fast dissolving drug delivery system

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GELATIN AND MATERIALS OTHER THEN GELATIN USED FOR CAPSULES FORMULATION

GELATIN AND MATERIALS OTHER THEN GELATIN USED FOR CAPSULES FORMULATION

Gelatin is a substantially pure protein food ingredient, obtained by the thermal denaturation of collagen, which is the structural mainstay and most common protein in the animal kingdom. Gelatin is a water soluble protein aqueous substance prepared by processes, which involve the destruction of the tertiary, secondary and to some extent the primary structure of native collagens specifically by the partial hydrolysis of collagen derived from the skin, white connective tissue and bones of animals. Gelatin is a high molecular weight polypeptide and an important hydrocolloid, which has proved popular with the general public and finds its uses in a wide range of food products largely because of its gelling and thickening properties. Cattle bones, hides, pig skins, fish and recently insects are the main commercial sources of gelatine. Many foods use gelatine as source for texture and binding agent, gelatine from insect can be used to produce ice cream by using 0.5% insect’s gelatine and compared with that made using 0.5% commercial gelatine as stabilizing agent.

1.      Reasons for choosing gelatin

·         It is non toxic widely used in foodstuff and acceptable for use worldwide.

·         It is readily soluble in biological fluid at body temp.

·         It has a good film forming properties with flexibility.

2.      Extraction of gelatin

Gelatin is a heterogeneous derived from hydrolytic extraction of animals collagen obtained from animals bones or hide protion from dry bone or pork skin.

TYPE OF GELATIN:

·         TYPE A gelatin is derived from an acid-treated precursor and exhibits an isoelectric point in the region of pH 9. It is manufactured mainly from pork skin.

·         TYPE B gelatin is derived from an alkali-treated precursor and has its isoelectric zone in the region of pH 4.7. It is manufactured mainly from animal bones.

PRODUCTION OF GELATIN:

 On a commercial scale, gelatin is made from by-products of the meat and leather industry, mainly pork skins, pork and cattle bones, or split cattle hides. Contrary to popular belief, horns and hooves are not commonly used. The raw materials are prepared by different curing, acid, and alkali processes which are employed to extract the dried collagen hydrolysate. The entire process takes several weeks.

Degreased dried crushed bone                                         Pork skins                                                                                                                                     Acid Treatment                                                       Chopping                                                                                                                                       Lime treatment                                                     Water wash                                                                                                                                            Washing                                                         Acid treatment                                                                                                 Acid treatment                                                       Washing Multiple hot water extraction   Filtration   Ion exchange deionization   Evaporation   Filtration   Final concentration Sterilization   Polish filtration   Chilling to set point Extrusion Drying   Milling   Blending and Packaging

 

 

Figure.1 Gelatin Production Processes

Criteria to check the properties of gelatin

Bloom strength:

It is a measure of gel rigidity. It is defined as weight in grams required to push a standard plunger 4 mm into a standard gel that has been maintained at 10⁰ C for 17 hours.

The gelatin used in hard gelatin capsule manufacture is of a higher bloom strength 200-250g than that used for soft gelatin capsules 150g.

Viscosity:

It controls the thickness of shell and it is the measure of molecular chain length. A gel containing 6.66% w/v of gelatin is prepared and viscosity is measured at 60⁰ C. low viscosity, high bloom gelatin are used for encapsulating hygroscopic solid/ liquids.

Iron contents:

Should not exceed 15 ppm.

TYPE OF GELATIN CAPSULES:

There are two types of gelatin capsules:

1.      HARD GELATIN CAPSULE:

The hard capsule is also called “two piece”. it consists of two pieces in the form of small cylinders closed at one end, the shorter piece is called the “cap” which fits over the open end of the longer piece, called the “body” and is then filled with the drug.

2.      SOFT GELATIN CAPSULES:

The soft gelatin capsule is also called as “one piece”. Capsules are available in many sizes to provide dosing flexibility. Soft capsules are formed in a single piece.

