INNOVATION IN CAPSULE DOSAGE FORM

LIST OF CONTENTS -

Introduction Innovations in capsules

1 . Innovation in capsule shells

2 . Innovation in capsule system Newer technologies Current research Reference

MAINLY TWO TYPES

1. HARD GELATIN CAPSULE 2. SOFT GELATIN CAPSULE

Some of the innovations are targeted to: Overcome the disadvantages associated with

conventional capsules. Achieve modified drug release. Encapsulation of various kind of material. Modified applications

Capsules are use for filling different materials like                                                                                                                                                                                       

Powder Granules Beads

PastesCapletsTablets

INNOVATIONS IN CAPSULES: Innovations in Capsule Shells: it includes

modification of capsule shell to improve shell property.

Improvement in the shell property Provide physical strength Protection from moisture Protection from microbial contamination Protection from light and oxygen Improve compatibility of fill material with capsule shell

Innovations in Capsule System: it includes modification of the system to achieve modified release.

1 INNOVATIONS IN CAPSULE SHELLS:

IT INCLUDES:

Non animal Capsule  Animal Capsule

HPMC Capsules Gelatine/ PEG Capsules Pullulan Capsules Coni-Snap®

Capsule(OceanCaps) PVA Capsule Press-fit® Gelcaps Starch Capsule LiCaps® V Caps® Posilock Minicapsule

1. NON-ANIMAL CAPSULE SHELL

A. HPMC CAPSULES(HYPROMELLOSE):

Hypromellose as a release controlling polymer with diffusion and erosion controlled release

Features :• Chemically stable.• Low moisture content than Gelatin capsule, Less brittle • Fast dissolution • Lower water vapor permeability than Gelatin capsule.

(Gelatin>PEG-Gelatin>HPMC)• High tolerance to temperature • Chemical inactivity

QUALI-V®-I: A New Key for Dry Powder Inhalers

Superior physical performance a moisture content.

Content could easily arises in the usage of DPI with capsules.

Better cutting & puncturing performance. Elimination of the generation of shell

particles in use.

B. PULLULAN CAPSULES:Pullulan is a neutral glucan (like Amylose, Dextran,Cellulose)

Water-soluble polysaccharide • Derived by bacterial fermentation from corn.• odorless, tasteless, and completely biodegradable .• Dried capsules are comparatively weak in physical strength • Requires water to act as a film plasticizer, which may have a negative

effect on active ingredients.

NP CapsTM: Made up of pullalan.

Pullulan is very stable and well-characterized, and has achieved wide regulatory acceptance with its proven safety record.

No chemical modification, Starch-free, Preservative-free, Gluten-free.

C. PVA CAPSULES:Insoluble drugs can be dissolved in solvents such as

macrogol 400, being filled in capsules. The bioavailability of insoluble drugs can be improved

very much. E.g. PONDAC Capsule (name)

D. STARCH CAPSULES: Manufactured by the injection moulding technique developed by Capsugel

(Capill®). Sealing is achieved by applying a hydro alcoholic solution to inner section of

the cap, immediately prior to its being placed on to the body.

Offers advantages like. pH independent dissolution Suitable for enteric coating Tamper evident

Enteric starch -Coating of starch capsules appear to be less problematic becoz of the

smooth seal, coupled with the higher bulk densityof the capsules, which provides for s more uniform coating bed.

VCaps®:

Two-piece capsules made from cellulosic raw materials

Vcaps capsules are also starch-free, gluten-free and preservative-free

Easy to swallowEffectively mask taste & odor

2. ANIMAL CAPSULE SHELL

A. Ocean CapsTM: It contain all-natural marine supplements Ideally suited for fish-eating vegetarians looking for

fish capsules, and marine supplements such as fish oil, DHA, salmon liver oil, shark cartilage, glucosamine iron,zinc, calcium and vitamins B2 and B12 .

B. PRESS FIT® GELCAPS: consisting of a high-gloss gelatin coating that encases

a caplet core.

Manufactured by exclusive cold- shrink process Press-fit gelcaps combine the best qualities of a

gelatin capsules with the density of a tablet, creating an exciting new dosage form that can be custom engineered to meet specific product performance criteria.

C. LICAPS®: specially designed to be sealed for secure containment of

liquids and semi-solids. They may be filled at temperatures up to 70° C.

D. POSILOK®: The locking system used by Qualicaps. It ensures that the contents reach the consumer intact, and

are protected at all times from external contamination.

