Professional Documents
Culture Documents
A Review of Progress and Challenges in Soft Gelatin Capsules Formulations For Oral Administration
A Review of Progress and Challenges in Soft Gelatin Capsules Formulations For Oral Administration
discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/215701596
ARTICLE in INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES REVIEW AND RESEARCH · OCTOBER 2011
CITATIONS READS
5 5,308
2 AUTHORS, INCLUDING:
Were L. L. Munyendo
Moi University
11 PUBLICATIONS 89 CITATIONS
SEE PROFILE
Review Article
formulation. Cyclosporin does give therapeutic blood gold Lippo plant capsules. The polymer material Hydroxyl
levels which are not achievable from tablet form. Similarly Propyl Methyl Cellulose (HPMC) have also been explored,
oral hypoglyceamic glipizide in softgel is also known to the odorless, milky, fibrous or granular powder, from lint
have better bioavailability results compared with tablet or wood pulp, dissolves completely in cold water but is
form. Softgel delivery systems can also incorporate almost insoluble in ethanol and other organic solvents.
phospholipids or polymers or natural gums to entrap the FDA has highlighted it as a non-active component that can
drug active in the gelatin layer with an outer coating to be used for ophthalmic preparations, oral capsules and
give desired delayed/control release effects7. suspensions5. The gelatin made of hypromellose and
pullulan displays chemical stability, friability, low moisture
The designs for a specific soft gelatin capsule formulation 10
content and oxygen absorption rate .
involve appropriate selection of the shell and fill
composition. This is followed by optimization of the two
PROGRESS IN SOFT CAPSULES LIQUID-FILL MATERIALS
to allow for efficient production of a chemically and
physically stable product with the desired The formulations of capsule fill have been developed to
biopharmaceutical properties. The shell of a soft gelatin fulfilling specifications and end-use requirements of the
capsule is composed of gelatin, a plasticizer or a product. Capsulation of liquids that are immiscible with
combination of plasticizers and water. In addition, it may water and non- volatile, such as vegetable oils and
contain preservatives, colouring and opacifying agents, vitamin E, have been easily made requiring little or no
flavourings and sweeteners, possibly sugars to impart formulation. However, solids which are not sufficiently
chewable characteristics to the shell, gastroresistant soluble in liquids are reported to be capsulated as
substances and in special cases even active compounds8. suspensions having a particle size of 80 mesh or finer11.
The formulation of the fill is individually developed to
A large group of dietary products are reported to have
fulfil the requirements for optimum therapeutic action.
been commonly capsulated in suspensions form. The two
This entails optimizing the chemical stability of the active
suspension formulation gel production equipment widely
compound to improve bioavailability. Emphasis is also put
utilized domestically is the Chatsworth Machine and the
on efficient and safe filling process in order to achieve a
GIC Engineering. Basically all these machines produce soft
physically stable capsule product6.
gels in a similar manner, they have rotating dies and an
independent wedge with a pump that control the fill7.
PROGRESS IN SOFT CAPSULE SHELL MATERIALS
Filling of soft gel capsules with liquid and semi-solid
Different types of capsule constitutive materials are materials has been successful carried out with selected
usually selected for different products. Apart from the "fillings" that do not dissolve the gelatin11.
traditional gelatin, in recent years new materials have
Donato and group (2008) showed that the following types
been explored and their application in the development
of compounds may not be suitable candidates for soft gel
of capsules is progressing rapidly5.
encapsulation12:
Traditionally used gelatine materials
Liquids that can easily migrate through the gelatin
Due to their availability, animal skins and bones have shell, such as water hygroscopic and volatile
been used extensive as a source of raw material for the compounds. Water soluble compounds that may
formulation of the shell of gelatin capsules. Their affect the gelatin shell unless they are minor
excellent film-forming ability and mechanical stability constituents of a formula or combined with a carrier
properties of gelatin result in the desired physical that reduces their effect on the shell.
properties. Furthermore they can be re-cycled and retain
6 Aldehydes, which have the ability to harden the shell
their good performance . The gelatin made from the
and hence affect its dissolution property.
