About Authors: NIDHI KARIA1, RAKHI CHANDAK1, ARATI RATHI2
1. P.WADHWANI COLLEGE OF PHARMACY,YAVATMAL
2. ASST PROFFESER AT SUMANDEEP DEPARMENT OF PHARMACY, VADODARA
INTRODUCTION:
The advent of the new drug delivery systems (oral, nasal, pulmonary, transdermal, needle-free, etc.) and the development of new biochemical compounds have resulted in a need not only for enhanced protection against such factors as moisture, light, oxygen, or mechanical forces, but also for packaging forms to play a more integral role in drug delivery. A large number of lyophilized or freeze-dried drugs, for example, are currently available, and the list is growing. Biotech drugs by their very nature are much less stable than conventional compounds and demand a different mode of delivery. In this article, we will describe in more detail several examples of delivery systems to show how packaging, with an emphasis on blister and flexible materials, is being put to the test today.
Reference Id: PHARMATUTOR-ART-1176
NOVEL DRUG DELIVERY SYSTEMS
New or novel drug delivery systems (NDDS) have many benefits. They can improve therapy by increasing the efficacy and duration of drug activity. Some can increase patient compliance through decreased dosing frequency and convenient routes of administration. Others can improve targeting for a specific site to reduce unwanted side effects. Still, others mimic the circadian rhythm of particular diseases in order to optimize a drug's therapeutic power, potentially differentiating a brand and giving it a competitive edge over less effective drugs. There are many resources available that describe these technologies, including some websites.1-4
Drug delivery technologies form a very rapidly growing segment of the pharmaceutical industry. The most recent forecast shows that drug delivery-related sales will grow to 20% of the total pharmaceutical sales by 2005.5 And packaging will be a critical component of this rapid growth.
Pharmaceutical companies have expressed very significant interest, accompanied by a concurrent amount of investment in NDDS technologies. Increased profit with reduced risk is the key to this interest, as well as increasing competition from generic manufacturers and fears of the huge financial impact resulting from patent expiration and the concomitant issues of drug life-cycle management. Combining a drug delivery technology with a patented active substance creates a new formulation of the original product and, thus, can extend patent life. The development of new drug delivery techniques for established active chemicals is also relatively low risk compared with the high risk involved in new chemical entity (NCE) drug discovery, development, and commercialization.
In general, the average cost for a new NDDS is $15 million to $50 million during an approximately 7-year development period. This represents a small fraction of the R&D effort and expense for a new drug discovery program (usually ranging from $300 million to $600 million). Currently, the estimate is that more than 60% of the NDDS technology effort is focused on drugs already being marketed.
However, the future of drug delivery systems is not confined to currently marketed drug compounds. It could be a much more successful and profitable proposition to introduce a drug delivery technology very early on in the NCE development cycle. This topic has been a subject of considerable interest to a variety of pharmaceutical companies at recent meetings. But due to the plethora of available delivery technologies with widely different maturity levels, this scenario will not necessarily unfold without its share of tribulations.
At the 6th Annual Drug Delivery Partnership meeting organized by the Institute for International Research this past January, several presentations discussed the importance of cooperation between drug delivery companies and pharmaceutical companies, both from a scientific and a business perspective.
Novel drug delivery systems have resulted in the emergence of specialized packaging needs because not all of them can be packaged in bottles or "standard" blisters. In many cases, the packaging must be unit-dose and actually becomes an integral part of the drug delivery technology, whether oral, pulmonary, nasal, transmucosal, transdermal, or needle-free.
PHARMACEUTICAL PACKAGING
Pharmaceutical packaging and packaging design provides stability and shelf life to the drug and the delivery system, and also becomes fundamental to the safety, convenience, and compliance of drug use. The achievement of a successful combination of packaging and design for pharmaceutical products creates an ongoing need for innovation and education in the field of packaging and packaging materials.
