INTRODUCTION
Over recent years, new drug molecules have tended to be more hydrophobic and therefore less soluble in aqueous systems. In the case of drugs for oral administration, it is becoming more difficult to formulate poorly water-soluble drugs into products from which the drug is fully released and well absorbed.
One of the best methods to overcome
this problem is to make a liquid formulation containing the drug. In order to convert this liquid formula into a solid dosage form, it may be encapsulated into soft gelatin capsules. The term ‘soft gelatin capsules’ is commonly abbreviated to softgels.
Softgels consist of a liquid or semisolid matrix inside a one-piece outer gelatin shell. Ingredients that are solid at room temperature can also be encapsulated into softgels, provided they are at least
semisolid below approximately 45°C.
The drug compound itself may be either in solution or in suspension in the capsule-fill matrix. The characteristics of the fill matrix may be hydrophilic (for example
polyethylene glycols) or lipophilic (such as triglyceride vegetable oils). Indeed, in many formulations, the matrix may be a mixture of both hydrophilic and lipophilic ingredients. Significant advances have been made in recent years in the formulation of softgel fill matrices and they include microemulsions and nanoemulsions encapsulated as preconcentrates in softgels.
The term ‘preconcentrate’ means that the softgel fill matrix is a combination of lipophilic and hydrophilic liquids as well as surfactant components, which after oral administration disperse to form a microemulsion. If the dispersion results in even smaller droplets in the nanoparticle range, then the dispersion is known as a nanoemulsion.
The softgel capsule shell consists of gelatin, water and a plasticizer. It may be transparent or opaque, and can be coloured and flavoured if desired. Preservatives are not required owing to the low water activity in the finished product. The softgel can be coated with enteric-resistant or delayed-release material. Although virtually any shape softgel can be made, oval or oblong shapes are usually selected for
oral administration.
Softgels can be formulated and manufactured to produce a number of different drug delivery system:
- Orally administered softgels: containing solutions or suspensions that release their contents in the stomach in an easy to swallow, convenient unit dose form. This is the most common type of softgel.
- Chewable softgels: where a highly flavoured shell is chewed to release the drug liquid fill matrix. The drug(s) may be present in both the shell and the fill matrix.
- Suckable softgels: which consist of a gelatin shell containing the flavoured medicament to be sucked and a liquid matrix or just air inside the capsule.
- Twist-off softgels: which are designed with a tag to be twisted or snipped off, thereby allowing access to the fill material. This type of softgel can be very useful for unit dosing of topical medication, inhalations, or indeed for oral dosing of a paediatric product.
- Meltable softgels: designed for use as ‘patient friendly’ pessaries or suppositories.
RATIONALE FOR THE SELECTION OF SOFTGELS AS A DOSAGE FORM
Softgels may be selected as the most suitable dosage form for some reasons which include:
- Improved drug absorption.
- Increased rate of absorption.
- Increased bioavailability.
- Decreased plasma variability.
- Patient compliance and consumer preference.
- Safety – potent and cytotoxic drugs.
- Oils and low melting-point drugs.
- Dose uniformity for low-dose drugs.
- Product stability
1. IMPROVED DRUG ABSORPTION.
i. INCREASED RATE OF ABSORPTION
Presentation of the drug to the gastrointestinal tract in the form of a solution from which it can be rapidly absorbed is one of the best methods to address drug absorption issues. This can be achieved using a drug-solution matrix in a softgel formulation whereby absorption is significantly faster than from other solid oral dosage forms, such as compressed tablets.
This is because absorption of a poorly soluble drug from a tablet formulation is rate-limited by the need for disintegration into granules, then drug dissolution into gastrointestinal fluid. With the approach of solution-softgel, the shell ruptures within minutes to release the drug solution, which is usually in a hydrophilic or highly dispersing vehicle that aids the rate of absorption.
