Thin-film drug delivery

Thin-film drug delivery uses a dissolving film or oral drug strip to administer drugs via absorption in the mouth (buccally or sublingually) and/or via the small intestines (enterically). A film is prepared using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity, delivering the drug to the systemic circulation via dissolution when contact with liquid is made.

Zuplenz 8 mg (approved by FDA, July 7, 2010). Photo courtesy of MonoSol Rx.

Prolific inventors in thin film drug delivery include Richard Fuisz, Joseph Fuisz, Garry Myers and Robert Yang.^[1] This group has contributed over thirty patents in this field.

Thin-film drug delivery has emerged as an advanced alternative to the traditional tablets, capsules and liquids often associated with prescription and OTC medications. Similar in size, shape and thickness to a postage stamp, thin-film strips are typically designed for oral administration, with the user placing the strip on or under the tongue (sublingual) or along the inside of the cheek (buccal). These drug delivery options allow the medication to bypass the first pass metabolism thereby making the medication more bioavailable. As the strip dissolves, the drug can enter the blood stream enterically, buccally or sublingually. Evaluating the systemic transmucosal drug delivery, the buccal mucosa is the preferred region as compared to the sublingual mucosa.

Different buccal delivery products have been marketed or are proposed for certain diseases like trigeminal neuralgia, Meniere's disease, diabetes, and addiction. There are many commercial non-drug product to use thin films like Mr. Mint and Listerine PocketPaks breath freshening strips. Since then, thin-film products for other breath fresheners, as well as a number of cold, flu, anti-snoring and gastrointestinal medications, have entered the marketplace. There are currently several projects in development that will deliver prescription drugs using the thin-film dosage form.^[2]

Formulation of oral drug strips involves the application of both aesthetic and performance characteristics such as strip-forming polymers, plasticizers, active pharmaceutical ingredient, sweetening agents, saliva stimulating agent, flavoring agents, coloring agents, stabilizing and thickening agents. From the regulatory perspectives, all excipients used in the formulation of oral drug strips should be approved for use in oral pharmaceutical dosage forms.

Oral drug strip development

Strip forming polymers

The polymer employed should be non-toxic, non-irritant and devoid of leachable impurities. It should have good wetting and spreadability property. The polymer should exhibit sufficient peel, shear and tensile strengths. The polymer should be readily available and should not be very expensive. Film obtained should be tough enough so that there won't be any damage while handling or during transportation. Combination of microcrystalline cellulose and maltodextrin has been used to formulate Oral Strips of piroxicam made by hot melt extrusion technique. Pullulan has been the most widely used film former (used in Listerine PocketPak, Benadryl, etc.)

Plasticizers

Plasticizer is a vital ingredient of the OS formulation. It helps to improve the flexibility of the strip and reduces the brittleness of the strip. Plasticizer significantly improves the strip properties by reducing the glass transition temperature of the polymer. Glycerol, Propylene glycol, low molecular weight polyethylene glycols, phthalate derivatives like dimethyl, diethyl and dibutyl phthalate, Citrate derivatives such as tributyl, triethyl, acetyl citrate, triacetin and castor oil are some of the commonly used plasticizer excipients.

Active pharmaceutical ingredient

Since the size of the dosage form has limitation, high-dose molecules are difficult to be incorporated in OS. Generally 5%w/w to 30%w/w of active pharmaceutical ingredients can be incorporated in the oral strip.^[3]

Sweeting, flavoring and coloring agent

An important aspect of thin film drug technology is its taste and color. The sweet taste in formulation is more important in case of pediatric population. Natural sweeteners as well as artificial sweeteners are used to improve the flavor of the mouth dissolving formulations for the flavors changes from individual to individual. Pigments such as titanium dioxide is incorporated for coloring.

Stabilizing and thickening agents

The stabilizing and thickening agents are employed to improve the viscosity and consistency of dispersion or solution of the strip preparation solution or suspension before casting. Drug content uniformity is a requirement for all dosage forms, particularly those containing low dose highly potent drugs. To uniquely meet this requirement, thin film formulations contain uniform dispersions of drug throughout the whole manufacturing process.^[4] Since this criterion is essential for the quality of the thin film and final pharmaceutical dosage form, the use of Laser Scanning Confocal Microscopy (LSCM) was recommended to follow the manufacturing process.^[5]

Commercial oral strip drugs

There are not yet many medications available in a thin film form on the market. Those that are include:

• Benadryl (diphenhydramine product, anti-cholinergic anti-histamine used for allergies and as a mild sedative)
• Gas-X (simethicone product for bloating, gas, and gastrointestinal complaint)
• Melatonin PM (hormonal product sold as a "dietary supplement" marketed for insomnia)
• Orajel Kids (benzocaine product for dental pain)
• Suboxone (buprenorphine and naloxone fixed dosage combination product for opioid addiction)
• Subutex (buprenorphine product for opioid addiction)
• Sudafed (phenylephrine or pseudoephedrine product for nasal congestion)
• TheraFlu (combination product of pain reliever, anti-pyretic and decongestant)
• Triaminic (children's anti-tussive product)

On July 2, 2010, Strativa Pharmaceuticals, the proprietary products division of Par Pharmaceutical, received approval from the US FDA for Zuplenz (ondansetron) oral soluble film (OSF) for the prevention of postoperative, highly and moderately emetogenic cancer chemotherapy-induced, and radiotherapy-induced nausea and vomiting.^[6]

