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d)     Erosion controlled release systems:
In erosion controlled extended release systems that rate of drug release is controlled by the erosion of a matrix in which the drug release is controlled by the erosion of a matrix in which the drug is dispersed. The matrix is normally a tablet, i.e. the matrix is formed by a tab letting operation, and the system can thus be described as a single unit system.

The erosion in its simplest form can be described as a continuous liberation of matrix material (both drug and excipients) from the surface of the tablet, i.e. surface erosion. The consequence will be a continuous reduction in tablet weight during the course of the release process.

Mechanism of drug release from a erosion based matrix tablet:
Drug release from an erosion system can thus be described in two steps.
1.      Matrix material, in which the drug is dissolved or dispersed, is liberated from the surface of the tablet.
2.      The drug is subsequently exposed to the gastrointestinal fluids and mixed with (if the drug is dissolved in the matrix) or dissolved in (if the drug is suspended in the matrix) the fluid.

The eroding matrix can be formed from different substances. One example is lipids or waxes, in which the drug is dispersed. Another example is polymers that gel in contact with water (Hydroxy ethyl cellulose). The gel will subsequently erode and release the drug dissolved or dispersed in the gel. Diffusion of the drug in the gel may occur in parallel.

e)      Release is controlled by ion exchange:
Ion exchangers are water insoluble resinous materials containing salt forming anionic or cationic groups. While manufacturing, the drug solution is mixed with resin and dried to form beads which are tableted. The drug release depends upon high concentration of charged ions in gastro intestinal tract where, the drug molecules are exchanged and diffused out of the resin into the surrounding fluid. This mechanism relies upon the ionic environment of resin and not pH or enzyme on absorption site.

Extended release (ER) dosage form is one of the drug products categorized under the term modified release dosage forms (FDA, 1997). It refers to products, which are formulated to make the drug available over an extended period after ingestion; thus, it allows a reduction in dosing frequency compared to a conventional type i.e. immediate release (IR) dosage form. Several advantages of ER products over IR ones have long been recognized. ER solid oral dosage forms can be classified into two broad groups:
(i)                 Single unit dosage forms (e.g. tablets) and
(ii)               Multiple unit dosage forms or multiparticulate pellet systems.

The systems can be further subdivided into two concepts regarding to the design of dosage forms:
(i)                 Matrix systems and
(ii)               Reservoir systems.


Matrix systems
Matrix or monolithic devices consist of drug dispersed homogenously throughout a continuous phase of polymer or lipid. The devices can be prepared either by the compression of a polymer/drug mixture or by the dissolution or melting, resulted in the molecularly dispersed drug. The drug transport often results from a combination of several mechanisms included dissolution, diffusion, swelling and erosion.

a. Water-soluble matrix formers
Water-soluble or hydrophilic matrices are a well known type of ER oral dosage forms. While hydroxypropyl methylcellulose (HPMC) is the most important hydrophilic carrier material, several others are also available; including
(i)                 Cellulose derivatives: hydroxypropyl cellulose (HPC), carboxymethylcellulose sodium (NaCMC),
(ii)               Natural polymers: sodium alginate, carrageenan, chitosan
(iii)             Synthetic polymers: polymerized acrylic acid (Carbopol), polyvinyl alcohol (PVA), polyethylene oxide (PEO). It has been suggested, however, that the term ‘swellable matrices’ is more appropriate as it better explains the characteristic of the systems.

b. Water-insoluble matrix formers
Water-insoluble carrier materials include
(i)                 Lipid-base excipients: white wax, carnauba wax, glycerylmonostearate, hydrogenated vegetable oil, paraffin and
(ii)               Polymer-based excipients: ethylcellulose (EC), cellulose acetate. In comparison to the hydrophilic matrices, the system has a greater physical stability, resulting in the less variable drug release and the lower incidence of ‘dose dumping’ in presence of food.

Reservoir systems
Reservoir systems are characterized by a drug-containing core surrounded by release-rate controlling polymer(s). The mechanism of the drug transport across the polymeric membrane has been extensively described by Lecomte (2004).

a. Coated tablets
An example of technology for ER coated tablet is MODAS (Multiporous Oral Drug Absorption System; Elan Corporation, Ireland). The tablet core consists of the mixture of active drug and other excipients, subsequently coated with a solution of water-insoluble polymers and water-soluble excipients. Upon exposure to aqueous media, the surrounded coating is transformed into a semi-permeable membrane through which the drug diffuses in a rate-limiting manner.

b. Osmotic pump systems
Osmotic device is a special type of the reservoir systems, where the release rate of the drug is controlled dynamically by an incorporated osmotic agent in the active drug core. The rigid surrounding semi-permeable membrane consists for example of cellulose acetate. The drug is released through a defined, laser drilled delivery orifice in the membrane.

Several advantages of multiparticulate systems over the single unit ones have been well documented. Following a proper preparation method, the ER pellets are either filled into a capsule or are compressed into a tablet.