 SOFT GELATIN CAPSULES:-

A soft gelatin capsule is a solid capsule (outer shell) surrounding a liquid or semi-solid centre (inner fill), as shown in figure 2. An active ingredient can be incorporated into the outer shell, the inner fill, or both.

Soft capsules are a single-unit solid dosage form, consisting of a liquid or semi-solid fill enveloped by one piece sealed elastic outer shell. The amount of drug or extract together with adjuvant is enclosed within a globular, oval or other shape of a soft shell1. Soft gelatin capsules (softgel) offer the possibility of delivering a liquid in a solid oral dosage form. The softgel can contain the active ingredient in solution, suspension or emulsion, which will inherently lead to better absorption of the active ingredient as compared with delivery in a tablet or as a powder.

Figure.2 Soft gelatin capsules

Soft gelatin capsules1 (referred to as soft elastic gelatin capsules, liquid gels or softgels) are a unique drug delivery system that can provide distinct advantages over traditional dosage forms such as tablets, hard gelatin capsules and liquids. However due to economic, technical and patent constraints there are relatively a few manufacturers of softgels in the world. Softgel is a hermetically sealed, one-piece capsule with a liquid or semisolid fill. The softgel consists of two major components, the gelatin shell and the fill. In the finished product gelatin shell is primarily composed of gelatin, plasticizer and water. The fill material can include a wide variety of vehicles and can either be a solution or a suspension. Softgels may be coated with suitable exterior coating agents such as Cellulose acetate phthalate (CAP) to obtain enteric release of encapsulated material. The standard softgel shape of oral pharmaceutical products is oval, oblong and round, though softgels can be manufactured in many shapes.

Soft gelatin capsules offer the possibility of delivering a liquid in a solid oral dosage form. The soft gelatin capsules can therefore contain the active ingredient in solution, suspension or emulsion, which will inherently lead to better absorption of the active ingredient as compared with delivery in a tablet or as a powder. Softgels are therefore the ideal solution –and sometimes the only solution – for delivery of compounds with poor oral bioavailability. Other properties that make softgels a useful and frequently applied dosage form include their aesthetic properties and ‘swallowability’, their tamper-resistance, their protection of the active ingredient from light and oxidation, their taste-masking of ingredients and their masking of unpleasant odours of ingredients.

ADVANTAGES OF SOFT GELATIN CAPSULES:

§  Ease of use - easy to swallow, no taste, unit dose delivery, temper proof.

§  Improved drug absorption and possible bioavailability advantages.

§  Avoids dust handling problems during manufacture and better operator safety.

§  Dose uniformity for low-dose drugs.

§  Good product stability (drugs are protected against oxidative degradation by lipid vehicles and gelatin shells).

§  Accommodates a wide variety of compounds filled as a semisolid, liquid, gel or paste.

§  Wide variety of colors, shapes and sizes.

§  Immediate or delayed drug delivery-can is used to improve bioavailability by delivering drug in solution or other absorption enhancing media.

§  Reduced dustiness; lack of compression stage in manufacture.

§  Possible reduced gastric irritancy compared to tablets and hard shell capsules.

                 

DISADVANTAGES OF SOFT GELATIN CAPSULES:

§  Soft gelatin capsules are not easily prepared except on a large scale and with specialized equipment.

§  They are an expensive dosage form, when compared with direct compression tablets.

§  There is a more intimate contact between the shell and its liquid contents than exists with dry-filled hard gelatin capsules, which increases the possibility of interactions.

§  Not adaptable to incorporation of more than one kind of fill into the same capsule (compare with hard shell capsules)

§  Stability concerns with highly water soluble compounds, and compounds susceptible to hydrolysis, Limited choices of excipients/carriers compatible with the gelatin Sensitive to heat and moisture, Dietary restrictions.