This may be a valuable attribute:
a. For therapeutic reasons, such as the treatment of migraine or acute pain, or
b. Where there is a limited absorptive region or ‘absorption window’ in the gastrointestinal tract.
ii. INCREASED BIOAVAILABILITY
As well as increasing the rate of absorption, softgels may also improve the extent of
absorption. This can be particularly effective for hydrophobic drugs with a relatively high molecular weight. An example of such a product is the protease inhibitor saquinavir, which has been formulated as a
solution-softgel product.
In some cases, a drug may be solubilized in a vehicle that is capable of spontaneously
dispersing into an emulsion on contact with gastrointestinal fluid. This is known as a SELF-EMULSIFYING SYSTEM.
In other cases, a drug may be dissolved in an oil/ surfactant vehicle that produces a
MICROEMULSION or a NANOEMULSION on contact with gastrointestinal fluids. A good example of this type of formulation is a nanoemulsion of progesterone. The vehicle, consisting of oils and surfactants in appropriate proportions, when in contact with aqueous fluids, produces an emulsion with an average droplet size less than 100 nm. An increased bioavailability is produced compared to formulations where the drug is dosed in the solid state when the solubility of the drug is maintained as long as possible, delivering solubilized drug directly to the enterocyte membrane.
Softgel formulations may contain excipients such as one or more surfactants which can aid the stability, wettability or even permeability of the drug.
iii. DECREASED PLASMA VARIABILITY
High variability in drug plasma levels is a common characteristic of drugs with limited
bioavailability. By dosing drug optimally in solution, the plasma level variability of such drugs can be significantly reduced. The cyclic polypeptide drug cyclosporine benefits from such an approach by using a microemulsion preconcentrate in a softgel.
2. PATIENT COMPLIANCE AND CONSUMER PREFERENCE
According to the results of a number of self-medicating consumer preferences carried out to gauge the relative perception of softgels compared to hardshell capsules and tablets, it showed that softgels were perceived to be a more accepted dosage form to most consumers, and it outperformed all other dosage forms in answering patient needs.
Consumers expressed their preference for softgels in terms of
- Ease of swallowing
- Absence of taste and
- Convenience
One further aspect of improved compliance is that if the bioavailability of a drug solution
is enhanced by using the drug solution in a softgel delivery system, it may be possible to reduce the dose administered in order to achieve therapeutic effectiveness. In this way, it may also be possible to reduce
the capsule size, which will further improve patient compliance.
3. SAFETY FOR POTENT AND CYTOTOXIC DRUGS
The mixing, granulation and compression/filling processes used in preparing tablets and hard-shell capsules can generate a significant quantity of airborne powders which can be of great concern for highly potent or cytotoxic compounds in terms of the operator and environmental protection required
for satisfactorily safe product manufacture. Such safety concerns can be significantly reduced by preparing a solution or suspension of drug where the active components are essentially protected from the environment by the liquid.
4. OILS AND LOW MELTING-POINT DRUGS
When the pharmaceutical active ingredient is an oily liquid and has a melting point less
than about 75°C or proves difficult to compress, liquid filling of softgels is an obvious approach to presenting a solid oral dosage form. If the drug is an oily liquid, then it can be encapsulated directly into a
softgel without adding a further diluent. Other low melting-point drugs may be formulated with a diluent oil in order to ensure satisfactory liquid flow and dosing into softgels.
5. DOSE UNIFORMITY OF LOW-DOSE DRUGS
In pharmaceutical manufacture, liquid dosing avoids the difficulties of poor powder
flow and therefore poor content uniformity. This is an important benefit for formulations containing drug doses in the microgram region. Attempts to produce adequate mixtures of small quantities of a low-dose drug in larger quantities of powdered excipients for tabletting or hard-shell filling are often unsatisfactory.
Improved homogeneity can be achieved by dissolving the drug in a liquid and then encapsulating the liquid matrix in a softgel.
6. PRODUCT STABILITY
If a drug would undergo oxidative or hydrolytic degradation, the preparation of a liquidfilled softgel may prove beneficial. The liquid is prepared and encapsulated under a protective nitrogen atmosphere and the subsequently dried shell has very low oxygen permeability. The drug can be protected from moisture by formulating in a lipophilic vehicle and packaging in well designed blister packs using materials of low moisture transmission.