E. GELATIN/PEG CAPSULES: Reduce the brittleness of standard gelatin

capsules when exposed to a low-moisture content thus making the capsules more compatible to hygroscopic formulations or moisture-sensitive ingredients

At moisture content b/w 8-12 %, gelatin / PEG capsules have equivalent mechanical strength to standard capsules with moisture b/w 13-16 %.

Gelatin/PEG Features Less brittle Good for hygroscopic formulations Good for moisture-sensitive ingredients Odorless, tasteless Three-year shelf life

MINICAPSULES (SIZE 9) Minicapsule dimensional specifications Minicapsules are available in both gelatin and

hypromellose (HPMC) options.

CAPACITY25 mm3

CAP LENGTH 4.3 mm +/- 0.30 mm

BODY LENGTH 7.3 mm +/- 0.30 mm

CAP DIAMETER 2.65 mm +/- 0.10 mm

BODY DIAMETER 2.40 mm +/- 0.10 mm

CLOSED JOINED LENGTH

8.40 mm +/- 0.30 mm

WEIGHT 9.5 mg +/- 2 mg

INNOVATIONS IN CAPSULE SYSTEM:To provide modified release :

PORT CAPSULE TECHNOLOGY: HYDROPHILIC SANDWICH (HS) CAPSULE L-OROS® PULSINCAP CHEWABLE SOFT GELATIN CAPSULE

ENCAPSULATING LIQUID FILL INNERCAP TECHNOLOGY GALACTICLES

1. PORT CAPSULE TECHNOLOGY:eg.Pseudoephedrine delayed release

2 . HYDROPHILIC SANDWHICH(HS) CAPSULES: time delayed probe capsule , This effectively created a “

Hydrophilic Sandwich “ between two gelatin capsule .

When the outer capsule dissolved, the sandwich of HPMC formed a gel barrier layer that provided a time delay before fluid could enter the inner capsule and cause drug release

3. L-OROS®:

Controlled Release of Non-Aqueous Liquid Formulation L-OROS Hard cap L-OROS Soft cap Delayed liquid bolus delivery systemconsists of liquid drug, an osmotic engine or push

layer and a semi permeable membrane coating ◦Advantages:

Enhanced bioavailability of class II drugs Uniform blood levels over specific period of time Reduced first pass effect Reduced dose Patient compliance Made of pharmaceutical acceptable excipient

1.L-OROS HARD CAP:

The drug layer and the osmotic engine are encased in hard capsule which is surrounded by the rate controlling semi permeable membrane.A barrier layer composed of an inert substance separates the drug layer from osmotic engine.A delivery orifice is laser drilled at the opposite end of the osmotic engine providing an outlet for the drug.

•The liquid drug formulation is encased in soft capsule. It is in turn surrounded by a barrier layer, osmotic engine, and a semi permeable membrane in order.•A delivery orifice in drilled through semi-permeable membrane,osmotic engine and barrier layer.

DELAYED LIQUID BOLUS SYSTEM:

Delivers the pulse of the liquid drug.The system consists of the placebo delay layer, a liquid drug layer, an osmotic engine all encased by a subcoat and then surrounded by semi-permeable membrane.

4. Innercap technology

The combination example consists of a high potency insoluble active in a lipid emulsion, sustained release tablet and a cocktail of two crystalline active materials.

A combination of release profiles can be incorporated in the system.

FINISHED INNERCAP

5. PULSIN CAP:Used for pulsatile drug delivery.consists of insoluble capsule body and a soluble

capsule cap.

GalacticlesTM Oral Lipid Matrix in Liquid-Filled Softgel Capsules: A Novel Drug Delivery System for Improved Oral Bioavailability & improve the formulation of poorly soluble drugs, administered in liquid-filled softgel capsules.

(Drug development & delivery Issue Date: Vol. 2 No. 7 October 2002)

50% neutral lipids (mono-, di-, and tri-glycerides), and 50% polar lipids (mixed galactolipids and phospholipids, 70:30) called galactolecithin

6. GalacticlesTM

NEWER TECHNOLOGIES :

1. ORBEXA® TECHNOLOGY:

It produces beads that are of controlled size and density and suitable for formulation as controlled release multiparticulates - using granulation, spheronization and extrusion technique.

The resultant beads can be coated with functional polymer membrane for additional release rate control and may be filled into capsules

Advantages of Orbexa Aqueous or solvent-based granulation High-speed process is well suited for

sensitive molecules like proteins Suitable for high drug loading

2. EURAND MINITABS® TECHNOLOGY: Eurand's microencapsulated drugs can be taste-

masked and directly compressed with Advatab to ensure an optimised drug delivery process.Microcaps® - microencapsulation of drug particles via a proprietary coacervation technique for uniform, precise taste-masking

3. SODAS® TECHNOLOGY:

SODAS® (Spheroidal Oral Drug Absorption System) is particulate drug delivery system.

