MODIFIED RELEASE CAPSULES

Presented By: HIREN PATEL

M.Pharm, Sem -II

APMCCPER, Himatnagar

09586017050

LIST OF CONTENTS Introduction Innovation Related To Capsule Shell• HPMC Capsule• Starch Capsule• PVA Capsule• Chitosan Capsule• Cross linked Dextran Capsule Innovations In Capsule Fill Material Innovation In Capsule System• Pulsincap• Hydrophilic Sandwich (Hs) Capsule• L-Oros System• Port System• Targeting Lymphatic Delivery• Fast Disintegrating Capsules References

Introduction

• Capsules are dosage forms in which unit doses of powder, semisolid, or liquid drugs are enclosed within either a hard or a soft envelope or shell.

• Administration route of capsules: orally (whole or mixed with food or drink after opening capsules)

• In early 19th century, Mothes developed the first capsule dosage form from gelatin.

• Since then this technology has been continuously improved and refined in terms of capsule shell, formulation and system, yielding range of capsule forms available today

Innovation related to capsule shell(Alternatives to gelatin)

Ideal requirements for gelatin alternatives includes:• Good film forming property

• Fast dissolution in biological fluid at 37º C

• Good gelation property so that a capsule film can be cast or dipped, hence enabling existing capsule machinery to be used

• Low toxicity

1. Hydroxy Propyl Methyl Cellulose (Hpmc) Cross linking:

• HPMC hard capsules avoid the issues of gelatin cross linking and product vulnerability to aldehydes Moisture content:

• HPMC hard capsules (Quali-V®) have low moisture content

• Hard gelatin capsule breaks easily when moisture drops below 10% where as HPMC hard capsule does not crack even with 1% or less in moisture content.

Water vapour permeability:

• Water vapor permeated more rapidly through gelatin film than HPMC film. Dissolution:

• Dissolution profile of HPMC hard capsule with model drugs did not change even after capsules were stored under different conditions of temperature and humidity i.e. 30ºC and 60% RH (for 1 year), 40ºC and 75% RH (for 6 months) and 60ºC (for 1 week). While, under similar conditions when the drugs were filled into gelatin capsules the dissolution profile changed and were prolonged except for 30ºC and 60% RH

Liquid filling:

• Nonaqueous fill material can be filled into HPMC hard capsule provided they do not soften the shell Advantages:

• High commercial supply

• Capability of being processed on commonly available equipment Disadvantages:

• High cost

2. Starch Moisture content: Moisture content in starch capsules lies between 12% to 14% w/w, with more than 50% being

tightly bound to starch. The presence of this bound moisture indicates that starch capsules may provide better stability properties and reduced susceptibility to changes on storage. 

Dissolution: Similar to that of gelatin capsules Advantages: Ready for filling immediately following manufacturing Offer greater resistance to humidity and heat than gelatin and allow easy filling as they are

non-static Dissolution is independent of pH Good surface finish Coating of hard gelatin capsule with aqueous spray formulations can lead to softening of

gelatin shell or gelatin shell may become brittle due to water evaporation and drying, especially at the onset of coating. On the contrary, the coating of starch capsules seems to be less problematic because of smooth seal of the filled unit, together with the higher bulk density of the capsules, which provide a more uniform coating bed.

TARGIT™ technology based on the application of pH-sensitive coatings onto injection-molded starch capsules is especially designed for site-specific delivery of drugs in the gastrointestinal (GI) track (colon)

3. Polyvinyl alcohol(PVA) copolymer

Advantages of PVA capsule:• No animal derived material• Low water content• Low electrostatic propensity• Very low oxygen permeability• Ability to tolerate macrogol 400• PVA copolymer does not have chemically active groups such as

those in gelatin and it is more tolerable to various agents than gelatin and HPMC

4. Chitosan: Used for colon targeting as chitosan is biodegrable in colon

  

5. Crosslinked dextran: Promising candidate for colon specific drug delivery system

Innovations in capsule fill material

• Previously active ingredients were formulated into capsule in form of powder or granules for immediate or modified release. But however now a day along with them pellets, minitablets, liquids, semisolids, etc can be filled into capsule. This is heavily because of innovation in filling machines.