Matrix systems
The matrix type of multiparticulate systems can be prepared by several techniques such as extrusion/spheronisation, spherical crystal agglomeration and melt-solidification. Although, the production of multiparticulate matrix systems is considered to be easier than that of the reservoir systems, their extent of retardation is limited because of pellet geometry.

Reservoir systems
Coated pellets as a mean to control drug delivery are widely used in the pharmaceutical industry, although the development and optimisation of the systems are rather complex. Numerous aspects of the system performance have been investigated, for instance, the influence of formulation and coating technique, the effect of drug solubility and core material, the use of polymer blends, in vitro/in vivo evaluation and the influence of release medium.

1.3 TABLET8,9
Tablets are solid dosage form containing ingredients with or without filler material. Tablets are oral solid dosage form of medicaments with or without suitable diluents and prepared either by molding or compression. They are solid, flat or biconvex disc in shape. They vary greatly in shape, size and weight which depend upon amount of medicament used and mode of administration. They also vary in hardness, thickness, disintegration and dissolution characteristics and in other aspects depending upon their intended use and method of manufacture. Tablets are the most widely used solid dosage form of medicament. Because of their advantages their popularity is continuously day by day.

Advantages of tablet dosage form:
*    Tablet is intact dosage form and offers the best capabilities of all oral dosage forms for accuracy in size and content of the lowest variability.
*    Tablet dosage form which is the lowest cost of manufacture (if it is calculated per dose).
*    Tablets is an oral dosage form of the lightest, most compact, easiest and most inexpensive way to packed and shipped.
*    The product identification on the tablets the easiest and inexpensive, requiring no additional work steps when using the printer surface that monogram or arising accessories.
*    Tablet can be used as a product of specific release profiles, such as the release in the intestine or slow release products.
*    A tablet is an oral dosage form of the most easy to be produced in bulk (large scale).
*    Tablets are easy to use, handle and carry by the patient.
*    Tablets provide prolonged stability to medicament.
*    Tablets are provides a sealed covering which protects the tablets from atmospheric conditions like air, moisture and light etc.
*    The unpleasant taste and odour of medicament can be easily masked by sugar coating.
*    Whenever a fractional dose is required, tablets are divided into halves and quarters by drawing lines of tablet.
*    Tablets provide administration of even minute dose of drug in an accurate amount.
*    Tablets are formulated as a special release of products such as enteric or delayed release products.

Disadvantages of Tablet Dosage Form:
*    Some drugs cannot be compressed into solid and compact, depending on its amorphous state, flocculation, or low density.
*    Drugs moistened difficult, slow dissolves, moderate or high dose, high optimum absorption via the gastrointestinal tract or any combination of the properties above, it would be difficult or impossible to be formulated and fabricated in the form of tablets that produce sufficient drug bioavaibility.
*    Medicine that tastes bitter, a drug with the smell was terrible and cannot be eliminated, or drugs that are sensitive to oxygen or air humidity needs to encapsulation or compression cloaking before (if possible) or require coating first. In this case, the capsule is a cheaper way out.

Types and classes of tablets:
a)    Oral tablet for ingestion
*    Compressed tablet
*    Multiple compressed tablets
*    Delayed action tablet
*    Modified release tablet
*    Sugar coated tablets

b)    Tablet used in oral cavity
*    Buccal tablets
*    Sublingual tablets
*    Troches and lozenges
*    Dental cones
*    Film coated tablets
*    Chewable tablets
*    Targeted tablet

c)    Tablet administered by other routes
*    Implantation tablets
*    Vaginal tablets

d)    Tablets used to prepare solution
*    Effervescent tablets
*    Dispensing tablets
*    Hypodermic tablets
*    Tablet triturates

Modified release tablet:
The main aim behind formulation of this dosage form is to release the medicament slowly for long time duration after administration of a single tablet. More over, these type of formulations are generally used to target the site specific releases.

Figure 1.4: Graphical comparison of blood concentration v/s time

A widespread use of this type of tablet is seen in present scenario, as well as many researchers have concentrated their attention in this direction. This is mainly because of improvement in patient’s compliance as the dosage frequency is reduced, patient can take an undisturbed sleep at night, it’s also beneficial for psychiatric patients who forget to take their tablets regularly and the dose related side effects and toxicities are reduced. Any adjuvant that can alter water uptake rate, swelling, and gelling characteristics of matrixing agents can alter the release rate of API example like electrolytes in HPMC matrix tablet.

