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INTRODUCTION

Softgel formulation characteristics consist of water or oil soluble fill solution, or suspension of drug covered by a layer of gelatine (made of gelatine, plasticiser, modifier, water, colour, antioxidant or flavour). The outer layer can be enteric coated.. The softgel delivery system offers improve d, rapid and consistent absorption of hydrophobic drugs.

The softgel delivery system is a unitary package, formed with gelatine outer layers, that contain between them the active ingredients in solution, suspension or paste form. The softgel capsule may have several shapes and sizes, dependent on the design.

Hydrophobic drugs can result in poor bio availability. These drugs will not dissolve readily in water, gastric or intestinal fluid and when they are compounded in solid dosage forms, the dissolution rate may be slow, absorption may vary and the bio availability may be incomplete. In the case of hydrochlorothiazide, isotretinoin and griseofulvin, bio availability is improved in the presence of fatty acids e.g. mono or diglycerides. Fatty acids can solubilise hydrophobic drugs in the gut and enable more rapid absorption. The softgel delivers drugs in solution and yet offers solid dosage form. Hydrophobic drugs are dissolved in hydrophilic solvent, which, when crushed or chewed, release the drug immediately to produce a solution of the drug in gastric juice ready for absorption from the gastrointestinal tract into the blood stream. This results in rapid onset of desired therapeutic effects. Acid soluble compounds may remain in solution and acid-insoluble compounds may precipitate as a fine particle cloud, but re dissolve quickly and give good bio availability results.

The development time for softgel is shorter due to lower bio availability concerns and such solutions can be marketed at a fraction of cost.

For example, Ibuprofen softgel gives rise to a shorter time to peak plasma concentration and greater peak plasma concentration compared to a marketed tablet formulation. Cyclosporin can give therapeutic blood levels which are not achievable from tablet form. Similarly oral hypoglyceamic glipizide in softgel is also known to have better bio availability results compared with tablet form. Softgel delivery systems can also incorporate phospholipids or polymers or natural gums to entrap the drug active in the gelatine layer with an outer coating to give desired delayed/control release effects.

It is important that formulations of softgel fills have pH2.5-7.5 otherwise hydrolysis or tanning can occur. The different acidic grades of gelatine blooms can be employed to address the problem of water migration and content greater than 20% will dissolve the capsule shell.

Some branches of industry in which softgels are used are:

Pharmaceutical: as an Oral, Anal, Vaginal and Ophthalmic drug delivery system,

Cosmetics: as unitary containers, for many products applied on the skin or hair, ie. vitamin E drops,

Nutrition: as an oral delivery system for a number of natural products, nutrients and alternative medications, such as the shark liver oil,

Veterinary: same as in the pharmaceutical industry, but the products are manufactured for animal consumption under different regulations and formulae.

SOFTGEL ADVANTAGES OVER HARDSHELL CAPSULES

The softgel capsule offers the following advantages over other oral delivery systems, such as hardshell capsules.

SHAPES AND SIZES

The shape and size of the capsule are defined depending on the needs of the product as well as the market. There is a wide variety of shapes and sizes as given in Fig 1 and 2.

Figure 1

Figure 2

SOFTGEL DELIVERY SYSTEM FINISHED APPEARANCES AND TEXTURES

A number of possible soft gel finished appearances and textures are possible:

• Transparent/colour.
• Solid colours.
• Natural Transparent.
• Solid colours in combination of two tones.
• Transparent in two tones.
• Transparent/solid colours.

Some examples are shown in Figure 1 above.

ENCAPSULATION PROCESS

Manufacturing soft gelatine capsules implicates the use of sophisticated technology. The rotary type softgel encapsulation process offers accuracy of dosage and higher production capacity. Before encapsulation process begins, Gelatine mass for out shell and medicine for the capsule fill are prepared. The Gelatine powder is mixed with water and glycerine, heated and stirred under vacuum. The outer layer of this special stainless steel vessel is steam- jacketed. Any required flavours or colours are added using a turbine mixer to molten gelatine and transferred to mobile vessels. The gelatine mass is kept in a steam-jacketed storage vessel at a constant temperature.

