Current issues with parenteral dosage forms

teaser

Steven L Nail
PhD

Wendy Saffell-Clemmer
MS

Michael J Akers
PhD

Baxter BioPharma Solutions
Bloomington
Indiana
USA

E: [email protected]

Formulation scientists worldwide are working diligently to meet the challenges in developing stable, soluble, deliverable and “manufacturable” formulations for all kinds of therapeutic molecules – small molecules, peptides, proteins, vaccines, genes and other biologicals. This article highlights some of those challenges involving formulation and packaging of parenteral dosage forms.

Formulation
The most common challenges in developing injectable formulations are:

• Overcoming solubility issues for drugs to be injected intravenously (IV).
• Overcoming stability limitations of injectable drugs, particularly biopharmaceutical (ie, large-molecular-weight) drugs.
• Overcoming potential pain and/or tissue irritation properties of the drug and/or its formulation.
• Achieving the desired rate of release of a drug formulated in a prolonged (sustained, long-acting, controlled) delivery system after intramuscular (IM) or subcutaneous (SC) injection.

According to a recent analysis,(1) new drug delivery systems have grown from just under $20 bn in product revenue in 1995 to nearly $70 bn at the end of 2005. In injectable drug delivery, the major revenue generators were depot/implant products such as Lupron Depot and pegylated products such as Pegsys.

Two drivers – biotechnology and novel treatments for cancer – are primarily responsible for the growth in parenteral drug delivery systems.(2) Biotechnology products are typically proteins with very short half-lives, thus requiring frequent injections. Sustained delivery systems, which are designed to reduce injection frequency, save some costs and increase patient compliance, have been important contributions for biotechnology drugs. Cancer drugs – many of which require solubilisation, stabililisation and targeting technologies – have also stimulated significant advancements in parenteral formulation and delivery systems.

Cyclodextrins continue to be a popular and relatively simple choice for increasing the solubility of poorly water-soluble injectable drugs. In the past few years, several new marketed products have been approved containing cyclodextrin components. They include sulphobutylether-β-cyclodextrin (Captisol) in Vfend IV and Zeldox/Geodon for Injection (Pfizer) and hydroxypropyl-β-cyclodextrin used in Sporono Injection (Janssen). Other injectable formulations containing cyclodextrins are currently in clinical studies.

Nanoparticle technology is a relatively new approach to overcoming the aqueous insolubility of drugs. Such technology is carrier-free, with solid drug nanoparticulate delivery systems, enabling high drug loading and delivery for various routes of parenteral administration, including IV. For example, Elan’s NanoCrystal technology dispersions of poorly water-soluble drugs provide improved performance characteristics for IV, SC or IM injection.(3) Baxter’s Nanoedge technology relies on the precipitation of friable materials for subsequent fragmentation under conditions of high shear and/or thermal energy, accomplished by a combination of rapid precipitation and high-pressure homogenisation.(4)

An explosion of advances and commercial successes in controlling and/or sustaining the delivery of injectable drugs has occurred in the past few years. Major technologies developed for injectable controlled release include primarily microspheres, implants or hydrogels. For pharmaceutical protein controlled or sustained release, microsphere or hydrogel technologies are the most likely choices.(5-7)

Microsphere formulations containing polylactide/polyglycolide (PLGA) copolymers have been the primary types of sustained or controlled release formulations marketed in the past few years.(8) Injectable gel formulations, such as Atrigel (QLT) and other formulations containing natural materials such as alginates, chitosans or collagens, rely on environmental changes, primarily temperature, to convert an SC-injected liquid to a semi-solid or solid depot. Subsequently, the active pharmaceutical ingredient is slowly released as the polymer degrades.

Dextran-based microspheres encapsulate liposomes and proteins using an aqueous-based emulsion technique tailored for solvent-unsuitable drugs.(9) Promaxx (Baxter-Epic) is based on completely aqueous systems to form well-�controlled, uniform microspheres, allowing high drug loading. Microspheres, which contain the active ingredient (low-molecular-weight compounds, peptides, proteins, antibodies, DNA and other oligonucleotides) and excipients such as dextran sulphate, hydroxy‒ethyl starch and albumin, are formed through patented adjustments of ionic strength, pH, active and polymer concentrations and temperature.10 Other microsphere formulations meeting clinical or commercial success include Prolease and Medisorb (Alkermes) and Saber (Southern BioSystems).