FORMULATION OF SOFT GELATIN CAPSULES:

PLASTICIZERS:

These are used to make the softgel shell elastic and pliable. They usually account for 20-30%. The most common plasticizers used in softgels is glycerol, although sorbitol and propylene glycol-400 are used frequently often in combination with glycerol. The amount and choice of the plasticizer contribute to the hardness of the final product and may even affect its dissolution or disintegration characteristics, as well as its physical and chemical stability. One of the most important aspect of softgel formulation is to ensure that there is minimum interaction or migration between the liquid fill matrix and the soft gel shell. The choice of plasticizer type and concentration is important in ensuring optimum compatibility of the shell with the liquid fill matrix.

WATER:

The other essential component of the soft gel shell is water. Water usually accounts for 30-40 % of the wet gel formulation and its presence is important to ensure proper processing during gel preparation and softgel encapsulation. In dry gels the equilibrium water content is typically in the range 5-8% w/w, which represents the proportion of water that is bound to the gelatin in the soft gel shell. This level of water is important for good physical stability, because in harsh storage conditions softgels will become either too soft and fuse together, or too hard and embrittled.

COLORANTS/OPACIFIERS:

Colorants can be either synthetic or natural, and are used to impart the desired shell colour for product identification. An opacifier, usually titanium dioxide may be added to produce an opaque shell when the fill formulation is a suspension, or to prevent photo degradation of light-sensitive fill ingredients. Titanium dioxide can either be used alone to produce a white opaque shell or in combination with pigments to produce a coloured opaque shell.

PRESERVATIVES:

Preservatives are used for preserve the drug medicament from the microbes. It is used about 0.2% concentration of total drug medicament. Methyl paraben and propyl paraben is mainly used as preservative. 

FLAVOURING AGENTS:

Flavouring agents is used for the taste masking. Ethyl vanillin, essential oils, and different sugar mainly sucrose is also used as flavouring agent.

SOFT GELATIN CAPSULE MANUFACTURING:

Following methods are used:

1.      Plate process:

2.      Rotary die process:

3.      Reciprocating die process:

4.      Accogel process:

5.      Seamless gelatin capsules:

1.   Plate process:          

In this process a warmed sheet of gelatin sheet is placed over a die plate having a number of depression or moulds or numerous die pockets. The sheet is drawn into these depressions or pockets by applying vacuum. A measured quantity of liquid medicament is pour over it. Over this another plate of the mould is placed and the pressure is then applied to the combine plate. The capsules are then simultaneously shaped, filled, sealed and cut into individual units. This method is uses for small scale preparation of soft gelatin capsules. It has 20-40% of net moisture content.

2.    Rotary die process:

Before encapsulation process takes place, there are two basic processes

 Production of gel mass which provide the soft gel shell:

The gel mass is prepared by dissolving the gelatin in water approximately at 80ºC and under vacuum, followed by addition of plasticizer. Once the gelatin is fully dissolved other components such as color, opacifier, flavours and preservatives may be added. The color is compared with the standard. Then the temperature maintained at 57-60ºC in melting tank. The hot gel mass is then supplied to the encapsulation machine through heated transfer pipes by a casting method that forms two separate gelatin ribbons. The gelatin mass is fed by gravity to a metering device which controls the flow of mass on to air heated (13-14ºC) rotating drums. Gelatin ribbons are produced. During the casting process the gelatin pass through the sol gel transformer and the thickness of each ribbon is controlled to ±0.1 mm. The thickness is checked regularly during the process. The ribbon of 0.022-0.045 inches but for most capsules it is between 0.025-0.032 inches. The two gel ribbons are then carried through rollers (at which a small quantity of vegetable oil lubricant is applied) and onwards to the rotatory die encapsulation. Each ribbon provide one-half of the softgel.

Fill matrix:

The liquid fill matrix containing the active drug substance is manufactured separately from preparation of molten gel. Manufacture of the active fill matrix involves dispersing or dissolving the drug substances in the non-aqueous liquid vehicle using conventional mixer homogenizers. They also break up the agglomerates of solids. Oxygen sensitive drugs are protected by mixing under vacuum and or inert gas or by addition of antioxidant.

