Thin film drug delivery
Encyclopedia
Thin film drug delivery uses a dissolving film or oral drug strip to administer drugs via absorption in the mouth (buccally or sublingual
ly) 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.
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
. The first commercial non-drug product to use thin films was the 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
.
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 excipient
s used in the formulation of oral drug strips should be approved for use in oral pharmaceutical dosage
forms.
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.
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.)
, 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.
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. 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.
on the market. Those that are include:
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.
For drug delivery see route of administration
Sublingual
Sublingual, literally 'under the tongue', from Latin, refers to the pharmacological route of administration by which drugs diffuse into the blood through tissues under the tongue...
ly) and/or via the small intestines (enterically
Enteric coating
An enteric coating is a barrier applied to oral medication that controls the location in the digestive system, where it is absorbed. Enteric refers to the small intestine, therefore enteric coatings prevent release of medication before it reaches the small intestine.Most enteric coatings work by...
). A film is prepared using hydrophilic polymers that rapidly dissolves on the tongue or buccal cavity, delivering
Drug delivery
Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. Drug delivery technologies modify drug release profile, absorption, distribution and elimination for the benefit of improving product efficacy and safety, as well...
the drug to the systemic circulation
Systemic circulation
Systemic circulation is the part of the cardiovascular system which carries oxygenated blood away from the heart to the body, and returns deoxygenated blood back to the heart. This physiologic theory of circulation was first described by William Harvey...
via dissolution
Dissolution (chemistry)
Dissolution is the process by which a solid, liquid or gas forms a solution in a solvent. In solids this can be explained as the breakdown of the crystal lattice into individual ions, atoms or molecules and their transport into the solvent. For liquids and gases, the molecules must be compatible...
when contact with liquid
Liquid
Liquid is one of the three classical states of matter . Like a gas, a liquid is able to flow and take the shape of a container. Some liquids resist compression, while others can be compressed. Unlike a gas, a liquid does not disperse to fill every space of a container, and maintains a fairly...
is made.
Thin film drug delivery has emerged as an advanced alternative to the traditional tablets, capsules and liquids often associated with prescription
Prescription drug
A prescription medication is a licensed medicine that is regulated by legislation to require a medical prescription before it can be obtained. The term is used to distinguish it from over-the-counter drugs which can be obtained without a prescription...
and OTC
Over-the-counter drug
Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...
medications. Similar in size, shape and thickness to a postage stamp
Postage stamp
A postage stamp is a small piece of paper that is purchased and displayed on an item of mail as evidence of payment of postage. Typically, stamps are made from special paper, with a national designation and denomination on the face, and a gum adhesive on the reverse side...
, 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
Trigeminal neuralgia
Trigeminal neuralgia , tic douloureux is a neuropathic disorder characterized by episodes of intense pain in the face, originating from the trigeminal nerve. It has been described as among the most painful conditions known...
, Meniere's disease
Ménière's disease
Ménière's disease is a disorder of the inner ear that can affect hearing and balance to a varying degree. It is characterized by episodes of vertigo and tinnitus and progressive hearing loss, usually in one ear. It is named after the French physician Prosper Ménière, who, in an article published...
, diabetes, and addiction
Addiction
Historically, addiction has been defined as physical and psychological dependence on psychoactive substances which cross the blood-brain barrier once ingested, temporarily altering the chemical milieu of the brain.Addiction can also be viewed as a continued involvement with a substance or activity...
. The first commercial non-drug product to use thin films was the 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
Dosage form
-Introduction:Dosage forms are a mixture of active drug components and nondrug components. Depending on the method of administration they come in several types. These are liquid dosage form, solid dosage form and semisolid dosage forms. A Liquid dosage form is the liquid form of a dose of a...
.
