Osmotic controlled-release oral delivery system

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A 54mg tablet of Concerta, which uses OROS technology. 22% of the drug is contained in the red overcoat, while the remaining 78% is split between two drug layers of differing concentration. The tablet uses an additional push layer that expands as water enters the tablet via the osmotic membrane. The drug is expelled via the laser-drilled hole visible on the left side of the tablet. Concerta 54mg OROS.png
A 54mg tablet of Concerta, which uses OROS technology. 22% of the drug is contained in the red overcoat, while the remaining 78% is split between two drug layers of differing concentration. The tablet uses an additional push layer that expands as water enters the tablet via the osmotic membrane. The drug is expelled via the laser-drilled hole visible on the left side of the tablet.

Osmotic Controlled-release Oral Delivery System is an advanced controlled release oral drug delivery system in the form of a rigid tablet with a semi-permeable outer membrane and one or more small laser drilled holes in it. As the tablet passes through the body, water is absorbed through the semipermeable membrane via osmosis, and the resulting osmotic pressure is used to push the active drug through the opening(s) in the tablet. OROS® is a tradmark owned by ALZA Corporation, which derives from osmotic controlled-release oral delivery system. ALZA pioneered the use of osmotic pumps for oral drug delivery. [1] [2] [3]

Tablet (pharmacy) solid form for doses of drugs or medication to be taken orally

A tablet is a pharmaceutical dosage form. Tablets may be defined as the solid unit dosage form of medicament or medicaments with or without suitable excipients and prepared either by molding or by compression. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose. The excipients can include diluents, binders or granulating agents, glidants and lubricants to ensure efficient tabletting; disintegrants to promote tablet break-up in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive or aid in visual identification of an unknown tablet. A polymer coating is often applied to make the tablet smoother and easier to swallow, to control the release rate of the active ingredient, to make it more resistant to the environment, or to enhance the tablet's appearance.

Laser drilling is the process of creating thru-holes, referred to as “popped” holes or “percussion drilled” holes, by repeatedly pulsing focused laser energy on a material. The diameter of these holes can be as small as 0.002”. If larger holes are required, the laser is moved around the circumference of the “popped” hole until the desired diameter is created; this technique is called “trepanning”.

Semipermeable membrane membrane which will allow certain molecules or ions to pass through it by diffusion

A semipermeable membrane is a type of biological or synthetic, polymeric membrane that will allow certain molecules or ions to pass through it by diffusion—or occasionally by more specialized processes of facilitated diffusion, passive transport or active transport. The rate of passage depends on the pressure, concentration, and temperature of the molecules or solutes on either side, as well as the permeability of the membrane to each solute. Depending on the membrane and the solute, permeability may depend on solute size, solubility, properties, or chemistry. How the membrane is constructed to be selective in its permeability will determine the rate and the permeability. Many natural and synthetic materials thicker than a membrane are also semipermeable. One example of this is the thin film on the inside of the egg.

Contents

Rationale

Pros and cons

Osmotic release systems have a number of major advantages over other controlled-release mechanisms. They are significantly less affected by factors such as pH, food intake, GI motility, and differing intestinal environments. Using an osmotic pump to deliver drugs has additional inherent advantages regarding control over drug delivery rates. This allows for much more precise drug delivery over an extended period of time, which results in much more predictable pharmacokinetics. However, osmotic release systems are relatively complicated, somewhat difficult to manufacture, and may cause irritation or even blockage of the GI tract due to prolonged release of irritating drugs from the non-deformable tablet. [1] [4] [5] [6] [7] [8] [9]

pH measure of the acidity or basicity of an aqueous solution

In chemistry, pH is a scale used to specify how acidic or basic a water-based solution is. Acidic solutions have a lower pH, while basic solutions have a higher pH. At room temperature (25 °C), pure water is neither acidic nor basic and has a pH of 7.

Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determine the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, pesticides, food additives, cosmetics, etc. It attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is completely eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics (PD) is the study of how the drug affects the organism. Both together influence dosing, benefit, and adverse effects, as seen in PK/PD models.

Oral osmotic release systems

Single-layer

An illustration of the different components of the Elementary Osmotic Pump. Elementary Osmotic Pump diagram.png
An illustration of the different components of the Elementary Osmotic Pump.