Schematic diagram or rotatory die:

This machine has two, side-by-side cylinders in each of which half-moulds are cut. These cylinders, like the rollers of a mangle, rotate in contrary direction and as they are mirror images the moulds come together precisely during rotation. Two ribbons of gelatin are fed between the rollers and, just before the opposing rollers meet, jets of medicament press the gelatin ribbon into the moulds, filling each half. The moment of pressure follows, immediately sealing the two halves together to form a capsule. These rotary machines are capable of producing between 25000 and 30000 capsules an hour with an accuracy of dosage of approximately ± 1 percent.     

Encapsulation:

      Liquid gelatin flowing from an overhead tank is forward into continuous ribbon by the rotating drum and brought together between twin rotating dies. The injection of liquid between the ribbons, force the gel to expend and into the packets of dies, which govern the size n shape of the softgels. The sealing of the capsules is done by mechanical pressure on the die rolls and the heating of ribbons by the wedge. After manufacture, it is subjected to IR drying and then they are separated on the tray and stacked in funnel drier that supplies air at 20% relative humidity.

Figure 3, Schematic diagram or rotary die machine

3.   Reciprocating die process:

This is similar to rotary process, but is differ in the actual encapsulating process. The gelatin ribbons are fed between a set of vertical dies that continuously open and close to form the rows of the pockets in the gelatin ribbons. These pockets are filled with the medication and are sealed, shaped and cut out of the film as they progress through the machinery.

 4.   Accogel process: (Stern Machine)

This is another rotary process involving the measuring roll, a die roll and a sealing roll. The measuring roll rotates directly over the die roll, and the pockets in the two rolls are aligned with each other. The powder or granular fill material is held in the pockets of the measuring roll under vacuum. A plasticized sheet is drawn in to the die pockets of the die roll under vacuum. As the measuring roll and the die roll rotate, the measured doses are transferred to the gelatin lined pockets of the die roll. The continue rotation of the filled die converges with the rotating sealing roll where second gelatin sheet is applied to form the other half of capsule. The pressure developed between the both rolls seals and cut out of the capsules.

5.   Seamless gelatin capsules:

It is a modern method for making soft gelatin capsules takes advantage of the phenomenon of drop formation. The essential part of the apparatus consists of two concentric tubes. Through the inner tube flows the medicament and, through the surrounding outer tube, the gelatin solution. The medicament, therefore, issues from the tube surrounded by gelatin and forming a spherical drop. This is ensured by allowing the drop to form in liquid paraffin in which the gelatin is insoluble. Regular induced pulsations cause drops of the correct size to be formed, and a temperature of 4°C ensures that the gelatin shell is rapidly congealed. The capsules are subsequently degreased and dried.

APPLICATIONS:

Ophthalmic Soft Gelatin Capsules:

It is very important that the ophthalmic ointments should be sterile and free from irritant effect. Therefore they must be packed in such a manner that the product remains sterile until whole of it is used up. The best method to keep the preparation free from contamination during use is to pack it in single dose containers. Now a day’s soft gelatin capsules are very commonly used for filling ophthalmic ointments. These capsules are meant for single application to the eye. Just before application, the capsule is punctured with a sterile needle, the contents instilled into the eye and the shell discarded.

Chewable Soft Gelatin Capsules:

The chewable gelatin dosage form offers excellent mouth feel and chewing experience as compared with other chewable dosage forms. Chewable soft gels are particularly suitable for pediatric populations, where swallowing whole tablets or capsules is often a problem, and chewable tablets are often rejected. Consumer preference testing with Banner’s new chewable gels showed that three out of four parents would buy this product for their children data on file. This approach has resulted in a highly acceptable end-product. Other taste-masking technologies can be combined with the chewable softgel.

Controlled Release Soft Gelatin Capsules:

Banner’s scientists have developed a controlled release technology that is able to achieve a large variety of release patterns. The controlled release softgel can be applied to a wide range of active molecules. Banner’s controlled release softgel technology uses a lipid matrix in a standard softgel shell. Depending on the physicochemical properties of the active molecule, an emulsion or a suspension is chosen as a matrix. The result is an oral dosage form offering controlled release of the active moiety, combined with all the benefits that the softgel dosage form offers.