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
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
stimulating agent, flavoring agents, coloring agents, stabilizing and thickening agents. From the regulatory perspectives, all excipient
Excipient
An excipient is generally a pharmacologically inactive substance used as a carrier for the active ingredients of a medication. In many cases, an "active" substance may not be easily administered and absorbed by the human body; in such cases the substance in question may be dissolved into or...
s used in the formulation of oral drug strips should be approved for use in oral pharmaceutical dosage
Dose (biochemistry)
A dose is a quantity of something that may impact an organism biologically; the greater the quantity, the larger the dose. In nutrition, the term is usually applied to how much of a specific nutrient is in a person's diet or in a particular food, meal, or dietary supplement...
forms.
Undergraduate biomedical engineering
Biomedical engineering
Biomedical Engineering is the application of engineering principles and design concepts to medicine and biology. This field seeks to close the gap between engineering and medicine: It combines the design and problem solving skills of engineering with medical and biological sciences to improve...
students at Johns Hopkins University
Johns Hopkins University
The Johns Hopkins University, commonly referred to as Johns Hopkins, JHU, or simply Hopkins, is a private research university based in Baltimore, Maryland, United States...
have created a new drug delivery system based on the thin film technology used by a breath freshener. Laced with a vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
against rotavirus
Rotavirus
Rotavirus is the most common cause of severe diarrhoea among infants and young children, and is one of several viruses that cause infections often called stomach flu, despite having no relation to influenza. It is a genus of double-stranded RNA virus in the family Reoviridae. By the age of five,...
, the strips could be used to provide the vaccine to infants in impoverished areas.
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 microcrystallineMicrocrystalline
A microcrystalline material is a crystallized substance or rock that contains small crystals visible only through microscopic examination.-See also:* Macrocrystalline* Microcrystalline silicon* Protocrystalline* Rock microstructure...
cellulose
Cellulose
Cellulose is an organic compound with the formula , a polysaccharide consisting of a linear chain of several hundred to over ten thousand β linked D-glucose units....
and maltodextrin
Maltodextrin
Maltodextrin is a polysaccharide that is used as a food additive. It is produced from starch by partial hydrolysis and is usually found as a creamy-white hygroscopic spraydried powder. Maltodextrin is easily digestible, being absorbed as rapidly as glucose, and might be either moderately sweet or...
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.)
Plasticizer
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. GlycerolGlycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
, Propylene glycol
Propylene glycol
Propylene glycol, also called 1,2-propanediol or propane-1,2-diol, is an organic compound with formula C3H8O2 or HO-CH2-CHOH-CH3...
, low molecular weight polyethylene glycols, phthalate derivatives like dimethyl, diethyl and dibutyl phthalate
Dibutyl phthalate
Dibutyl phthalate is a commonly used plasticizer. It is also used as an additive to adhesives or printing inks. It is soluble in various organic solvents, e.g. in alcohol, ether and benzene...
, Citrate
Citrate
A citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...
derivatives such as tributyl, triethyl, acetyl citrate, triacetin
Triacetin
The triglyceride 1,2,3-triacetoxypropane is more generally known as triacetin and glycerin triacetate. It is the triester of glycerol and acetic acid....
and castor oil
Castor oil
Castor oil is a vegetable oil obtained from the castor bean . Castor oil is a colorless to very pale yellow liquid with mild or no odor or taste. Its boiling point is and its density is 961 kg/m3...
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 OS.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 titaniumdioxide is incorporated for coloring.Stabilizing and thickening agents
The stabilizing and thickening agents are employed to improve the viscosityViscosity
Viscosity is a measure of the resistance of a fluid which is being deformed by either shear or tensile stress. In everyday terms , viscosity is "thickness" or "internal friction". Thus, water is "thin", having a lower viscosity, while honey is "thick", having a higher 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. 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.
Commercial oral strip drugs
There are not yet many medications available in a thin film formDosage form
-Introduction:Dosage forms are a mixture of active drug components and nondrug components. Depending on the method of administration they come in several types. These are liquid dosage form, solid dosage form and semisolid dosage forms. A Liquid dosage form is the liquid form of a dose of a...
on the market. Those that are include:
- Zuplenz: The first oral soluble film approved by the FDA as a prescription medication.
