drug delivery, and they studied various drugs via liposomal drug delivery, studies show that the liposomal drug delivery systems are showing less toxic effects than the conventional formulations of the same drugs. For example liposomes of doxorubicin and amphotericin B were less toxic when compared with free drug. Haematopoietic toxicity study was conducted on the zidovudine loaded liposomes on mice. The study showed that the drug loaded liposomes are more active than the convention zidovudine formulations. Thus the zidovudine liposome showed significant reduction in toxicity, and also increased the antiviral activity and enhanced drug localization in the liver and spleen.

          Further, it was clearly observed that liposomes of dideoxycytidine-5‟-triphosphate (ddCTP) exhibited better chemical stability of the drug molecule. The results of the encapsulated liposomes with dideoxycytidine-5‟-triphosphate in murine AIDS model indicate that ddCTP encapsulated- liposomes reduced proviral DNA in cells of the mononuclear phagocyte system (MPS) in both bone marrow and spleen. And also the liposome drug delivery increases the efficacy of the drugs, reduces the adverse and toxic effects and also increases the drug‟s elimination half life^25-27.