It’s also possible to achieve pulsed drug release. Weakly basic drugs exhibit good solubility at low pH while less soluble at high pH conditions, which can result in incomplete drug release for sustained release formulations. The drug release can be modified by providing suitable micro environmental pH in the tablet e.g., acidic polymer, succinic acid, etc. Similarly, inclusion of alkaline polymers results in desirable drug release of acidic drugs. On the other hand, formulation of this type of dosage form presents challenge for the formulator: increases the cost of manufacturing, chances of burst drug release and drop in drug release rate in terminal phase and thus incomplete release on API. In case of accidental poisoning, the doctor has to deal with special treatment problems. Due to large size, patient may feel difficulties in swallowing as the matrixing agent to drug ratio is high. Classic approaches are usually based on adaptation of either film coated or multiparticulate technologies or those involving slow release matrices.

1.4 CAPSULE10,11
The word ‘capsule’ in the English language is derived from the Latin word ‘capsula’, which means a small box or container. In more recent times, capsule has been used primarily to describe a solid oral dosage form, which consists of a container, usually made of gelatin, filled with a medicinal substance. There are many forms of capsules and they can be divided into two main categories, which in current English usage are described by the adjectives ‘hard’ and ‘soft’. The ‘hard capsule’ consists of two separate parts, each a semi-closed cylinder in shape. One part, the ‘cap’, has a slightly larger diameter than the other, which is called the ‘body’ and is longer. The cap fits closely over the body to form a sealed unit.

Figure 1.5: Self-lock capsule

Capsule is a solid particle which has a size of 0.1 to 10,000 μ. According to the pharmacopoeia of Indonesia, the capsule is a solid dosage of the drug in hard or soft shell that can be dissolved. Shells are generally made of gelatin, can also be made from starch or other suitable material.

Gelatin is the commercial protein derived from the native protein collagen, which is present in animal skin and bone, and the term ‘gelatin’ originates from the Latin ‘gelatus’, meaning stiff or frozen. Gelatin has all the properties required to meet the technical needs of the pharmaceutical capsule industry. These include solubility, solution viscosity and thermally reversible gelation properties in aqueous solution. It produces strong, clear, flexible, high-gloss films, which dissolve readily under the conditions existing in the stomach. Furthermore, current scientific evidence indicates that gelatin is a safe raw material.

Advantages of Capsule dosage form:
*    Hard-gelatin capsules suitable for extemporaneous compounding so that the dose and combination of ingredients may vary depending on the patient's needs
*    Stable than liquid dosage forms
*    Can cover up the taste and smell unpleasant medicine
*    Liquid preparations can be made with a certain concentration
*    Used for depot capsules and enteric coated capsule
*    Capsules, because of their elongated shape, are easy to swallow, which is one reason for the number of capsule-shaped tablets manufactured today.
*    Biggest formulation advantage of capsules is that there is less need for additional excipients.
*    Since capsules are tasteless, they effectively mask any unpleasant taste or odor of their contents.
*    They offer rapid release characteristics, due to the rapid dissolution rate of the capsules.
*    The use of hard capsules is also a common feature in clinical trials, as the filling of tablets or even capsules themselves will blind the dosage forms studied.
*    Controlled release can be achieved using capsules. Dry powder mixtures, granules, pellets and tablets can be filled into hard capsules. Moreover combination of two or three types (i.e. dry powder mixtures, tablets or pellets) also can be put into capsules.

Disadvantages of Capsule:
*    Not suitable for very soluble ingredients such as KCl, CaCl2, KBR, NH4Br. When the capsule is broken contact with the wall of the stomach, then the solution will be concentrated so that irritate the stomach and the stomach becomes tense.
*    Can not be used for materials that are very efflorescent or deliquescent. Efflorescent material make capsule become soft while deliquescent material causing the capsule to become brittle and easily broken.
*    The bitter-medicine will cause vomiting and corrosive which are difficult to overcome
*    It took a relatively long compounding

Type of Capsules
There are various forms of capsule, including:
1. Based on consistency:
*  Hard-capsule
*  Soft-capsule

2. Based on how to use:
*  Per Oral
*  Per-rectal
*  Per vaginal
*  Topical

3. Based on purpose of use:
*  For animals
*  For human

Hard Gelatin Capsule
Hard gelatine capsules can be filled with a large variety of materials of different physicochemical properties (i.e. dry solids, semisolids, non-aqueous liquids, etc), while soft gelatin capsule are generally used to contain liquid and semisolid materials.

Specialist capsules have been made to meet the demands of certain applications, e.g. gastro-resistant capsules, modified-release capsules, self-locking capsules, capsules for liquid filling, capsules for administration to animals and capsules used for certain clinical trials. For current applications there are certain design features that all hard capsules must possess, viz. a feature to hold the empty capsule shells together, a self-locking feature, an air venting system and a feature to allow accurate rejoining after filling.

Hard gelatin capsule shell consisting of: 
1. Basic ingredients: Gelatin, Sugar, Water 
2. Other ingredients: Dyes, preservatives (eg SO2), Blur agent (eg TiO2), flavoring agent

The size and capacity of hard gelatin capsule shell : 
1. For human: 000, 00, 0, 1, 2, 3, 4, 5 
2. For animals: 10, 11, 12



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