Oral strips in development

An increasing number of film-based therapeutics are in development, including:

• Montelukast indicated for the treatment of asthma and allergy, is being developed for use as a film by Monosol Rx.
• Midatech, a company specializing in nanotechnology, is partnering with Monosol Rx to create a film-based insulin. (Sachs Associates. 5th Annual European Life Science CEP Forum for Partnering and Investing. March 6–7, 2012. Zurich, Switzerland.)
• Rizatriptan indicated for the treatment of migraine, is being developed for use as a film by Monosol Rx.
• Monosol Rx is also developing a testosterone film-based therapeutic for the treatment of male hypogonadism. The product is currently in phase 1.
• Undergraduate biomedical engineering students at Johns Hopkins University have created a new drug delivery system based on the thin-film technology used by a breath freshener. Laced with a vaccine against rotavirus, the strips could be used to provide the vaccine to infants in impoverished areas.^[7]

Advantages

The design of thin film as an oral drug delivery technology offers several advantages over other modes of drug delivery, such as ingestible tablets, chewable tablets, orally dissolving tablets, softgels, liquids or inhalants:^[8]

• The sublingual and buccal delivery of a drug via thin disolvable film has the potential to improve the onset of action, lower the dosing, and enhance the efficacy and safety profile of the medicament.
  • All tablet dosage forms, softgels and liquid formulations primarily enter the blood stream via the gastrointestinal tract, which subjects the drug to degradation from stomach acid, bile, digestive enzymes and other first-pass effects. As a result, such formulations often require higher doses and generally have a delayed onset of action.
  • Conversely, buccal and sublingual thin-film drug delivery can avoid these issues and yield quicker onsets of action at lower doses.
• Thin film is more stable, durable and quicker dissolving than other conventional dosage forms.
• Thin film enables improved dosing accuracy relative to liquid formulations since every strip is manufactured to contain a precise amount of the drug.
• Thin film not only ensures more accurate administration of drugs but also can improve compliance due to the intuitive nature of the dosage form and its inherent ease of administration. These properties are especially beneficial for pediatric, geriatric and neurodegenerative disease patients where proper and complete dosing can be difficult.
• Thin film's ability to dissolve rapidly without the need for water provides an alternative to patients with swallowing disorders and to patients suffering from nausea, such as those patients receiving chemotherapy.
• Thin film drug delivery has the potential to allow the development of sensitive drug targets that may otherwise not be possible in tablet or liquid formulations.
• From a commercial perspective thin film drug delivery technology offers an opportunity to extend revenue lifecycles for pharmaceutical companies whose drug patent is expiring and will soon be vulnerable to generic competition.
• Pharmaceutical drugs can be contained within an abuse-deterrent film matrix that cannot be crushed or injected by patients, and rapidly absorbs under the tongue to ensure compliance.
• Facilitates absorption 3 to 10 times greater than an oral tablet---only surpassed by hypodermic injection.

References

1. "Thin film with non-self-aggregating uniform heterogeneity and drug delivery systems made therefrom". Google Patents. Retrieved 2005-10-26.
2. "Oral Thin Films," in Orally Disintegrating Tablet and Film Technologies, 5th ed. (Technology Catalysts International, Falls Church, VA, 2008)
3. Dixit, R.; Puthli, S. (2009). "Oral strip technology: Overview and future potential.". Journal of Controlled Release. Mumbai,India. 139 (2): 94–107. doi:10.1016/j.jconrel.2009.06.014. PMID 19559740.
4. "FDA Office of Regulatory Affairs, Sec. 460.600 Content Uniformity Testing of Tablets and Capsules". Fda.gov. Retrieved 2009-09-21.
5. Le Person, S; Puiggali, J.R.; Baron, M.; Roques, M. (1998). "Near infrared drying of pharmaceutical thin films: experimental analysis of internal mass transport". Chem. Eng. & Processing. 37: 257–263. doi:10.1016/S0255-2701(98)00032-4.
6. http://www.medicalnewstoday.com/articles/194180.php
7. "Drug Delivery Via Dissolving Strips.". Drug Discovery & Development. 10 (7): 10. 2007. ISSN 1524-783X.
8. Biradar, S.; Bhagavati, S; Kuppasad, I (2006). "Fast Dissolving Drug Delivery Systems: A Brief Overview.". The Internet Journal of Pharmacology. Ispub.com. 4 (2). Retrieved 2009-09-21.

• Hariharan, Madhu; Bogue, B. Arlie (February 2009). "Orally Dissolving Film Strips (ODFS): The Final Evolution of Orally Dissolving Dosage Forms". Drug Delivery Technology. Montville, New Jersey. 9 (2): 24–29. ISSN 1537-2898. OCLC 48060225.
• "Drug Delivery Via Dissolving Strips.". Drug Discovery & Development. 10 (7): 10. 2007. ISSN 1524-783X.
• Dixit, RP; Puthli, SP (2009). "Oral strip technology: overview and future potential.". Journal of Controlled Release. 139 (2): 94–107. doi:10.1016/j.jconrel.2009.06.014. PMID 19559740.
• Patel, P; Makwana, S; Jobanputra, U (2011). "Sublingual route for the systemic delivery of ondansetron." (PDF). Int J Drug Dev & Research. 3 (4): 36–42.

External links

• How do you want your cold medicine? – Associated Press (10/10/05)