Inorder to achieve a more stable product, the choice of excipients, an understanding of the drug degradation pathways and appropriate preformulation studies are vital.
MANUFACTURE OF SOFTGELS
Softgel capsules were used in the 19th century as a means of administering bitter-tasting or liquid medicines. These were manufactured individually by preparing a small sack of gelatin and allowing it to
set. Each sack, or gelatin shell, was then filled with the medication and heat-sealed.
This method of manufacture was improved using a process that involved sealing two sheets of gelatin film between a pair
of matching flat brass dies. Each die contained pockets into which the gelatin sheet was pressed and into which the medication was filled. The pressure between the two plates enabled individual capsules to be cut out from the die mould, and these capsules were subsequently dried.
Softgels were manufactured this way until the invention of the rotary die encapsulation machine by Robert Pauli Scherer in 1933.
The rotary die process involves the continuous formation of a heat seal
between two ribbons of gelatin, simultaneous with dosing of the fill liquid into each capsule.
Before the encapsulation process takes place, there are two subprocesses that are often carried out simultaneously, yielding the two components of a softgel. These are:
- the gel mass which will provide the softgel shell, and
- the fill matrix for the contents.
THE GEL MASS
This is prepared by dissolving the gelatin in water at approximately 80°C and under vacuum, followed by the addition of the plasticizer, for example glycerol. Once the gelatin is fully dissolved then other components, such as colours, opacifier, flavours and preservatives, may be added.
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, each approximately 150 mm wide. During the casting process the gelatin passes through the sol-gel transition and the thickness of each gel ribbon is controlled to ± 0.1 mm, in the range of about 0.5-1.5 mm. The thickness is checked regularly during the manufacturing process.
The two gel ribbons are then carried through rollers (at which a small quantity of vegetable oil lubricant is applied) and onwards to the rotary die encapsulation tooling. Each ribbon provides one
half of the softgel.
THE LIQUID FILL MATRIX CONTAINING THE ACTIVE DRUG
The manufacture of the liquid fill matrix containing the active drug involves dispersing or dissolving the drug substance in the non-aqueous liquid vehicle using conventional mixer-homogenizers.
Different parameters are controlled during the preparation of the active fill matrix, depending on the properties of the drug substance. For example, oxygen-sensitive drugs are protected by mixing under vacuum and/or inert gas; and in some cases an antioxidant component may be added to the
formulation. Also, if the drug substance is present as a suspension in the liquid fill matrix, it is important to ensure that particle size of the drug does not exceed approximately 200 um . By doing this it is possible to ensure that drug particles do not become trapped within the capsule seal,
potentially leading to loss of integrity of the softgel.
ROTARY DIE ENCAPSULATION
This is the process by which the gel ribbon and the unit dose of liquid fill matrix are combined to form the softgel. The process involves careful control of three parameters:
- Temperature: This controls the heat available for capsule seal formation.
- Timing: The timing of the dosing of unit quantities of fill matrix into the softgel during its formation is
critical. - Pressure: The pressure exerted between the two rotary dies controls the softgel shape and the final cutout from the gel ribbon.
Accurately metered volumes of the liquid fill matrix are injected from the wedge device into the space between the gelatin ribbons as they pass between the die rolls. The wedge-shaped injection system is itself heated to approximately 40°C. The injection of liquid between the ribbons forces the
gel to expand into the pockets of the dies, which govern the size and shape of the softgels. The ribbon continues to flow past the heated wedge injection system and is then pressed between the die rolls.
Here the two softgel capsule halves are sealed together by the application of heat and pressure. The capsules are cut automatically from the gel ribbon by raised rims around each die on the rollers. After
manufacture the capsules are passed through a tumble drier and then, to complete the drying process, spread on to trays and stacked in a tunnel drier that supplies air at 20% relative humidity. The tunnel drying process may take 2 or 3 days, or possibly as long as 2 weeks, depending on the specific softgel formulation. Finally, the softgels are inspected and packed into bulk containers in order to prevent further drying and for storage.
