Osmotic controlled-release oral delivery system (OROS) /
Gastrointestinal therapeutic system (GITS)
Time edited : 2018/05
I. Technology introduction
The controlled-release technology nowadays can produce oral osmotic pump pharmaceutical formulation or Implantable osmotic pump devices, which can release the active pharmaceutical ingredients (API) in a constant rate in vivo. (zero-order kinetic) ALZA corporation is the pioneer of OROS[i][ii][iii], who first invented single-layer osmotic release system called The Elementary Osmotic Pump (EOP) in 1974.
Since then, there have been nearly seventeen commercial available OROS drugs, most of which only taken once daily due to their long acting period. The driving force of the single-layer osmotic pump is the osmotic pressure differences between inside and outside of the semi-permeable membrane[iv]. The formulation of zero-order kinetic release of drug substance is the most ideal formulation for oral controlled-release drugs. The advantage of osmotic controlled-release are[v][vi][vii][viii][ix][x]:
1. Zero-order kinetic release of drug substance.
2. Minimal affected by gastrointestinal environment including pH, food intake and GI motility, which have better in vivo/in vitro correlation.
3. Reduce the plasma drug concentration fluctuation caused by the normal oral formulation of drugs.
4. Reduce dosing times, significantly increase safety, efficacy and compliance.
Elementary Osmotic Pump (EOP)
EOP is the first generation of osmotic controlled-release product, which can only apply to water soluble API (1 g per 10 to 30 mL water). Because of the unparalleled advantage of OROS formulation, the improvement of EOP needs to be done to extend the applicable range to poorly soluble APIs and find new, replaceable excipients. Thus, push-pull osmotic pump (PPOP) was invented.
Push-Pull Osmotic Pump (PPOP)
PPOP is also a semi-permeable membrane coating tablet with a laser-drilled hole, which contains multi-layer (two or three) rather than a single-layer. One layer contains API, osmotic hydrophilic polymer and other excipients, which called “drug-containing layer”. Another layer called “push layer” contains hydrophilic polymers, a swellable polymer which expand when it absorbs water, and other excipients. The two layers form a drug core, outside the core is a semi-permeable membrane, which contains one or several lase-drilled holes[i][v].
When a OROS tablet enters a water-surrounding environment, surrounding water enters the drug core through semi-permeable membrane, causing the API partly dissolved or suspended in the water with an osmotic pressure, simultaneously, the push-layer absorbs water and starts to expand, as the result, the two forces combined push the API out of the laser-drilled hole. The hydrophilic polymers in the core dissolved in the water contributes to maintaining the osmotic pressure difference, thus also regarded as osmopolymers, the typical representative of osmoploymer is Polyoxyethylene (PEO).
Below is a diagram of the structure and the release mechanism of OROS.
Among the commercial available drugs (i.e. Adalat GITS, Glucotrol XL, etc.), the PEO usually be chosen as main excipient. US2005100602[xi] and US2005100603[xii] patents mentioned the use of PEO as a core excipient of tamsulosin hydrochloride osmotic pump tablets. It is more suitable for poorly soluble APIs to use PEO as the main excipient in OROS tablets, but there still are some disadvantage that mentioned as following:
1. The water absorption rate and hydration rate of PEO are slower, causing delayed onset time.
2. The glass-transition temperature Tg of PEO is around 65~67°C, so it is not ideally thermostable, which would cause unwanted effect during product process and storage. For example, it is more difficult to dry the solvent during granulation process, due to the dry temperature should not excess 40°C which may cause PEO whose Tg is low changed and the amount of residual solvent may increase. As a result, it takes longer to completely dry the granules which may cause unwanted effect to the formulation and the release of the drug. During high speed compression of the tablets, the dies will generate heat and reach around 50°C, and when combined with the usage of PEO, the increased viscosity will lead to unwanted effect, which may need to be solved through extra procedure like lowering the temperature or lowering the speed of compression. Likewise, the storage temperature of OROS tablets containing PEO should not be too high, which will lead to physical or chemical properties changes of PEO and then change the release pattern of the API. So the storage temperature control is crucial.
As a result, the pharmaceutical industries need to find a new formulation , which is convenient to produce OROS controlled-release tablets with low-solubility API, have zero-order release kinetic, have the shortest delayed onset time, can be stored and produced with minimal temperature limit and is ideally taken once a day (QD).
