Bioinformatics, Bio-medicine and Gene Manipulation in Drug Development and Future Medical Care

nice one.

Liquid filled in hard gelatin capsules – The new dosage delivery system

Conventionally hard gelatin capsule has been used as a solid dosage form products, formulated either as powder or pellets. However, market demands new and different ways of formulation delivery to be developed and launched in minimum time period. Liquids filled into hard gelatin capsules can fulfill some of these demands and in particular to drugs for which the liquid and semi-solid filled capsule is particularly relevant.

·Drugs with poor bioavailability
·Drugs with low melting point
·Drug with low dose / High potency
·Drugs requiring better content uniformity
·Drugs requiring no Cross-contamination
·Drugs requiring increased critical stability
·Drugs with Sustained release Possibility

·Poor bioavailability: The bioavailability of the poorly water-soluble drug dioxin could be significantly enhanced when formulated as a liquid in a hard gelatin capsule. This increases the effectiveness of the drug. 

·Low melting point: Materials which have low melting points or are liquid at room temperature present difficulties when formulating as dry powders, often requiring high concentrations of excipient to avoid processing problems. The manufacturing process can be considerably simplified (five step process to manufacture a tablet can be reduced to a simple mixing and filling operation) by filling as a hot melt into a hard gelatin capsule.  Consumer acceptance was also enhanced due to the smaller size of the final dosage form.  

·Low dose / High potency: Drugs in this category present two main challenges; how to achieve acceptable content uniformity and how to control cross-contamination and worker protection. This type of drugs can be delivered easily in liquid dosage in hard gelatin capsule. 

·Content uniformity: The liquid filling operation is capable of achieving fill weight variations of < 1%. If a drug sub-stance is in solution or is uniformly dispersed in a liquid vehicle then it follows that good drug content uniformity can also be achieved (Triamterene at 25µg.)

·Cross-contamination: Companies manufacturing solid dosage forms of hormones and cytotoxic agents from powders are forced to install extremely elaborate systems to reduce contamination. Incorporation of the highly potent agent into a liquid for filling into a hard gelatin capsule can reduce the dangers when working with such drugs. 

·Critical stability: Sensitivity to moisture is an aspect of formulation, which can be minimized by incorporating the drug into either a hydrophilic or lipophilic matrix. For example, the antibiotic vancomycin hydrochloride is highly hygroscopic and to achieve acceptable stability it needed to be formulated as a lyophilized powder for reconstitution. (Hard gelatin capsule filled with a PEG 6000 matrix). 

·Sustained release: By choosing an appropriate excipient the release rate of an active can be modified. For example Gelucire, which is available as a semi-solid with a range of melting points and HLB values, can be mixed to obtain different drug release rates compared the bioavailability of an oily semi-solid matrix of captopril in hard gelatin capsules with that of a tablet. 

Looking beyond the formulation advantages:

·Novel drug delivery system (NDDS) 
This new technology of delivering the drug in hard gelatin can circumvent the existing patenting of the drug in soft gel or any other form. This will be a novel drug delivery system for the brand owner and the product can be launched without any change in the formulation but only by delivering the drug in the hard gelatin. This not only opens new opportunity but also reduces the cost of the new product considerably and thus can add to the contribution.

·Brand advantage
In the overcrowded market where there is a jungle of products of similar types with soft gelatin as the conventional delivery system for the liquid product, this technology unfolds new opportunity for building unique brand for the liquid based formulations.  This new delivery system empowers the product managers with a tool for re-launching existing products and launching new products with better results and customer acceptance.







 

PARAMETER 	HARD GEL		SOFT GEL
Bio-Availability	Good 	Good 
Stability	Good	Good
Losses	No losses in formulation	High (up to 6%).
Combination Filling(Liquids + pellets)	Possible	Not possible
Hot melts	Up to 70 degree centigrade	Up to 35 degree centigrade
Gelatin preparation	Not applicable	Yes
Gelling time	Not applicable	Up to 10 hours.
Tumble Drying	Not applicable	Yes.
Drying	Under 10 minutes in band sealing machine	Up to 60 hours for soft gel line.
Shell product interactions	No such issue	This is a concern .
Combination filling	Liquids & pellets possible	Not possible.
Shrinkage	No such issue	Non uniform during long period of drying process.
Process	Simple	Operation, complex & messy .
In house control	Yes	Out sourced.
Gelatin wastage	Not applicable	Up to 40% in web.
Social & health issues	No such issue	Gelatin ribbon wastage generated during the process has to be   buried directly or buried after incineration.

Additional Information:
1.Power consumption is more than 5 Times in soft gel plant to that of Liquid Encapsulation in Hard capsule 
2.Man Power cost in soft gel is   six times in hard capsule, as soft gel line is a 24-hour operation, unlike soft gel, which is a single shift operation.
3.Wastages are high in soft gel process if there are sudden stoppages in production line.














Advantages of Liquid Filling in Hard Capsules from Formulation & Market perspective 

Formulation Perspective 

Time release formulation possible
Alternative solution for stability problems
Improved bioavailability 
Super - critical uniformity
Incompatible drugs in single dose
Combination Fills- Liquid & Pellet
Lower investment for R & D
Semi Solid Matrix forms cover formulations with wide range of viscosities. 
Use excepients with melting points up to 70°C.
Combination Filling: Liquid & Pellet
Brings operation in-house 
Simplified Process, operator friendly
Preventive maintenance – convenient
The "clean label" concept, i.e. no additives, fewer excipients, no allergens, no GMOs.  


Marketing perspective 

Liquid Appeal span all supplement products & demographic Groups .
Product security as dosage & formulation are tamper resistant
Patent Protection
Protection against counterfeit
NDDS offers one more   platform for marketing activities as an alternative dosage delivery system
HPMC Capsules will provide the right   alternative for TSE/BSE free capsules
Extending the life of a brand
Cost effective / no wastage
Brand shield
Attractive new dosage form enhances branding

Raghuram Bhuvanagiri
Product Manager 
Pam Pharmaceuticals & Allied Machuinery co. Pvt. Ltd

i would like to give some inputs of stages of drug development.
The drug development process involves three stages:

    * Drug discovery

    * Drug development

    * Drug delivery
and drug discovery mainly deals with gene manipulation and genemoics