FORMULATION OF SOFTGELS
GELATIN SHELL FORMULATION
Typical softgel shells are made up of gelatin, plasticizer, and materials that impart the desired appearance (colourants and/or opacifiers), and sometimes flavours. The following sections describe each of these materials, their functions, types, and amounts most often used in manufacturing softgel shells.
GELATIN
Most commonly the gelatin is alkali- (or base-) processed (type B) and it normally constitutes 40% of the wet molten gel mass. Type A acid-processed gelatin can also be used.
PLASTICIZERS
These are used to make the softgel shell elastic and pliable. They usually account for 20-30% of the wet gel formulation. The most common plasticizer used in softgels is glycerol, although sorbitol and propylene glycol are also frequently used, 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. Plasticizers are selected on the basis of their compatibility with the fill formulation, ease of processing, and the desired properties of the final softgel, including hardness, appearance, handling characteristics and physical stability.
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.
COLOURANTS/OPACIFIERS
Colourants (soluble dyes, or insoluble pigments or lakes) and opacifiers are typically used at low concentrations in the wet gel formulation. Colourants 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 photodegradation of light-sensitive fill ingredients,
PROPERTIES OF SOFT GELATIN SHELLS
I. OXYGEN PERMEABILITY
The gelatin shell of a softgel capsule provides a good barrier against the diffusion of oxygen into its contents. The quantity of oxygen (q) that passes through the gelatin is
governed by the area (A), thickness (h), particle pressure difference (pl – p2), time of diffusion (t) and the permeability coefficient (P) of the shell by the following equation:
q= PAt(pl – p2)/ h
The permeability coefficient (P) is related to the diffusion coefficient (D) and the solubility coefficient (S) by the equation P = DS. This relationship, described by Henry’s Law, assumes no interaction between the gas and the polymeric film, but P is clearly affected by the formulation of the gelatin shell.
II. RESIDUAL WATER CONTENT
Softgels contain little residual water, and compounds which are susceptible to hydrolysis are protected if dissolved or dispersed in an oily liquid fill material and encapsulated as a soft gelatin capsule.
FORMULATION OF SOFTGEL FILL MATERIALS
In terms of formulation requirements, the softgel should be considered as a biphasic dosage form: a solid-phase capsule shell and a liquid-phase fill matrix. The choice of components is made according to one or more of a number of criteria, including the following:
- Capacity to dissolve the drug
- Rate of dispersion in the gastrointestinal tract after the softgel shell ruptures and releases the fill
matrix - Capacity to retain the drug in solution in the gastrointestinal fluid
- Compatibility with the softgel shell
- Ability to optimize the rate, extent and consistency of drug absorbed.
TYPES OF SOFTGEL FILL MATRICES
A. LIPOPHILIC LIQUIDS/OILS
Triglyceride oils, such as soya bean oil, are commonly used in softgels. When used alone, however, their capacity to dissolve drugs is limited. Nevertheless, active ingredients such as hydroxycholecalciferol and other vitamin D analogues, plus steroids such as oestradiol, can be formulated into simple oily solutions for encapsulation in softgels.
B. HYDROPHILIC LIQUIDS
Polar liquids with a sufficiently high molecular weight are commonly used. Polyethylene glycol (PEG) is the most frequently used, for example PEG 400, which has an average molecular weight of approximately 400 Da. Smaller hydrophilic molecules, such as ethanol or indeed water,
can be incorporated in the softgel fill matrix in low levels, typically below 10% by weight.
C. SELF-EMULSIFYING OILS
A combination of a pharmaceutical oil and a non-ionic surfactant such as polyoxyethylene sorbitan mono-oleate can provide an oily formulation which disperses rapidly in the gastrointestinal fluid. The resulting oil/surfactant droplets enable rapid transfer of the drug to the absorbing mucosa and subsequent drug absorption.
D. MICROEMULSION AND NANOEMULSION SYSTEMS
A microemulsion of a lipid-surfactant-polar liquid system is characterized by its
translucent single-phase appearance. The droplet size is in the submicrometre range, and light scattering by these droplets results in a faint blue colouration known as the Tyndall effect.