- BenadrylBenadrylBenadryl is a brand name allergy medicine marketed over-the-counter by Johnson & Johnson subsidiary McNeil Consumer Healthcare. Prior to 2007, Benadryl was marketed by Pfizer Consumer Healthcare...
(diphenhydramineDiphenhydramineDiphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
product, anti-cholinergic anti-histamine used for allergies and as a mild sedative) - Gas-X (simethiconeSimethiconeSimethicone is an oral anti-foaming agent used to reduce bloating, discomfort and pain caused by excess gas in the stomach or intestinal tract. It is a mixture of polydimethylsiloxane and silica gel.-Chemical action and pharmaceutical effects:...
product for bloating, gas, and gastrointestinal complaint) - Melatonin PMLeiner Health ProductsLeiner Health Products is a company based in Carson, California, and is one of America's largest manufacturers of vitamins, minerals, herbal nutritional supplements, and generic medications...
(hormonal product sold as a "dietary supplement" marketed for insomnia) - Orajel Kids (benzocaineBenzocaineBenzocaine is a local anesthetic commonly used as a topical pain reliever, or in cough drops. It is the active ingredient in many over-the-counter anesthetic ointments...
product for dental pain) - Suboxone (buprenorphineBuprenorphineBuprenorphine is a semi-synthetic opioid that is used...
and naloxoneNaloxoneNaloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...
fixed dosage combination product for opioid addiction) - Subutex (buprenorphine product for opioid addiction)
- SudafedSudafedSudafed is a brand name and registered trademark for over the counter decongestants manufactured by McNeil Laboratories for sale in Australia, New Zealand, Canada, Ireland, the United Kingdom, and the United States...
(phenylephrinePhenylephrinePhenylephrine is a selective α1-adrenergic receptor agonist used primarily as a decongestant, as an agent to dilate the pupil, and to increase blood pressure...
or pseudoephedrinePseudoephedrinePseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent....
product for nasal congestion) - Suppress
- TheraFluTherafluTheraflu is a brand of over-the-counter cold and flu medicines from Novartis that contain different groupings of various cold and flu symptom medications. The original version of Theraflu contained Acetaminophen , Chlorpheniramine maleate , Dextromethorphan hydrobromide , and Pseudoephedrine...
(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
Par Pharmaceutical
Par Pharmaceutical develops, manufactures and markets generic and branded specialty pharmaceuticals. Par was founded in 1978 and initially traded on the New York Stock Exchange in 1987...
, received approval from the US FDA for Zuplenz (ondansetron
Ondansetron
Ondansetron is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic , often following chemotherapy. Its effects are thought to be on both peripheral and central nerves...
) oral soluble film (OSF) for the prevention of postoperative, highly and moderately emetogenic cancer chemotherapy-induced, and radiotherapy-induced nausea and vomiting.
Advantages
The design of thin film, often referred to as PharmFilm, 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:- The sublingualSublingualSublingual, literally 'under the tongue', from Latin, refers to the pharmacological route of administration by which drugs diffuse into the blood through tissues under the tongue...
and buccalBuccalBuccal may refer to:* Mouth, a body cavity** Specifically the cheek* Buccal artery...
delivery of a drug via thin 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.
- Sublingual film delivers a convenient, quick-dissolving therapeutic dose contained within an abuse-deterrent film matrix that cannot be crushed or injected by patients, and rapidly absorbs under the tongue to ensure compliance.
External links
- It's On The Tip Of Your Tongue - BusinessWeek (7/31/06)
- How do you want your cold medicine? – Associated Press (10/10/05)
- MonoSol Rx Announces FDA Approval of Zuplenz Oral Soluble Film for Treatment of Nausea and Vomiting - monosolrx (07/02/10)
- MonoSol Rx Announces Reckitt Benckiser FDA Approval of Suboxone Sublingual Film for Treatment of Opioid Dependence - PR Newswire (08/31/10)
For drug delivery see route of administration
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...