• Formulation considerations to be taken into mind while formulating pellets as fill material includes dose and type of release required

Drug Type of pellet capsulated

Ingredients used Uses of each ingredient

Rosiglitazone Maleate and Metformin Hydrochloride

Rapid release pellet Dibasic calcium phosphate dihydrate

Filler

Polyvinyl pyrrolidone BinderSodium Starch

GlycolateSuper disintegrant

Magnesium Stearate LubricantAlprazolam Sustain release

pelletsMicrocrystalline

cellulose Filler

Polyvinyl pyrrolidone BinderSURELEASE Sustain release

polymerNifedipine Controlled release

pelletHydroxy propyl

methyl cellulose E-6

Binder

30 D Control release polymer

Calcium stearate Antifoam suspension

Bupropion Enteric coated controlled release

pellet

Talc Antiadherant

Table 1: Patented formulation of Pellet as a fill material for hard capsule

• While formulating tablets as a fill material for hard capsule important points to be considered includes size of the tablet and type of the release required.

• Size of the tablet should be such that it can be easily filled into capsule.

• If the dose is high, then more than one minitablets can be filled into capsule.

• The same approach can be used to deliver first loading dose followed by maintenance dose by minitablet.

• Different types of tablets (Immediate or modified release) can be filled into hard capsule to get desired release

Drug Type of tablet capsulated

Ingredients used Uses of each ingredient

Riboflavin Controlled release minitablet

Aluminium oxide Weighting agentMicrocrystalline cellulose Filler, binder Polyvinyl pyrrolidone BinderMagnesium stearate LubricantEthyl cellulose or Eudragit RS Controlled release

polymerProgestrone Sustain release

osmotic minitablet

Sodium CMC Osmopolymer

Sodium chloride OsmagentsHydroxy proply methyl cellulose in water

Binder

Ferric oxide ColorantMagnesium stearate Lubricant

Lansoprazole Enteric coated minitablets

Lactose Filler

Hydroxy propyl methyl cellulose E- 5LV

Binder

Sodium starch glycolate Super disintegrantMagnesium stearate LubricantEudragit L30D 55 Enteric polymerTriethyl citrate Plasticizer used in

coating solutionPurified water Coating solvent

Table 2: Patented formulation of Minitablet as a fill material for hard capsule

• It has been found that stable preparations could be made from liquids and deliquescent materials by preparing them as a semi-solid matrix in commercially available excipients.

• Sustained release formulations have been prepared by using excipients that influences the hydrophilic-lipophilic balance (HLB) of the semisolid matrices.

• A principal constraint of such formulation is the interaction of certain excipients and/or water with gelatin.

• The choice of excipient is made in relation to capsule shell integrity

Formulation ingredients UsesPropantheline bromide Active ingredientMiglyol 829 Liquid excipientsAerosil 200 Gel forming agent

Table 3 : Example of thixotropic gel filled into hard capsule

Drug Type of material capsulated

Ingredients used Uses of each ingredient

Propranolol hydrochloride

Beads Sugar spheresPolyvinylpyrrolidone BinderEthyl cellulose Release rate

controlling polymerHydroxy Propyl Methyl Cellulose Phthalate

Enteric polymer

Diethyl phthalate Plasticizer used in coating solution

Acetone/water Coating solventTolterodine L-tartrate

Controlled release beads

Sugar spheresSurelease Release rate

controlling polymerHypromellose Release rate

controlling polymerFractionated coconut oil

Plasticizer used in coating solution

Water Coating solvent

Table 4: Patented formulation of miscellaneous material that can be filled into hard capsule

Innovation in capsule system

A: Pulsincap

• Used for pulsatile drug delivery

• Three main approaches have been tried for it

• In general pulsincap consist of insoluble capsule body and a soluble capsule cap

First approach:• Based on separation of a plug from an insoluble capsule body

• Consists of a water permeable body prepared from a water-swellable hydrogel i.e. crosslinked Polyethylene glycol (PEG)

• In cavity of capsule body, mixture of drug and a swelling agent is placed.

• Internal cavity is then sealed by a plug.

• Upon oral administration by patient, cap dissolves. Water diffuses through capsule body. Swelling causes plug to move in upward direction causing drug release.

• Water diffusion into the core through semi permeable membrane is controlled by: – Hydrogel composition and

– Wall thickness of the capsule

Plug

Drug Formulation

Swelling Agent

Water Permeable Body (Crosslinked PEG hydrogel)

Second approach: Here only difference to first approach is that capsule body is made

of gelatin coated with ethyl cellulose. In presence of fluid the plug swelled at a controlled rate and this

swelling is independent of the nature of pH of the fluid. As the plug swells it attains frustroconial shape and it gets slowly

pulled out of the capsule Pulse time is controlled by:

• The length of the plug and

• Insertion distance of plug

into the capsule

Third approach:

• Here in this approach in place of hydrogel plug, simple erodible compressed tablet is placed.

• This overcomes the need for the precise dimensional tolerance between capsule and plug for sliding mechanism of the plug

B: Hydrophilic Sandwich (Hs) Capsule

• Capsule within capsule• Between 2 capsules there is layer of HPMC

(hydrophilic polymer) creating hydrophilic sandwich between 2 gelatin capsules.