A nanoemulsion is a similar system but contains emulsion droplets in the 100 nm size range. Microemulsion and nanoemulsion systems have the advantage of a high capacity to solubilize drug compounds and to retain the drug in solution even after dilution in gastrointestinal fluids. In order to produce a microemulsion or nanoemulsion in the gastrointestinal tract a ‘preconcentrate’ is formulated in the softgel fill matrix.
E. SUSPENSIONS
Drugs that are insoluble in softgel fill matrices are formulated as suspensions. Suspension formulations provide significant advantages for certain low-solubility drugs which are very poorly absorbed after oral administration.
F. LIPOLYSIS SYSTEMS
The advantage of the microemulsion approach lies in the high surface area presented by the microemulsion particles, which are essentially surfactant micelles swollen with solubilized oil and drug. This high surface area facilitates the rapid diffusion of drug from the dispersed oil
phase into the aqueous intestinal fluids, until an equilibrium distribution is established.
Thereafter, as drug is removed from the intestinal fluids via enterocyte absorption, it is quickly replenished by the flow of fresh material from the microemulsion particles.
FORMULATION USING THE LIPOLYSIS SYSTEMS
In addition to promoting the solubility of drug compounds, lipid formulations can also facilitate dissolution by taking advantage of lipolysis. This is because the lipid components of a softgel fill matrix, which comprise triglycerides or a partial (mono-/di-) glyceride, are often subject to intestinal fat digestion or lipolysis.
Lipolysis is the term used to describe the action of the enzyme pancreatic lipase on
triglycerides and partial glycerides, to form 2-monoglycerides and fatty acids. These 2-
monoglycerides and fatty acids, known as lipolytic products, then interact with bile salts to form small droplets, or vesicles. These vesicles are broken down into smaller and smaller vesicles, ultimately resulting in the formation of mixed micelles that are approximately 3-10 nm in size.
If a drug compound possesses higher solubility in lipolytic products than in triglyceride oils, then it is advantageous for lipolysis to occur in the intestinal lumen. In this way, the process of lipolysis promotes the formation of an excellent dissolution medium for the drug, namely lipolytic products. On the other hand, the absorption of a drug compound may be adversely
affected by the presence of bile salt, and in such a case it may be advantageous for lipolysis to be reduced or blocked completely. It has been found that certain hydrophilic and lipophilic surfactants have the ability to block or promote lipolysis respectively.These hydrophilic and
lipophilic surfactants are often used in softgel fill matrix formulations.
PRODUCT QUALITY CONSIDERATIONS
INGREDIENT SPECIFICATIONS
All of the ingredients of a softgel are controlled and tested to ensure compliance with pharmacopoeial specifications. However, additional specification tests may be added for certain excipients in order to ensure the manufacture of a high-quality softgel product. For example, it is important to limit certain trace impurities, such as aldehydes and peroxides which may be present in polyethylene glycol. The presence of high levels of these impurities gives rise to cross-linking of the gelatin polymer, leading to insolubilization through further polymerization. On prolonged storage this can lead to slow dissolution of the capsule shell and subsequent retarded drug release.
The ingredient requiring the most careful control is gelatin itself. Once a particular grade of gelatin is used in a softgel formulation the quality is controlled using parameters such as the viscosity of a hot solution and the bloom strength of the gel (bloom strength is a measure of the
hardness of a gel).
IN-PROCESS TESTING
During the encapsulation process the four most important tests are:
- The gel ribbon thickness
- Softgel seal thickness at the time of encapsulation
- Fill matrix weight and capsule shell weight
Softgel shell moisture level and softgel hardness at the end of the drying stage.
FINISHED PRODUCT TESTING
Finished softgels are subjected to a number of tests in accordance with compendial
requirements for unit dose capsule products. These normally include
- capsule appearance
- active ingredient assay and related substances assay, as well as
- fill weight,
- content uniformity and
- microbiological testing.