traditional material like animal skin, bone, tendon and
collagen have been noted to meet the necessary Acidic or alkaline solutions should be avoided, unless
pharmaceutical requirements as being quickly hydrolysed they are adjusted to become neutral; acids and
by gastrointestinal enzymes. In addition they contain a alkalis can cause hydrolysis and leakage of the
variety of nutritious amino acids. The purified products gelatin shell.
obtained therefore are easily swallowed and rapidly
absorbed5. THE SOFT GELATIN CAPSULES AS A DOSAGE FORM
Development of news materials Improved drug absorption is the primary reason for
selection of softgel as a dosage form. Nevertheless as a
In the recent past a number of new sources of raw
drug delivery system for oral administration of
materials for the gelatin capsule shell have been
therapeutic agent several advantages as well as
reported. This range from natural resources like fish to
disadvantages have been reported with soft gelatin
polymers, the fish gelatin has been obtained from fish
capsules;
skin products and formulated as natural hollow capsules
of fish oil, spirulina and cellulose9. Natural herbal capsules
have been reported as concentrated herbal capsules of
supplements, such as cod liver oil that come in both liquid disintegration speed, higher bioavailability and
and soft gel capsules form. In most cases, the price is convenient ingestion.
greater for the soft capsules than for the liquid. 3 The capsule can cover unpleasant odor of the
Sensitive to heat and moisture medicine.
The capsule has been made into instant-effective,
The effective dissolution of gelatin in the body has been
slow-releasing, enteric coated or gastro coated soft
attributed to it’s extremely water solubility. On the other
gelatin capsule.
hand in regard to shelf stability it has been realized that
this is a drawback given soft gelatin capsules are very Achievement has been reported in formulation of
sensitive to heat and humidity. In hot or humid climates, medicines with dosage form of higher oil
soft gel caps may stick together or even break open and concentration that cannot be easily made into
this decreases their life expectancy8. tablets or pills and small dosage principle agent that
is not water-soluble and hard to be ingested in the
Dietary restrictions digestive.
Gelatin is traditionally made out of the bones and skins of Soft capsules technology have facilitated light-
pigs and cows. Many groups, however, have dietary sensitive and unstable drugs to be filled into opaque
proscriptions that prevent them from consuming animal lightproof opageopa capsule to improve the stability
products found in soft gelatin capsules. Soft gel caps and prevent the drug from been affected by
violate the religious dietary restrictions of observant moisture, oxygen and light in the air.
Jews, Muslims, Buddhists and Hindus. Because soft
Advances have enabled soft gelatin capsules to be used to
capsules are made out of animal parts, many vegetarians
make neutriceuticals, cosmetics and paintball for
also opt not to use them. Due to this there is an
simulated shooting27.
emergence of animal-free substitute gelatin capsules
made out of seaweed extract or other sources, but they Challenges in development of soft gelatin capsule
are generally more expensive and harder to find9.
Although the formulation of drugs into softgel capsules
has been reported to solve many problem associated with
ADVANCES AND CHALLENGES IN SOFTGEL CAPSULES
tableting including poor compaction, lack of content or
DEVELOPMENT
weight uniformity, and other powder flow or mixing
Advances in development of softgels as a dosage form. problems10, several problems affecting the development
of softgel capsules have been revealed.
Soft gelatin capsules have received enormous consumer
acceptance due to their numerous advantages over other Poor differentiation and /or mismatching of gel material
traditional dosage forms such as tablets and even hard added to cross-linking with the drug. The stability of an
capsules22. It has become not uncommon for API in a liquid dosage form, as opposed to a solid dosage
pharmaceutical companies to reformulate marked solid form is, in itself, a challenge, as is matching the
dosage form in the form of soft gelatin capsules in order formulation with the characteristics of the capsule shell
improve consumer acceptability owing to dissolution in and the dosing system of the capsule filling machine. In
the gastrointestinal tract of drugs formulated as soft cases where gelatin as a capsule material is not suitable,
gelatin capsules23. alternative polymers for capsule production may be
exploited28.