Liposomal formulations have also seen an increase in successful commercial products.(11) Sequus (now Ortho Biotech) marketed the first stealth liposome (Doxil) in 1995. Stealth liposomes are nanoparticles with special polyethylene derivatives that allow the liposome to avoid detection by the reticuloendothelial system that would normally update these injected particles and minimise their circulation to the appropriate receptor sites. Earlier problems with economic and reproducible large-scale production of liposomes have been largely solved. Liposome-based technologies have been used to deliver genetically-engineered, nonviral plasmids across cellular barriers that target brain cancer. This is also called RNAi (RNA interference) technology that inhibits a growth factor responsible for keeping cancer cells alive.(12) Other examples of liposome technology include SkyePharma’s multivesicular liposome formulation (DepoFoam), Neopharm’s NeoLipid and Genzyme’s Lipobridge. DepoFoam technology includes at least two marketed products – DepoDur for controlled release of morphine and DepoCyt, an intrathecally injected sustained release anticancer product.

The advent of formulation development of monoclonal antibodies (at least 18 antibodies approved and approximately 100 in clinical development) has brought new challenges to formulation scientists to overcome potential problems with high-dose proteins. These problems include overcoming issues with highly viscous solutions and the tendency of high-concentration proteins to aggregate and become physically unstable.

Formulation scientists developing products containing antisense molecules and other nucleic acid active ingredients are facing challenges of both stabilisation during processing and storage, and targeting of these molecules in sufficient quantities to appropriate cell or tissue receptor sites for therapeutic activity.

The effectiveness of combining polyethylene glycol and proteins to produce sustained-release protein products has resulted in several relatively new commercial products.(13) The first pegylated oligo‒nucleotide (Mucagen, Pfizer) for treatment of macular degeneration by intravitreal administration was launched in 2005. Many other pegylated products have been approved. Amgen used pegylation to create a second-generation formulation of filgrastim (Neupogen, for the treatment of neutropenia in cancer patients undergoing chemotherapy or �radiation treatment). The pegylated form is pegfilgrastim (Neulasta�), which increases the bioavailability of filgrastim and reduces the dosing frequency from up to 11 injections per chemo‒therapy cycle to only one. Pegasys (Roche) is another second-generation formulation using pegylation to increase the bioavailability, activity and sustained response of interferon alfa-2a antiviral agent (Roferon-A) for the treatment of hepatitis C.

Packaging
Components (glass, rubber, plastic) used to package parenteral dosage forms can potentially produce many serious problems, such as:

• Insoluble, unsafe leachables.
• Leachates causing aggregation and other incompatibilities with formulation components.
• Protein aggregation due to silicone interactions.
• Hydrophobic interactions and denaturation (eg, protein adsorption).
• Foreign particles from rubber and glass.
• Glass-delaminated particles from glass.

In the past few years, packaging advances related to sterile dosage forms have been concentrated in these areas:

• Prefilled syringes.
• Use of plastics.
• Reducing or eliminating the use of silicone.
• Reducing the level of leachable substances.
• More user-friendly packaging systems for home healthcare.

Prefilled syringe usage has exploded due to several factors:(14)

• The emergence of biotechnology and the need to eliminate the overfill (reduced waste) of expensive biomolecules compared to vials and other containers. Vaccines, antithrombotics and various home healthcare products such as growth hormone and treatments for rheumatoid arthritis and multiple sclerosis are much more conveniently used and administered using prefilled syringes.
• Ready availability of presterilised, ready-to-fill syringes such as BD Hypak SCF and BunderGlas RTF.
• The advent of contract manufacturers specialising in syringe processing with lower costs and high-speed filling equipment.
• Ease of use because several of the steps required before a drug contained in a vial can be used are eliminated.
• Elimination of dosage errors because, unlike vials, syringes contain the exact amount of deliverable dose needed.

Prefilled syringes will fare the best in the marketplace based on infection prevention and response time advantages in the delivery of critical and emergency care medication. Vials, ampoules and IV containers will generate below-average demand gains, with competition from prefilled syringes holding back growth for vials and ampoules. Trends toward less invasive surgical procedures and advances in alternative drug delivery systems will soften market growth for IV containers.

Use of plastic packaging for vials and syringes is increasing. Plastics have the obvious advantage of eliminating the risk and consequences of broken glass, especially if containing cytotoxic drugs. Plastics also eliminate concerns regarding glass delamination and alkali leachates. Futhermore, plastic syringes may offer advantages for proteins because of less surface adsorption, and for hydrophobic proteins because of little to no silicone coating compared with glass syringes. Disadvantages of plastic containers include aseptic transfer issues of pre‒sterilised containers into classified production environments and potential for greater problems with product-package interactions. There is also less compendial standardisation for plastics used in parenteral product packages compared with glass.(15) Thus, subtle changes in plastic composition, vendors for plastic components and/or manufacture of those components may cause new problems, requiring extra time and effort to study these changes.