The Elementary Osmotic Pump (EOP) was developed by ALZA in 1974, and was the first practical example of an osmotic pump based drug release system for oral use. [1] [2] [10] [11] [12] It was introduced to the market in the early 1980s in Osmosin (indomethacin) and Acutrim (phenylpropanolamine), but unexpectedly severe issues with GI irritation and cases of GI perforation led to the withdrawal of Osmosin. [1]

ALZA former pharmaceutical and medical systems company

ALZA Corporation was a pharmaceutical and medical systems company.

Phenylpropanolamine chemical compound

Phenylpropanolamine (PPA) is a sympathomimetic agent which is used as a decongestant and appetite suppressant. It is commonly used in prescription and over-the-counter cough and cold preparations. In veterinary medicine, it is used to control urinary incontinence in dogs.

Gastrointestinal perforation perforation in the wall of part of the gastrointestinal tract.

Gastrointestinal perforation, also known as ruptured bowel, is a hole in the wall of part of the gastrointestinal tract. The gastrointestinal tract includes the esophagus, stomach, small intestine, and large intestine. Symptoms include severe abdominal pain and tenderness. When the hole is in the stomach or early part of the small intestine the onset of pain is typically sudden while with a hole in the large intestine onset may be more gradual. The pain is usually constant in nature. Sepsis, with an increased heart rate, increased breathing rate, fever, and confusion may occur.

Merck & Co. later developed the Controlled-Porosity Osmotic Pump (CPOP) with the intention of addressing some of the issues that led to Osmosin's withdrawal via a new approach to the final stage of the release mechanism. [1] Unlike the EOP, the CPOP had no pre-formed hole in the outer shell for the drug to be expelled out of. Instead, the CPOP's semipermeable membrane was designed to form numerous small pores upon contact with water through which the drug would be expelled via osmotic pressure. The pores were formed via the use of a pH insensitive leachable or dissolvable additive such as sorbitol. [13]

Merck & Co., Inc., d.b.a. Merck Sharp & Dohme (MSD) outside the United States and Canada, is an American multinational pharmaceutical company and one of the largest pharmaceutical companies in the world.

Leaching is the process of extracting substances from a solid by dissolving them in a liquid, naturally. In the chemical processing industry, leaching has a variety of commercial applications, including separation of metal from ore using acid, and sugar from sugar beets using hot water.

Sorbitol chemical compound

Sorbitol, less commonly known as glucitol, is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, which changes the aldehyde group to a hydroxyl group. Most sorbitol is made from corn syrup, but it is also found in nature, for example in apples, pears, peaches, and prunes. It is converted to fructose by sorbitol-6-phosphate 2-dehydrogenase. Sorbitol is an isomer of mannitol, another sugar alcohol; the two differ only in the orientation of the hydroxyl group on carbon 2. While similar, the two sugar alcohols have very different sources in nature, melting points, and uses.

Multi-layer

An illustration of the different components of the Push-Pull Osmotic Pump. Push-Pull Osmotic Pump diagram.png
An illustration of the different components of the Push-Pull Osmotic Pump.

Both the EOP and CPOP were relatively simple designs, and were limited by their inability to deliver poorly soluble drugs. [1] This led to the development of an additional internal "push layer" comprised of material (a swellable polymer) that would expand as it absorbed water, which then pushed the drug layer (which incorporates a viscous polymer for suspension of poorly soluble drugs) out of the exit hole at a controlled rate. [1] [4] Osmotic agents such as sodium chloride, potassium chloride, or xylitol are added to both the drug and push layers to increase the osmotic pressure. [1] [4] [5] The initial design developed in 1982 by ALZA researchers was designated the Push-Pull Osmotic Pump (PPOP), and Procardia XL (nifedipine) was one of the first drugs to utilize this PPOP design. [1] [2]

Solubility Capacity of a designated solvent to hold a designated solute in homogeneous solution under specified conditions

Solubility is the property of a solid, liquid or gaseous chemical substance called solute to dissolve in a solid, liquid or gaseous solvent. The solubility of a substance fundamentally depends on the physical and chemical properties of the solute and solvent as well as on temperature, pressure and presence of other chemicals of the solution. The extent of the solubility of a substance in a specific solvent is measured as the saturation concentration, where adding more solute does not increase the concentration of the solution and begins to precipitate the excess amount of solute.