Although stability of the drug dosage format is the overriding factor, the process of packaging selection has many components. Selection is usually based on type, size, and shape of the package; barrier; and mechanical/chemical stability requirements and "opening" features, such as child resistance or senior-friendliness.
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In most cases, pharmaceutical companies determine packaging options and selections. However, an increasing number of drug delivery companies are determining packaging selection independent of the pharmaceutical companies based on their technologies. Viable commercial entrée to a pharmaceutical company requires at least stability testing and technology maturity as well as selection of a packaging type early on in the development process. The FDA requires packaging data for every NDA or other application.7
Access to packaging information is difficult at best. Often, a combination of material and machinery suppliers support the development of a drug package because each new package, despite appearances to the contrary, is custom-designed for a particular application. In some cases, packaging is outsourced to a contract packager. This makes it a difficult endeavor, even for well-established pharmaceutical companies. Packaging suppliers can bear some of the burden of the packaging development utilizing testing, materials, and prototype development programs.8-10
With all the packaging options available, pharmaceutical manufacturers must still meet the very stringent stability standards recently defined. The stability guidelines from the International Conference on Harmonization (ICH) show that stability studies must support both storage and shipping conditions, thus making packaging even more important to overall drug stability.
For pharmaceutical solid oral dosage forms, studies are conducted for 6 months under accelerated conditions of 40 and 75% RH, or under normal conditions for 24 months at room temperature (20 C) and 60% RH.11 Climatic conditions must be considered as well. For instance, Zone V tropical conditions require testing at 45 C and 98% RH. Few drugs can survive these conditions without substantial barrier packaging. New drug delivery systems, because they can be based on or incorporate highly moisture-sensitive materials, demand particular barrier protection against the likes of moisture, oxygen, UV, and other environmental conditions.
Current pharmaceutical packaging runs the gamut from plastic or glass bottles for solid dosage forms or liquid injectables to blister packaging and more flexible material structures for pouches and lidding. All of these options are available for any type of drug delivery technology, including transdermal, pulmonary, transmucosal, or oral. There have been several recent articles describing some of these options for drug delivery, but this overview is focused on blister and flexible materials.
BLISTER PACKAGING
Blister packaging (Figure 1) has long been popular in Europe for both unit-dose and multi-dose formats, and is becoming increasingly popular in the US. A blister package is usually made up of two layers of materials, one being a multi-layered film that can be thermoformed to form the pockets, or blisters that contain the pills or tablets. The other structure is usually a (heat) sealable foil-based material. There are many patents on the different blister designs pertaining to their method of opening a blister or making blisters more child-resistant.
The total US demand for pharmaceutical packaging is currently at an annual level of approximately $3 billion. This includes all forms related to packaging, such as bottles, closures, pouches, and blister or push-through-packaging. However, in the US, 85% of all drugs are packaged in bottles, while only physician samples and hospital unit-doses are packaged in blisters. The blister packaging market is growing the fastest however because of its attributes toward unit-dose, compliance, clinical trials, high-barrier, and high-visibility formats.
Drug delivery is changing the packaging landscape with, for instance, the advent of fast-dissolve systems or orally disintegrating dosage forms, such as Biovail's Flashdose®, RP Scherer's Zydis® system, and CIMA Labs' OraSolvTMsystem. These systems are currently marketed through the products of various pharmaceutical companies. Examples include Merck's Maxalt-MLT (Zydis® system), Organon's Remeron Sol-Tabs (CIMA Labs system). In the latter two systems, the pharmaceutical companies selected a rigid, multi-layer foil-based barrier material to protect the dosage form, with the blister actually forming the tablet during the formulation process. Both RP Scherer and CIMA Labs have filed patents where the packaging is mentioned as part of the process.13,14 This shows the importance of packaging not only from a dosage form protection standpoint, but also from an intellectual property protection position.
Now that blisters are used in the actual product-shaping process, packaging has become significantly different from the standard blister packages of old. In a lot of cases, the fast-dissolve systems can be very fragile, and regular push-through blister packaging would destroy the tablet upon removing from the blister, so the packaging requires a peelable closure.