II. Our patented technology
Through years of highly-participated research, we developed a new formulation of OROS drug, which overcome the disadvantage like low thermostability and delayed released time caused by the traditional osmoploymer. Our new formulation can release API, including poorly solubility API, in a 24 hours pattern with zero-order kinetic, which can be taken once a day.
III. New patented technology, wider temperature storage limit.
The new controlled-release technology of Beijing Honglin Parma.Co. is better than the former controlled-release technology with stricter quality control, better quality of our products, wider range of storage temperature. The new formulation we used overcome the temperature and humidity instability, so the storage temperature is not higher than 30°C, on the contrary, the traditional storage temperature of the traditional controlled-release tablet is lower than 20°C. The advantage brings hospitals and other commercial organizations with more convenient, energy-saving storage condition.
IV. Our controlled release technology platform
The research, producing, quality test, social security, environmental protecting and daily maintaining cost of the OROS technology owned by the Beijing Honglin Pharma.Co. The Beijing Honglin Pharma.Co. owns five Chinese patents and four U.S patents, forming a special OROS technology platform including research, pilot plant, scale-up and large commercial scale.
The OROS technology is belong to ALZA corporation, who have had 261 related technology U.S. patents until December, 2001, forming a patent barrier. We broke the patent barrier, made new invention and formed our exclusive new patent technology platform. The OROS tablets requires highly participated production, extremely complex art of manufacture, long manufacturing cycle, precise critical process parameters and high technology automatic production line.
The critical automatic production machineries are imported from different countries, which requires high investments and high maintaining cost. We insist high quality control and quality tests, every product needed to be tested through different test requirements including intermediate product, residual solvent, etc. and some unique tests like special critical process parameters including the position, diameter, depth and appearance of the laser-drilled hole, etc.
Depends on this technology platform, we acquire two production approval, which are glipizide controlled-release tablets and nifedipine extended-release tablets (III).
V. Industrialized, sustainable development of Beijing Honlin Pharma.Co.
The Beijing Honlin Pharma.Co. is a national high and new technology enterprises, also certification by the Beijing Municipal Science and Technology Commission for high-tech enterprises in Zhongguancun Members. The Beijing Honlin Pharma.Co., as the only corporation having commercial available OROS technology in Beijing, is looking forward to enhancing the health quality of people and the level of pharmaceutical industry in China and in Beijing.
We also imported cutting edge, one and only in Southeast Asia laser drilling machine from the U.S., which having automatic online detection and rejection system. And other high quality machine including production machine and high performance liquid chromatography machine, gas chromatography machine, etc.
To protect our staff and the environment, we also imported cycling absorptive exhaust gas purification tower and catalytic combustion device for purifying exhaust gas generated from the coating process.
[i] Malaterre, V; Ogorka, J; Loggia, N; Gurny, R (November 2009). "Oral osmotically driven systems: 30 years of development and clinical use". European Journal of Pharmaceutics and Biopharmaceutics. 73 (3): 311–23.
[ii] Theeuwes, F; Yum, SI; Haak, R; Wong, P (1991). "Systems for triggered, pulsed, and programmed drug delivery". Annals of the New York Academy of Sciences. 618: 428–40.
[iii] Conley, R; Gupta, SK; Sathyan, G (October 2006). "Clinical spectrum of the osmotic-controlled release oral delivery system (OROS), an advanced oral delivery form". Current medical research and opinion. 22 (10): 1879–92.
[iv] Theeuwes, F. (1975). Elementary Osmotic Pump. Journal of Pharmaceutical Sciences, 64(12), pp.1987-1991.
[v] Gupta, BP; Thakur, N; Jain, NP; Banweer, J; Jain, S (2010). "Osmotically controlled drug delivery system with associated drugs". Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques. 13 (4): 571–88
[vi] Verma, RK; Mishra, B; Garg, S (July 2000). "Osmotically controlled oral drug delivery". Drug development and industrial pharmacy. 26 (7): 695–708.
[vii] 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.
[viii] 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.
[ix] 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.
[x] 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.
[xi] Yamanouchi Pharmaceutical Co Ltd (2005). Sustained release pharmaceutical composition. US2005100602.
[xii] Yamanouchi Pharmaceutical Co Ltd (2005). Sustained release pharmaceutical composition. US2005100603.