• Upon oral administration, outer capsule dissolves into the fluid. This exposes HPMC which forms gel (barrier layer). This barrier layer provides desired lag time for fluid to enter into second capsule and causing 2 lot of drug release.

• Molecular weight and concentration of polymer (HPMC) decides lag time

C: L-OROS system• Developed by ALZA corporation for liquid drug formulation,

especially for drug’s with low solubility leading to low bioavailability

• 3 types are available

1. L-OROS Hard cap

2. L-OROS Soft cap

3. Delayed liquid bolus delivery system 

• Basically L-OROS system consists of liquid drug, an osmotic engine or push layer and a semi permeable membrane coating.

• Water passes through the semi permeable membrane, expands the osmotic engine which is turn pushes the drug layer releasing the drug through a delivery orifice into the GI tract.

• The duration and rate of drug release are controlled by the composition of the membrane.

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 the osmotic engine

• A delivery orifice is laser drilled at the opposite end of the osmotic engine providing an outlet for the drug

L-OROS HARDCAP System

Before Ingestion During Release

Semi permeable membrane Push layer Barrier layer Liquid drug formulation

2. L-OROS soft cap:• 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

• When the osmotic engine expands it compresses the soft capsule and the drug formulation is pushed out through the delivery orifice

Before Ingestion During Release

L-OROS SOFTCAP System Rate controlling membrane

Osmotic layer Barrier layer Soft gelatin capsule Liquid drug formulation Delivery orifice

3. Delayed liquid bolus delivery system:• Delivers the pulse of the liquid drug.

• The system consists of placebo delay layer, a liquid drug layer, an osmotic engine all encased by a sub coat and then surrounded by semi permeable membrane.

• The delivery orifice is drilled on the placebo layer of the system

• When the osmotic engine expands, the placebo is released first delaying the drug release

• Delay in drug release can be from 1-10 hours depending on the permeability of the rate controlling membrane and the size of the placebo layer.

Delayed Liquid Bolus System

Semi permeable membraneSub coatDelay layerLiquid drug formulationOsmotic layerDelivery orifice

D: Port system• Here capsule body made up of HPMC or gelatin is

divided into two compartments by non swelling slidable separator.

• The entire capsule body is encased by semi permeable membrane.

• One or both compartment contain drug and the lower compartment below the separator contains water soluble excipients

• When the water diffuses through semi permeable membrane, the water soluble excipients contained in the capsule body are solubilized, creating the osmotic pressure gradient

• Under the influence of osmotic pressure gradient, the slidable separator start moving outside the capsule and starts releasing the initial dose

• At predesigned time, the separator completely slides out of the capsule body and the delayed dose is then released.

PORT SYSTEM

E: Targeting Lymphatic delivery

• Developed by Encap Drug Delivery Ltd

• Aim behind the development of capsule targeting the lymphatic system is to improve the absorption of low-solubility/lipophilic compounds through lymphatic absorption

• Capsule contains micro emulsion or self emulsifying system for improving solubility.

F: Fast disintegrating capsules

• Novel capsule which disintegrates within 30-45 second (in vitro) and 9-13 seconds in vivo

• Disintegrates fast (twice) than regular hard gelatin capsule

• For fast disintegrating capsule low bloom strength gelatin is used as shell material

• The disintegration time of films can be decreased further by the addition of sugars or PEGs

REFERENCES• Podczeck F. and Jones B.; Pharmaceutical Capsules; Second edition; Chapter 3- Gelatin alternatives

and additives: 61 - 63.

• Encyclopedia Of Pharmaceutical Technology.

• http://www.in-pharmatechnologist.com/news-by-product/news.asp?id=62545&k=stanelco-develops-alternative

• http://www.samedanltd.com/members/archives/PMPS/Summer2002/WilliamBowtle.htm

• http://www.qualicaps.com/

• http://www.capsugel.com/

• http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=30

• http://www.ffnmag.com/NH/ASP/strArticleID/579/strSite/FFNSite/articleDisplay.asp

• http://www.lsbu.ac.uk/water/hysta.html

• http://www.ashley-pub.com/doi/abs/10.1517/17425247.2.1.159

• U.S patent number 4,609,675 : Stable, high dose, high bulk density ibuprofen granulations for tablet and capsule manufacturing

• U.S patent number 6,258,816 : Anti-allergy anti-inflammatory composition

• U.S patent number 20050136127 : Gastrointestinal compositions

• U.S patent number 6,767,555 : Pharmaceutical compositions

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• U.S patent number 6,110,493 : Terazosin capsules