Advancement of softgel capsules are traced back to
Fuccella et al study which showed that, softgel capsules Another phenomenon seen in capsules, especially softgels
of temazepam ensured a more rapid and complete is extensive cross-linking to the gelatin, which could occur
absorption of the drug and seemed to be an appropriate during storage and result in the formation during
pharmaceutical form for treatment of sleep dissolution testing of swollen, rubbery water-insoluble
24
disturbances . This observation led to the development membranes known as pellicles that have been reported
of the soft gel capsules and assessment of bioavailability to act as barrier to drug release12.
of the formulation, plasma levels of temazepam
The major challenge in the development of the softgel
determined in healthy volunteers25. Formulation of a
dosage form is that the system is very dynamic in terms
hydrophobic amine antimalarial with oleic acid in softgel
of;
capsules has been reported as an advancement which
resulted in the enhancement of bioavailability26. The physical migration of components between the
shell and the fill and the shell and the external
Several advances have been made in the development of
environment,
softgel capsules including;
The occurrence of physical and chemical interactions
Ensuring of suitable physical features. The soft
within and between the shell and fill components21.
gelatin capsule has been developed to have a tidy
and beautiful appearance compared to tablet pills. It is critical to understand these interactions to develop a
These features have been reported to ensure faster softgel product that is stable and provides desired in vitro
and in vivo characteristics.
International Journal of Pharmaceutical Sciences Review and Research Page 23
Available online at www.globalresearchonline.net
Volume 10, Issue 1, September – October 2011; Article-004 ISSN 0976 – 044X
CONCLUSION 12. Donato EM, Martins LA, Froehlich PE and Bergold AM.
Development and validation of dissolution test for lopinavir, a
Interesting advances have recently been made in the area poorly water-soluble drug, in soft gel capsules, based on in vivo
of developing liquid and semi-solid formulation in a soft data , Journal of Pharmaceutical and Biomedical Analysis 2008, 47:
547–552.
gelatin capsule to address particular bioperformance
13. Azarmia S, Roa W and Lobenberg R. Current perspectives in
issues, namely an increase of bioavailability and decrease dissolution testing of conventional and novel dosage forms.
of plasma variability by improving solubility and International Journal of Pharmaceutics 2007, 328: 12–21.
absorption-enhancing techniques. 14. Horter D and Dressman JB. Influence of physicochemical properties
on dissolution of drugs in the gastrointestinal tract. Advanced Drug
Although the softgel capsules have many advantages, Delivery Reviews 2001, 46: 75–87.
they also face stability problem, mainly for the soft 15. Lissy M, Scallion R and Stiff DD. Pharmacokinetic comparison of an
capsules stored for longer than six months. After this oral diclofenac potassium liquid-filled Soft gelatin capsules with a
time, their soluble products decreased, and the remnants diclofenac potassium tablet. Expert opin pharmacother 2010,
cannot be re-dissolved and/or reabsorbed into the gastro- 11(5):701-8
intestinal tract. These problems could be investigated as a 16. Scallion R and Moore KA. Effects of Food Intake on the
Pharmacokinetics of Diclofenac Potassium Soft Gelatin Capsules: A
research subject.
Single-Dose, Randomized, Two-Way Crossover Study, Clinical
The proper designs for a specific softgel capsules Therapeutics 2009, 31:10.
formulation requires the appropriate selection of shell 17. Ciper M and Bodmeier R. Preparation and characterization of novel
fast disintegrating capsules (Fastcaps) for administration in the oral
and fill composition and the optimization of the two to cavity. International Journal of Pharmaceutics 2005, 303: 62–71.
allow for the efficient production of a chemically and
18. Lissy M, Scallion R and Stiff DD. Pharmacokinetic comparison of an
physically stable product with the desired oral diclofenac potassium liquid-filled Soft gelatin capsules with a
biopharmaceutical properties. diclofenac potassium tablet. Expert opin pharmacother. 2010,
11(5):701-8.