Polymer substance composed of macromolecules with repeating structural units

A polymer is a large molecule, or macromolecule, composed of many repeated subunits. Due to their broad range of properties, both synthetic and natural polymers play essential and ubiquitous roles in everyday life. Polymers range from familiar synthetic plastics such as polystyrene to natural biopolymers such as DNA and proteins that are fundamental to biological structure and function. Polymers, both natural and synthetic, are created via polymerization of many small molecules, known as monomers. Their consequently large molecular mass relative to small molecule compounds produces unique physical properties, including toughness, viscoelasticity, and a tendency to form glasses and semicrystalline structures rather than crystals. The terms polymer and resin are often synonymous with plastic.

Viscosity physical property of a fluid

The viscosity of a fluid is a measure of its resistance to deformation at a given rate. For liquids, it corresponds to the informal concept of "thickness": for example, syrup has a higher viscosity than water.

An animation illustrating the exterior/interior compositions of a tablet of Concerta, a PSOP OROS design. Concerta OROS overcoat.gif
An animation illustrating the exterior/interior compositions of a tablet of Concerta, a PSOP OROS design.

In the early 1990s, an ALZA-funded research program began to develop a new dosage form of methylphenidate for the treatment of children with Attention Deficit Hyperactivity Disorder (ADHD). [14] Methylphenidate's short half-life required multiple doses to be administered each day to attain long-lasting coverage, which made it an ideal candidate for the OROS technology. Multiple candidate pharmacokinetic profiles were evaluated and tested in an attempt to determine the optimal way to deliver the drug, which was especially important given the puzzling failure of an existing extended-release formulation of methylphenidate (Ritalin SR) to act as expected. The zero-order (flat) release profile that the PPOP was optimal at delivering failed to maintain its efficacy over time, which suggested that acute tolerance to methylphenidate formed over the course of the day. This explained why Ritalin SR was inferior to twice-daily Ritalin IR, and led to the hypothesis that an ascending pattern of drug delivery was necessary to maintain clinical effect. Trials designed to test this hypothesis were successful, and ALZA subsequently developed a modified PPOP design that utilized an overcoat of methylphenidate designed to release immediately and rapidly raise serum levels, followed by 10 hours of first-order (ascending) drug delivery from the modified PPOP design. This design was called the Push-Stick Osmotic Pump (PSOP), and utilized two separate drug layers with different concentrations of methylphenidate in addition to the (now quite robust) push layer. [1] [14]

Methylphenidate Medication of the stimulant class

Methylphenidate, sold under the trade names Ritalin among others, is a stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is a first line medication for ADHD. It is taken by mouth or applied to the skin. Different formulations have different durations of effect.

Half-life is the time required for a quantity to reduce to half its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo, or how long stable atoms survive, radioactive decay. The term is also used more generally to characterize any type of exponential or non-exponential decay. For example, the medical sciences refer to the biological half-life of drugs and other chemicals in the human body. The converse of half-life is doubling time.

Hypothesis Proposed explanation for an observation, phenomenon, or scientific problem

A hypothesis is a proposed explanation for a phenomenon. For a hypothesis to be a scientific hypothesis, the scientific method requires that one can test it. Scientists generally base scientific hypotheses on previous observations that cannot satisfactorily be explained with the available scientific theories. Even though the words "hypothesis" and "theory" are often used synonymously, a scientific hypothesis is not the same as a scientific theory. A working hypothesis is a provisionally accepted hypothesis proposed for further research, in a process beginning with an educated guess or thought.

An illustration of the different inner components of a tablet of Concerta, a PSOP OROS design. Concerta OROS diagram.png
An illustration of the different inner components of a tablet of Concerta, a PSOP OROS design.

List of OROS medications

OROS medications include: [1] [3] [4] [7]

Related Research Articles

Pseudoephedrine chemical compound

Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses.

Loratadine chemical compound; medication used to treat allergies

Loratadine, sold under the brand name Claritin among others, is a medication used to treat allergies. This includes allergic rhinitis and hives. It is also available in combination with pseudoephedrine, a decongestant, known as loratadine/pseudoephedrine. It is taken by mouth.