PACKAGING & MATERIAL OPTIONS
Packaging, from our perspective, can take two forms: formable (thermoformable or cold-formable) materials and flexible materials. Formable materials (such as blisters and trays) can offer a water, oxygen, or UV barrier as well as a physical and mechanical barrier as a primary way to protect a drug and its delivery system against damage before administering (for example, an oral quick-dissolve). Thermoformable materials are based on rigid polymer materials (PVC, PETG, APET, CPET, PP or COC) usually combined by coextrusion, coating, or lamination to barrier materials. Typical barrier materials include PCTFE (polychloro-trifluoroethylene, such as Honeywell's Aclar® fluoropolymer film), PVDC (polyvinylidene chloride), aluminum foil, or EVOH (ethylene vinyl alcohol) coextrusions (like Honeywell's OxyShield®). Transparency is often a desirable characteristic for such packages and is readily achieved by adhesive lamination of a rigid sheet to a transparent barrier web. Current blister packaging is mostly made from PVC or, when barrier is needed, from PVDC/PVC, PCTFE/PVC or foil-based structures. Table 1 shows a comparison of available thermoformable barrier materials with respect to their MVTR (moisture vapor transmission rate) and moisture-barrier properties. Each system offers its particular benefits.
Flexible materials can offer barrier protection for the drug delivery system as well as flexibility in a number of different applications, such as pouches, bags, sachets; lidding (peelable or weld-sealed); or overwraps (secondary packaging). Transparency is highly desirable for flexible pharmaceutical packaging. It enhances product aesthetics, emphasizes product branding, and offers manufacturer and consumer alike a final quality control check before administration of the drug.
PACKAGING CONSIDERATIONS FOR NEW DRUG DELIVERY SYSTEMS
Packaging demands for new drug delivery systems are different than those of conventional delivery systems. In the case of new drug delivery systeSms, bottles, vials, or non-barrier blister packaging is not always the best or most suitable choice for the package. Table 2 shows a comparison of and considerations needed when designing packaging for new drug delivery systems. Currently, not all of the mentioned systems are commercial, but they are far enough along to discuss their packaging selection.
REFERENCES
1. For a general overview of many of the different drug delivery technologies and/or companies, please visit www.drugdel.com.
2. Verma RK, Garg S. Current status of drug delivery technologies and future directions. Pharm Tech. On-line 2001; 25(2):1-14.
3. Henry CM. Special delivery: alternative methods for delivering drugs improve performance, convenience and patient compliance. Chem Eng News. 2000; 78(38):49-65.
4. Kermani F, Findlay G. Novel drug delivery technologies: a perspective from the pharmaceutical industry. Am Pharm Outsourcing. 2001; Jan/Feb 2001:22-29.
5. Drug Delivery Technologies: Innovations and Market Challenges. SCRIP Reports. May 2001.
6. Lecture presented at 6th Annual Drug Delivery Partnerships Conference hosted by International Institute of Research. Los Angeles, CA. January 28-30, 2002.
7. US Government Report. Guidance for container closure systems for packaging human drugs and biologics. Federal Register. 1999;64(129):36694-36695.
8. Information available at aclar.com in 2002.
9. Info available at unitdose.org in 2002.
10. Information available at iopp.org in 2002.
11. Current Good Manufacturing Practices for Finished Pharmaceuticals. Code of Federal Regulations, 21 CFR Part 211. (fda.gov/cder/dmpq/cgmpregs.htm).
12. Cremer K. Orally disintegrating dosage forms. Pharma Concepts. 2001 (Special Report).
13. US Patent No. 5, 631,023. Method for Making Freeze Dried Drug Dosage Forms. Patrick Kearny et al. RP Scherer Corp., May 1997.
14. US Patent No. 6,155,423 Blister Package and Packaged Tablet. Katzner et al. CIMA Labs, December 2000.
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