The medicine fill is prepared using standard procedures used in pharmaceutical liquid ,paste or suspension manufacturing.

The encapsulation process begins when molten gel is pumped to the machine and two thin ribbons of gel are formed on either side of machine. These ribbons then pass over a series of rollers and over a set of die that determine the size and shapes of capsules. The medicine fill is fed from its container to a positive displacement pump, which accurately doses the fill and injects it between two gelatine ribbons prior to sealing them together through the application of heat and pressure. The capsules formed at this stage are incredibly flexible due to water in gel mass. To remove excess water capsules pass through a conveyer into tumble dryers where about 25% of water is removed. The capsules are then placed on trays which are stacked and transferred into drying rooms where dry air is forced over capsules to remove any excess moisture. The moisture is measured at regular intervals, when the moisture is limited to approx. 8% the drying process is complete and capsules are ready for packaging.

PRODUCTION PROCESS

The manufacturing of softgel delivery systems is carried out in a high productivity rotatory die machine and capsules are dried using an advanced Tumble drier(as shown in Figure 3), offering:

• dosage precision and accuracy.
• automation.
• easy cleaning and sanitation.
• high productivity.
• product variety.
• encapsulation in absence of oxygen and/or light.

Figure 3. Showing encapsulation and tumble drier equipment

It is also possible to manufacture round seamless capsules (pearls) using a unique technology that allows manufacturing using the physical properties of superficial tension.

The productivity increases or diminishes upon considering the following variables:

• asset to encapsulate (density, consistency, etc.)
• capsule size.
• capsule shape.

CANDIDATES FOR SOFTGEL DELIVERY SYSTEM

A number of compounds can be formulated to deliver faster onset of effect with lower dosage and lower side effects. There are at present a number of compounds in early phase of development that could benefit from softgel formulation to give faster absorption, improved and uniform bio availability. Moreover there are a number of poorly-soluble pharmaceutical compounds offering a huge market potential when delivered in softgels. Scherasol from RP Scherer Ltd and BritHealth's Fast Absorption Systems(B-FAS) offer opportunities for these pharmaceutical compounds for faster and uniform absorption.

According to Technology Catalysts International(TCI), there are at least 83 drugs with World-wide sales exceeding US$100 million that are insoluble or poorly soluble in water, and have total combined sales of approximately US$45 billion. Of these candidates ,TCI has identified 26 drugs which are most suitable for reformulation in softgel delivery system. If these lead compounds are coupled with novel delivery systems, TCI estimates that the reformulated products will generate an additional US$8 billion in revenues.

The compounds are:

Antihistamines - clemastine,chlorpheniramine,dexchlorpheniramine,astemizole,loratadine,decongestants

Analgesics - ibuprofen, paracetamol, ketoprofen, naproxen and combinations

Antidepressants - fluoxetine(Prozac),buspirone(Buspar),Phyto compounds

Antinauseants - compazine,chlorpromazine,perphenazine,phyto compounds

Anorexiants - dextroamphetamine, phentermine, mazindol

Biological compounds - bromocryptine, apomorphine, selegiline, amitriptyline, dopamine precursors, serotonin precursors

Cardiovascular compounds - nitroglycerin, ACE inhibitors, calcium antagonists, beta blockers

Decongestants - dextromethorphan, pseudoephedrine,phenylpropanolamine

Peptides/Proteins and other biopharmaceuticals - cyclosporine, insulin, calcitonin etc

Sedatives - barbiturates, benzodiazepines

Steroids - testosterone, estradiol, progesterone and combinations

Sleeping Drugs - temazepam, diphenhydramine, zolpidem, triazolam, nitrazepam

Softgel delivery systems also offer opportunities for many new chemical entities including peptides/other biopharmaceuticals and other pharmaceuticals those requiring reformulation due to bio availability concerns/patent extension.

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