REFERENCES 19. Vegicaps Softgel Technologies People, facilities and technologies to
deliver superior softgel solutions. Copyright 2007 Catalent Pharma
1. Reich G, Podczeck F and Jones BE. Formulation and physical Solutions.
properties of soft capsules. 2004, - Medical - 272 pages
20. Sima JS, Juna G, Toidab T, Choc SY, Woong D, Seung-Yeup C,
2. Bussemer T and Bodmeier R. Formulation parameters affecting the Linhardtd RJ and Kima YS. Quantitative analysis of chondroitin
performance of coated gelatin capsules with pulsatile release sulfate in raw materials, ophthalmic solutions, soft capsules and
profiles. International Journal of Pharmaceutics 2003, 267: 59–68. liquid preparations. Journal of Chromatography B, 2005, 818: 133–
3. Softgel Technologies People, facilities and technologies to deliver 139.
superior softgel solutions. 21. Martins GZ, Souza CRF, Shankar TJ and Oliveira WP. Effect of
http://www.catalent.com/pharma/pdf/Softgel_Technologies_Oral process variables on fluiddynamics and adhesion efficiency during
_Technologies. Accesed 2010/11/19. spouted bed coating of hard gelatine capsules. Chemical
4. Nazzal S. and Wang Y. Characterization of soft gelatin capsules by Engineering and Processing 2008, 47: 2238–2246.
thermal analysis International Journal of Pharmaceutics 2001, 230: 22. Yang D, Li Y and Nie J. Preparation of gelatin/PVA nanofibers and
35–45 their potential application in controlled release of drugs.
5. Karim AA and Bhat R. Fish gelatin: properties, challenges, and Carbohydrate Polymers 2007, 69: 538–543.
prospects as an alternative to mammalian gelatins. Food 23. Frutos G, Prior-Cabanillas A, París R and Quijada-Garrido I. A novel
Hydrocolloids 2009, 23: 563–576. controlled drug delivery system based on pH-responsive hydrogels
6. Marques MRC, Cole E, Kruep D, Gray V, Murachanian D, Brown WE included in soft gelatin capsules. Acta Biomaterialia 2010, 6 (12):
and Giancaspro GI. Liquid-filled Gelatin Capsules. Pharmacopeial 4650-4656
Forum 2009 Vol. 35(4). 24. Fuccella LM, Tosolini G, Moro E and Tamassia V. Study of
7. Pearnchob N, Dashevsky A and Bodmeier R. Improvement in the physiological availability of temazepam in man, Int. J clin
disintegration of shellac-coated soft gelatin capsules in simulated Pharmacol. 1972, 6 (4):303-309.
intestinal fluid. Journal of Controlled Release 2004, 94: 313– 321 25. Lucas RA, Bowtle WJ and Ryden R. Disposition of Vancomycin.in
nd
8. Shanker G and Tabibi E. Water insoluble Drug Formulation, 2 healthy volunteers from oral solution and Semi-solid matrix
Edition, CRC Press 2008. capsules. Clin.Pharm.ther. 1987, 12: 27-31.
9. R & D progress of hollow capsules - capsule, new materials, coating 26. Gershanik T and Benita S. Self-dispersing lipid formulations for
materials -the pharmaceutical industrie. improving oral absorption of lipophilic drugs. European Journal of
http://news.frbiz.com/pharmaceutical_excipients_ply. Accessed Pharmaceutics and Biopharmaceutics 2000, 50: 179-188
2010/12/21. 27. Mei X, Etzler FM and Wang Z. Use of texture analysis to study
10. Colea ET, Cadé D, and Benameur H. Challenges and opportunities hydrophilic solvent effects on the mechanical properties of hard
in the encapsulation of liquid and semi-solid formulations into gelatin capsules. International Journal of Pharmaceutics. 2006,
capsules for oral administration, Advanced Drug Delivery Reviews 324: 128–135.
2008, 60: 747–756. 28. Rossi RC, Dias CL, Donato EM, Martins LA, Bergold AM and
11. Riff DS, Duckor S, Gottlieb I, Diamond E, Soulier S, Raymond G and Froehlich PE. Development and validation of dissolution test for
Boesing SE. Diclofenac Potassium Liquid-Filled Soft Gelatin ritonavir soft gelatin capsules based on in vivo data. International
Capsules in the Management of Patients With Postbunionectomy Journal of Pharmaceutics 2007, 338: 119–124.
Pain. Clinical Therapeutics 2009, 31:10.
****************