Enteric Coated Soft Gelatin Capsules:

In contrast to existing enteric dosage forms, Banner’snew enteric softgel is not coated. The enteric features of the dosage form reside in the shell itself. The result is a clear enteric dosage form with the exact same appeal and patient benefits that the standard softgel offers. Traditionally, enteric softgels were prepared by coating with enteric polymers using traditional coating technology. Coating has its own disadvantages such as unsuccessful adhesion of the enteric polymer onto the soft gelatin shell due to the shell’s inherent flexible nature.

Gelatin-Free Soft Gelatin Capsules:

Gelatin-free soft capsules are made from vegetable ingredients. They have all the advantages of standard softgels, but do not contain gelatin. Gelatin free soft capsules are particularly suitable for vegetarians or other populations that prefer non-animal products.

EVALUATION OF SOFT GELATIN CAPSULES:

     The Soft gelatin capsules should be subjected to following tests for their standardization. 

Disintegration Test:

For performing disintegration test on capsules the tablet disintegration test apparatus is used but the guiding disc may not be used except that the capsules float on top of the water. If hard capsules float on the surface of the water, the discs may be added. One capsule is placed in each tube which is then suspended in the beakers to move up and down for 30 minutes. The beaker containing 600 ml water and temperature is 37 °C. Unless otherwise stated in the monograph. The capsules pass the test if no residue of drug or other than fragments of shell remains on No. 10 mesh screen of the tubes. If the disc is used, any residue remaining on its lower surface should only consist of fragments of shell.

Dissolution:

It is done if capsules contain drug which have limited solubility in gel fluid. The dissolution test is carried out using the dissolution apparatus official in both the U.S.P. and N.F. The capsule is placed in a basket formed from 40-mesh stainless steel fabric. A stirrer is attached to the basket, and the basket is immersed in the dissolution medium and caused to rotate at a specified speed. The dissolution medium is held in a covered 1000 ml glass vessel and maintained at 37°C ± 0.5°C by means of a suitable constant temperature water bath. The stirrer speed and type of dissolution medium are specified in the individual monograph.

Weight Variation Test:

Twenty capsules are taken at random and weighed. Their average weight is calculated, then each capsule is weighed individually and their weight noted. The capsule passes the test if the weight of individual capsule falls within 90-110% of the average weight. If this requirement is not met, then the weight of the contents for each individual capsule is determined and compared with the average weight of the contents. The contents from the shells can be removed just by emptying or with the help of small brush. The remainder contents are removed by washing with a suitable solvent. After drying the shells, they are weighed and the content weights of the individual capsules are calculated. The requirements are met if not more than 2 of the differences are greater than 10 % of the average net content and in no case the difference is greater than 25 %.

Moisture Permeation Test:

By packing the dosage unit together with color revealing desiccant pellet; exposing the packaged unit to known relative humidity over a specified time, observing the desiccant pellet for color change and comparing the pre and post weight of the packaged unit, moisture permeation can be determined.

Capsule Stability:

This inherent characteristic warrants a brief discussion of the effects of temperature and humidity on these products, and points to the necessity of proper storage and packaging conditions and to the necessity of choosing an appropriate retail package. The variety of materials capsulated, which may have an effect on the gelatin shell, together with the many gelatin formulations that can be used, makes it imperative that physical standards are established for each product.

Materials other than gelatin used for capsule formulation

Traditionally gelatin has been used almost exclusively as shell forming mat of soft capsules. This is due to its legal status its unique physical chemical properties namely

·         its oxygen impermeability

·         combination of film forming capability

·         thermoreversible sol gel formation

Despite three general adv. Gelatin has several draw back that limits its use for soft capsule.

·         The animal source can be problem for gelatin for certain consumers such as vegetarions or vellgious or ethnic groups.