SODAS® Technology is based on the production of uniform spherical beads of 1-2mm in diameter containing drug plus excipients and coated with product specific controlled release polymers.

4. CODAS® TECHNOLOGY: Chronotherapeutic Oral Drug Absorption

System(CODASTM Technology) was developed to achieve this prolonged interval.

Delay is introduced by the level of release controlling polymer applied to the drug loaded beads. The release controlling polymer is a combination of water soluble and water insoluble polymers.

As water from the GIT contacts the polymer coat beads, the water soluble polymer slowly dissolves and the drug diffuses through the resulting pores in the coating.

The water insoluble polymer continues to act as a barrier, maintaining the controlled release of the drug.

5. PRODAS® TECHNOLOGY:

which is unique in that it combines the benefits of tabletting technology within a capsule.

It can be used to pre-program the release rate of a drug.

PRODAS® technology, by incorporating minitablets with different release rates, can display the characteristics of a number of different conventional dosage forms:

delayed release component for site/regional release and/or food resistance

sustained release component for additional controlled release/profile extension

6. BANNER’S VERSETROLTM TECHNOLOGY:

Drug is incorporated in lipophilic or hydrophilic matrix and that is than incorporated in soft gelatin capsule shell.

7. Bijel Capsules: Co-release Micro-gel

new generic route to gel capsule formulation, involving particles suspended in fluid-bicontinuous mixture of two solvents.

The bijel capsules are made of two fluids and hence they are both a gel and an emulsion. The water and oil domains inside the capsules can be used to deliver chemically different active ingredients. The capsules can be designed to release or mix the active ingredients in response to a specific external stimulus.

Chewable SGC require mixture of gelatin having different bloom values.

Most preferable combination ration : 3:1 to 5:1 It contains ingredients like,

Low bloom gelatin Medium bloom gelatin Placticizers Water Moisture retaining agent Other

Chewable soft gelatin capsule encapsulating liquid fill

    Jintan Capsule

Mira cell Soft Capsule Hard capsule

APPEARNCE                                                         

MANUFACTURING

DROPPING METHODFILLER ROTARY DIE PROCESS DIPPING METHOD

SHELL RATIO

10%~ 30%~ 20~50%

DIAMETER 0.3mm~10mm 5mm~20mm 10mm~21mm

CONTENTLIPOPHILIC

HYDROPHILICPOWDER

LIPOPHILICPOWDER IN SUSPENSION

POWDER

SHELL MATERIAL

GELATINAGAR

NATURAL GELLING SUBSTANCE

GELATINGLYCERIN

GELATINGLYCERIN

SHELL FUNCTION

HEAT RESISTANCEACID RESISTANCE

FREEZING RESISTANCENO FUNCTION NO FUNCTION

CHARACTERISTICS

FUNCTIONS CAN BE ADDED TO THE SHELL.POSSIBLE TO DESIGN

MULTIPLE LAYER CAPSULES

SHELL THICKNESS IS LARGE ENOUGH TO JOINT

TWO PCS OF GELATIN SHEETS.

USE OF GLYCERIN CAN CAUSE BLOCKING.

ONLY AVAILABLE FOR POWDER, NOT

LIQUID AS CONTENT.NO USE FOR SMALL

CAPSULES.

NifedipineGel-filledCapsule

Procardia (Pratt)Adalat (Bayer)

10 and20 mg/capsule

Glycerin, peppermintoil, PEG, softgelatin capsule

Swallow whole,bite and swallow,or bite and holdsublinguall

10 Approx 2 hr

Drugs and Dosage Forms Used for Oral Transmucosal system

Drug Brand Name Availability Formulation/ Dose/ Onset of Duration of

(Manufacturer) Excipients Directions Action (min) Action

EXAMPLES OF MARKETED PRODUCTS FORMULATIONSDrug Name

Compound Dosage form Company Indication

Neoral® Cyclosporine Soft gelatin Capsule Novartis ImmuneSuppressant

Norvir® Ritonavir Soft gelatin capsule AbbottLaboratories

HIV antiviral

Fortovase® Saquinavir Soft gelatin capsule Hoffmann-LaRoche

HIV antiviral

Agenerase® Amprenavir Soft gelatin capsule GlaxoSmithkline

HIV antiviral

Convulex® Valproic acid Hard gelatin Capsule Ligand Antiepileptic

Lipirex® Fenofibrate Soft gelatin capsule Genus Antihyperlipoproteinemic

Sandimmune®

Cyclosporine Soft gelatin capsule Pharmacia ImmunoSuppressant

CURRENT RESEARCH Invitro – invivo evaluation of a novel capsule for colon specific

drug delivery (JPS Vol. 98 No. 08 Aug. 2009 Page no. 2626)