Nifedipine chemical compound

Nifedipine, sold under the brand name Adalat among others, is a medication used to manage angina, high blood pressure, Raynaud's phenomenon, and premature labor. It is one of the treatments of choice for Prinzmetal angina. It may be used to treat severe high blood pressure in pregnancy. Its use in preterm labor may allow more time for steroids to improve the baby's lung function and provide time for transfer of the mother to a well qualified medical facility before delivery. Nifedipine is taken by mouth and comes in fast and slow release formulations.

Transdermal patch

A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of medication delivery such as oral, topical, intravenous, intramuscular, etc. is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. The main disadvantage to transdermal delivery systems stems from the fact that the skin is a very effective barrier; as a result, only medications whose molecules are small enough to penetrate the skin can be delivered by this method. A wide variety of pharmaceuticals are now available in transdermal patch form.

Dexmethylphenidate chemical compound

Dexmethylphenidate, sold under the brand name Focalin among others, is a medication used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of 5 years. If no benefit is seen after 4 weeks it is reasonable to discontinue its use. It is taken by mouth. The immediate release formulation lasts up to 5 hours well the extended release formulation lasts up to 12 hours.

Baclofen group of stereoisomers

Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life. It is taken by mouth or by delivery into the spinal canal.

Atosiban chemical compound

Atosiban is an inhibitor of the hormones oxytocin and vasopressin. It is used as an intravenous medication as a labour repressant (tocolytic) to halt premature labor. It was developed by Ferring Pharmaceuticals in Sweden and first reported in the literature in 1985. Originally marketed by Ferring Pharmaceuticals, it is licensed in proprietary and generic forms for the delay of imminent preterm birth in pregnant adult women. In India it is marketed under the brand name Tosiban by Zuventus healthcare ltd.

Phenylephrine medication with a number of uses

Phenylephrine is a medication primarily used as a decongestant, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids. While marketed as a decongestant, taken by mouth at recommended doses it is of unclear benefit for hay fever. It can be taken by mouth, given by injection into a vein or muscle, or applied to the skin.

Daytrana is a transdermal patch developed and marketed by Noven Pharmaceuticals, Inc. that was approved in April 2006. In the literature, Daytrana is most commonly referred to as methylphenidate transdermal system (MTS).

Drug delivery methods for transporting a drug in the body as needed to safely achieve its desired effect

Drug delivery refers to approaches, formulations, technologies, and systems for transporting a pharmaceutical compound in the body as needed to safely achieve its desired therapeutic effect. It may involve scientific site-targeting within the body, or it might involve facilitating systemic pharmacokinetics; in any case, it is typically concerned with both quantity and duration of drug presence. Drug delivery is often approached via a drug's chemical formulation, but it may also involve medical devices or drug-device combination products. Drug delivery is a concept heavily integrated with dosage form and route of administration, the latter sometimes even being considered part of the definition.

Modified-release dosage is a mechanism that delivers a drug with a delay after its administration or for a prolonged period of time or to a specific target in the body.

Attention deficit hyperactivity disorder management options are evidence-based practices with established treatment efficacy for ADHD. The American Academy of Pediatrics recommends different treatment paradigms depending on the age of the person being treated. For those aged 4–5, the Academy recommends evidence-based parent- and/or teacher-administered behavior therapy, with the addition of methylphenidate only if there is continuing moderate-to-severe functional disturbances. For those aged 6–11, the use of medication in combination with behavior therapy is recommended, with the evidence for stimulant medications being stronger than that for other classes. For those aged 12–18, medication should be prescribed with the consent of the treated adolescent, preferably in combination with behavioral therapy. The evidence for the utility of behavioral interventions in this aged group was rated only "C" quality, however.

Thiolated polymers or designated thiomers are experimental polymers used in biotechnology product development with the intent to enhance absorption of drugs. Thiomers have thiol bearing side chains. Thiomer compounds with low molecular mass are covalently bound to a polymeric backbone consisting of biodegradable polymers, such as chitosan, hyaluronic acid, gelatin, polyacrylates, cyclodextrins, or silicones.