·         Since unmodified gelatin is prone to cross linking when in contact with aldehydes solubility problems might be expected with certain fill formulations.

·         Transparent low colour capsules are difficult produce because of intrinsic Millard reaction on gelatin colour.

·         For low price health and nutrition products pricing of commercially gelatin might be additional problem

Several concepts based on synthetic polymers and plant derived hydrocolloids have been described few gained commercial interact. This is due to fact that change in capsule shell polymer material require. Legal approval and machinability

1.      Use of combination of iota carrageenan (12-24% w/w of dry shell) and modified starch namely starch (30-60% w/w of dry shell as gelatin substitution).

Both components are accepted as food additives with numbers. This allowing their use in health and nutrition products. it can be formulated with conventional plasticizer such as glycerol, sorbital etc. Water to from molten mass that can be extruded to set elastic films on temp controlled casting drums.

2.      Describe formulation of soft capsules from potato starch (45-80% w/w) with specific molecular weight distribution and amylopectin as glycerol. (>12% w/w) a gllidant and disintegrant. Soft capsules are low price alternative to soft gelatin capsules

3.      Brown 1996 describe preferable use of PVA and optional use of some other material all being film forming polymers that lack properties necessary for soft capsule production PVA films according to invention may be composes of 70-75% w/w PVA, 10-15 w/w qlycer and 5% w/w, depending on degree of salvation PVA as an optional less hyqroscopic this lead to soft capsule shells that are moistur that soft gelatin capsule shells.

 REFERENCES:

1.      Lachman Leon, Lieberman Herbert A., et al “The Theory and Practice of Industrial Pharmacy” 3^rd edition, reprint1991, Published by Varghese publishing house, Dadar Bombay, PP 398.

2.      Ansel Howard C. Allen Loyed V., et al “Pharmaceutical dosage forms and drug delivery system” 7^th edition 2000, published by Lippincott Williams Philadelphia, PP 215.

3.      Bhatt Bhawna, Aggrawal S.S Pharmaceutical Technology Delhi Institute of Pharmaceutical Science and Research Sector – 3, Pushp Vihar New Delhi, PP 2, 18.

4.      L.L. Augsburger, "Hard and Soft Gelatin Capsules," Chapter 11 in Modern Pharmaceutics, 3nd Edition, G. Banker and C.T. Rhodes (Editors), Marcel Dekker, Inc., New York,1995 PP 44, 47.

5.      Dr. Ali Javed, Dr. Kar RK, Dr. Alka Ahuja “Dosage form Design”, 4^th Edition, Published by Birla Publication Pvt. Ltd. Delhi, PP 45,56.

6.      Softgel Technologies People, facilities and technologies to deliver superior softgel solutions.http://www.catalent.com/pharma/pdf/Softgel-Technologies-Oral-Technologies. Accessed 2010/11/19.

7.      Aulton Michael E., “Pharmaceutics the science of dosage form design” 2^nd Edition 2002, Published by Churchill Livingstone, PP 527.   

8.      Remington – The Science and Practice of Pharmacy, 21^th edition, Volume – 1, published by Lippincott Williams Philadelphia, PP 918, 923.

9.      Vegicaps Softgel Technologies People, facilities and technologies to deliver superior softgel solutions. Copyright 2007 Catalent Pharma Solutions.

10.  Reich G, Podczeck F and Jones BE. Formulation and physical properties of soft capsules. 2004, - Medical, PP 272

11.  Soft gelatin manufacturing and Marketed preparation METHOXALONE softgels,  http://www.drugs.com/cdi/methoxsalen-soft-gelatin-capsules.html

12.  Gershanik T and Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. European Journal of Pharmaceutics and Biopharmaceutics 2000, 50: 179-188

13.  Martins GZ, Souza CRF, Shankar TJ and Oliveira WP. Effect of process variables on fluid dynamics and adhesion efficiency during spouted bed coating of hard gelatine capsules. Chemical Engineering and Processing 2008, PP 2238–2246.