Historically, silicone has been required for rubber closures and cylindrical containers such as syringes and cartridges. Silicone facilitates ease of movement of closures in stoppering equipment and plungers to glide smoothly through syringes and cartridges. While silicone on glass is typically “baked” (polymerised) onto glass surfaces during dry heat sterilisation/depyrogenation, there still exist trace amounts of “free” silicone that can interact with hydrophobic protein groups, causing insoluble aggregate formation. Silicone on rubber is not polymerised and can be more of a problem interacting with formulation components.

Advances in rubber closure technologies have introduced closures that do not require siliconisation because of a special polymer coating applied to the outer surface of the closure. Examples are the Daichyo/West closures (FluroTec) and the Helvoet (Omniflex) closures. The Daichyo/West Flurotec is a laminated stopper containing a coating of copolymer film of tetrafluoroethylene (EFTE) and ethylene. The Omniflex stopper is coated with a mixture of polyethylene and tetrafluoroethylene (PTFE) film. These coated stoppers offer the following advantages compared with stoppers that must be siliconised:

• Eliminates the need for adding silicone oil.
• Provides lubricity for machinability.
• Reduces rubber stopper clumping problems.
• Decreases particulate matter levels.
• Reduces potential for formulation adsorption and absorption.
• Reduces chemical extractable levels.

One further advance with FluroTec-coating is a stopper called LyoTec (West), in which the top surface of the stopper is treated with FluroTec, which prevents the stopper from sticking to the top pressure plates of the freeze dryer shelves and either coming off the vial or the stopper plus the vial sticking to the shelf.

Plastic containers, such as Daikyo RESIN CZ�, can be combined with FluoroTec-coated stoppers to produce a silicone-free syringe. Baxter produces a plastic syringe called Clearshot that also reduces the potential adverse effects of silicone with silicone-sensitive products.

Most plastic materials have the disadvantage of not being as clear as glass and, therefore, inspection of the contents is impeded. However, recent technologies have overcome this limitation, as evidenced by plastic resins such as CZ (polycyclo‒pentane, Daikyo Seiko) and Topas COC (cyclic olefin copolymer, Ticona). In addition, many of these materials will soften or melt under the conditions of thermal sterilisation. However, careful selection of the plastic used and control of the autoclave cycle has made thermal sterilisation of some products possible (for example, large-volume parenterals). Ethylene oxide or radiation sterilisation may be employed for the empty container with subsequent aseptic filling. However, careful evaluation of the residues from ethylene oxide or its degradation products and their potential toxic effect must be undertaken. Investigation is required for potential interactions and other problems that may be encountered when a parenteral product is packaged in plastic.

Coated rubber closures reduce leachable substances from rubber. What about glass and plastic? Glass leachates are reduced using either “treated” glass or special prepared coated glass (Schott Type I Plus). The glass vial interior is lined with pure, fused silica that essentially eliminates all leachates and any interaction between the glass surface and product components.

Because of market demands for more “user-friendly” injectable delivery systems and the consistent need to reduce costs and wastes, several advances in convenient injectable drug delivery packaging devices have been achieved. Examples include:

• Prefilled syringes, already discussed.
• Cartridges in reusable or disposable pen delivery systems for precise, multidose administration of chronic-use drugs in diabetes and other hormonal therapies.
• Combination systems for facilitating transfer of lyophilised drug powders in vials to syringes or bags (eg, Mix2Vial [ZLB Behring], BIO-SET [Baxter], BAXJECT II [Baxter], Mixject [West], Clip’n’Ject [West], SOLOMIX [Baxter]), systems that easily connect a diluent syringe to a lyophilised drug vial or connect one vial to another.
• Wet-dry packaging such as LyoJect (Vetter) or Genotropin MiniQuick dual chamber cartridge for growth hormone (Pfizer).
• Needleless (needle-free) injector system. While the concept behind needle-free injection has been around for decades, it has only been recently, with the convergence of synthetic materials and computerised design software, that reliable and cost-effective devices have begun to appear. There are now many vendors (eg, Bioject, MIT, Antares, Aradigm, Crossject, Penjet, Injex, MediJect, Vitajet, AdvantaJet and many others) and several others manufacture devices that depend on compressed nitrogen gas to eject drug product from device to tissue SC. The pressure required supposedly does not damage proteins. Pegasys and Imitrex (GSK) use the Aradigm Intraject device. There is some pain, bruising and bleeding depending on patient and injection site. Also, costs are higher than with needle/syringe delivery.

Summary
The market needs for parenteral dosage forms to deliver a variety of new and unique therapeutic molecules continue to increase. The development of such dosage forms requires a high level of expertise both in formulation science and in packaging engineering in order to overcome many scientific challenges and provide convenience in drug delivery. There are plenty of opportunities for scientists and engineers to contribute in providing solutions to these challenges.

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