Ethylphenidate chemical compound

Ethylphenidate (EPH) is a psychostimulant and a close analog of methylphenidate.

Itopride chemical compound

Itopride (INN) (brand name Ganaton) is a prokinetic benzamide derivative unlike domperidone. These drugs inhibit dopamine and acetylcholine esterase enzyme and have a gastrokinetic effect. Itopride is indicated for the treatment of functional dyspepsia and other gastrointestinal conditions. It is a combined D2 receptor antagonist and acetylcholinesterase inhibitor.

Bioadhesion is the mechanism by which two biological materials are held together by interfacial forces. When relating this mechanism to the pharmaceutical sciences, mucoadhesion describes the attractive forces between a biological material and mucus or mucous membrane. Mucus membranes adhere to epithelial surfaces such as the gastrointestinal tract (GI-tract), the vagina, the lung, the eye, etc. They are generally hydrophilic as they contain many hydrogen macromolecules due to the large amount of water within its composition. However, mucin also contains glycoproteins that enable the formation of a gel-like substance. Understanding the hydrophilic bonding and adhesion mechanisms of mucus to biological material is of utmost importance in order to produce the most efficient applications. For example, in drug delivery systems, the mucus layer must be penetrated in order to effectively transport micro- or nanosized drug particles into the body.

Insufflation is the act of blowing something into a body cavity. Insufflation has many medical uses, most notably as a route of administration for various drugs.

4-Fluoromethylphenidate

4-Fluoromethylphenidate is a stimulant drug that acts as a higher potency dopamine reuptake inhibitor than the closely related methylphenidate.

References

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  6. ↑ van den Berg, G; van Steveninck, F; Gubbens-Stibbe, JM; Schoemaker, HC; de Boer, AG; Cohen, AF (1990). "Influence of food on the bioavailability of metoprolol from an OROS system; a study in healthy volunteers". European journal of clinical pharmacology. 39 (3): 315–6. doi:10.1007/bf00315121. PMID   2257873.
  7. 1 2 Bass, DM; Prevo, M; Waxman, DS (2002). "Gastrointestinal safety of an extended-release, nondeformable, oral dosage form (OROS: a retrospective study". Drug Safety. 25 (14): 1021–33. doi:10.2165/00002018-200225140-00004. PMID   12408733.
  8. ↑ Modi, NB; Wang, B; Hu, WT; Gupta, SK (January 2000). "Effect of food on the pharmacokinetics of osmotic controlled-release methylphenidate HCl in healthy subjects". Biopharmaceutics & drug disposition. 21 (1): 23–31. doi:10.1002/1099-081x(200001)21:1<23::aid-bdd212>3.0.co;2-v. PMID   11038435.
  9. ↑ Auiler, JF; Liu, K; Lynch, JM; Gelotte, CK (2002). "Effect of food on early drug exposure from extended-release stimulants: results from the Concerta, Adderall XR Food Evaluation (CAFE) Study". Current medical research and opinion. 18 (5): 311–6. doi:10.1185/030079902125000840. PMID   12240794.
  10. ↑ Theeuwes, F (December 1975). "Elementary osmotic pump". Journal of pharmaceutical sciences. 64 (12): 1987–91. doi:10.1002/jps.2600641218. PMID   1510.
  11. ↑ Eckenhoff, B; Yum, SI (April 1981). "The osmotic pump: novel research tool for optimizing drug regimens". Biomaterials. 2 (2): 89–97. doi:10.1016/0142-9612(81)90005-3. PMID   7248427.
  12. ↑ Heimlich, KR (1983). "The evolution of precision drug delivery". Current medical research and opinion. 8 Suppl 2: 28–37. doi:10.1185/03007998309109821. PMID   6851623.
  13. ↑ Haslam, John L.; Rork, Gerald S. "Controlled porosity osmotic pump". Google Patents. United States Patent and Trademark Office. Retrieved 19 March 2016.
  14. 1 2 Swanson, J; Gupta, S; Lam, A; Shoulson, I; Lerner, M; Modi, N; Lindemulder, E; Wigal, S (February 2003). "Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies". Archives of General Psychiatry. 60 (2): 204–11. doi:10.1001/archpsyc.60.2.204. PMID   12578439.
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