A novel approach to prepare insulin-loaded poly ( lactic –co-glycolic acid microcapsule) (JPS Vol. 98 no.05 May 2009 page no.1712)

Effect of lipophilic compounds on the compatibility of lipid based formulation with HG capsules. (JPS Vol. 99 no.01 Jan 2010 )

The Bilayer floating capsule : A stomach – directed drug delivery system for misoprostol. ( Pharmaceutical research Vol. 9 No.3 1992)

Self micro emulsifying drug delivery system (IJPS Vol-1, Issue-2, 2010)

Self micro emulsifying drug delivery systems are isotropic mixtures of oil, surfactant, co-surfactant and drug with a unique ability to form fine oil in water microemulsion upon mild agitation following dilution with aqueous phase.

Pulsatile delivery systems: An approach for chronotherapeutic diseases (Year : 2010  |  Volume : 1  |  Issue : 1  |  Page : 55-61)

Marketed technologies such as PULSYS™, CODAS® , TIMERx® , and DIFFUCAPS® follow one of the above mechanisms to render a sigmoidal drug release profile.

Novel iron- polysaccharide multilayered microcapsule for controlled insulin release.

(C.A. vol. 150 no. 22, 2009 page no. 1469)

cholesterol mediated anchoring of enz. Loaded liposomes within disulfide stabilized polymer carrier capsule. (C.A. vol. 150 no. 21 , 2009 page no. 1479)

achieved by non covalently sandwiched the liposomes b/w a tailor made cholesterol modified poly(-lysine) precursor layer & a poly ( methacrylic acid) –co- (cholesteryl methacrylate) capping layer.

COATING METHOD FOR SOFT GELATIN CAPSULES WITH IMPROVED STABILITY .

(Ref: Chemical Abstracts, Vol 151, Number 13, September 28,2009 , Page2156, 297838p)

Adding 10-90% ethanol into mixture of HPMC 20-150parts, Tween80 8.5-25vol parts, Titanium white powder 7.5-25wt parts, Talc powder 7.5-25wt parts, 2%chocolate brown solution, 7.5-25wt parts, castor oil 15-40 vol parts to obtain coating solution, regulating flow rate of coating material at 25-40°C under relative moisture of 20-60%.

hydrocapsule : A new method for aqueous drug delivery.

(C.A. vol. 149 no. 2 2008 page no. 1479)

development of boron nanocapsule for neutron capture therapy.

(C.A. vol. 150 no. 22, 2009 page no. 1455)

Cross-linked DNA capsules templated on porous calcium carbonate microparticles: (Colloids and Surfaces A: Physicochemical and Engineering Aspects, Volume 356, Issues 1-3, 5 March 2010, Pages 126-133)

first, DNA was adsorbed onto calcium carbonate microparticles, and then the adsorbed DNA was covalently cross-linked with each other by using ethylene glycol diglycidyl ether.

This method has the potential to be used for the preparation of various single-component polymer capsules.

LIST OF REFERENCE Chemical Abstracts, Vol 151, Number 13,

September 28,2009 , Page no. 2156 JPS Vol. 98 No. 08 Aug. 2009 Page no. 2626 JPS Vol. 98 no.05 May 2009 page no.1712 JPS Vol. 99 no.01 Jan 2010 JPS Vol. 69 no.04 April 2007 page no. 479-488 Pharmaceutical research Vol. 9 No.3 1992 Angewandte Chemie International Edition

Volume 49, Issue 39, pages 6954–6973, September 17, 2010)

IJPS Vol-1, Issue-2, 2010 Drug development & delivery Issue Date: Vol. 2 No.

7 October 2002

Journal of Pharmaceutics and Cosmetology Vol 1: 2 (2011) page no 56-66

Drug development & delivery Issue Date: Vol. 2 No. 7 October 2002

www. morishita jintan co.ptd http://en.wikipedia.org/wiki/

Encapsulation_(pharmacology) www.innercaps.com www.capsugel.com http://www.emisphere.com http://www.qualicaps.co.jp/ http://www.capstech.com.cn  C.A. vol. 150 no. 22, 2009 page no. 1469 C.A. vol. 149 no. 2 2008 C.A. vol. 150 no. 21 , 2009

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