Patent Application
20160074329
This invention relates to a multi-configured pharmaceutical dosage form and, more particularly, to a multi-layered tablet pharmaceutical dosage form or various multi-unit formulations suitable for the rate-modulated delivery of single or multiple pharmaceutical compositions.
BACKGROUND TO THE INVENTION
With pain management, it is necessary to develop methods of facilitating treatments that promote compliance with prescriptions and simplify prescribing without increasing adverse effects. Poly-pharmacy is seen as a barrier to prescription compliance and highlights a need for the development of fixed dose combinations which allow the number of tablets taken daily to be reduced, but with no loss in efficacy or an increase in the incidence of side effects. The expected benefits of analgesic combinations include reduced onset of action, increased duration of action, improved efficacy, reduced opioid intake and reduced adverse reactions.
The combining of analgesic drugs with differing mechanisms of nociceptive pain modulation offers benefits including synergistic analgesic effects where the individual agents or components of a therapeutic composition act in a greater than additive manner, and a reduced incidence of side effects. The combinations are most effective when the individual agents act via unique analgesic mechanisms and act synergistically by inhibiting multiple pain pathways, This multimodal coverage offers more effective relief for a broader spectrum of palm Opioids are considered first line medication for relieving severe nociceptive pain but are inadequate in controlling dynamic pain as well being associated with significant side effects. Alternative pain relief using non-opioid analgesics historically relied on paracetamol supplemented with non-steroidal anti-inflammatory drugs (NSAIDs).
Analgesic superiority of a fixed dose combination of paracetamol and tramadol over either individual component, without an increase in side effects has been shown. The fixed combination allows for a reduction in the dose of tramadol, and thereby a reduction in its associated adverse effects, with an equivalent level of analgesia. Data demonstrates that rather than being additive in therapeutic effect, such combinations are, in fact, synergistic.
In a recent study, a codeine/paracetamol/ibuprofen combination was compared against a tramadol/paracetamol combination for the total pain relief that occurred and the sum of the pain intensity differences. During the five- and six-hour assessments of this study the triple combination, that included a different opioid and NSAID than those proposed, showed significant superiority. The vast improvement in duration of action observed four to six hours post-dosing was thought to be due to the anti-inflammatory component.
A pharmacokinetic explanation for this may have been observed in a study which showed that diclofenac transiently reduced the glomerular excretion of the active codeine metabolites, by decreasing prostacyclin production and reducing renal blood flow. This addition of diclofenac to paracetamol and codeine, significantly prolonged the time until analgesic rescue medication was required. No renal pathology is anticipated for the combined used of tramadol and diclofenac as the parenteral combination was tolerated similarly as well as diclofenac or tramadol alone and with no significant increases in side effects compared with placebo dosing, when used for pain in a recent study.
U.S. Pat. No. 5,516,803 describes a composition of tramadol and a NSAID. In a study using tramadol and ibuprofen on the acetylcholine-induced abdominal constriction in mice, the combination resulted in unexpected analgesic activity enhancement. It was postulated from these results that other NSAIDs, when combined with tramadol, would show similar synergistic activity.
As referenced in U.S. Pat. No. 6,558,701, describing a multilayer tablet for the administration of a fixed combination of tramadol and diclofenac, the World Health Organisation recommends combining opioid analgesics with NSAIDs for the treatment of moderate to severe pain. The invention of a parenteral suspension of a salt of tramadol and diclofenac, shown in beagle dogs to retard the metabolism of tramadol and thereby prolong analgesia, is described in U.S. Pat. No. 6,875,447.
The fixed combination of tramadol and paracetamol in Tramacet™ (Janssen-Cilag Ltd.) has proved to be a therapeutic advantage and the efficacy of both these active pharmaceutical ingredients seems to benefit from the addition of a NSAID according to the above-cited research. U.S. Pat. No. 5,516,803 describes the super-additive advantage gained by combining tramadol and a NSAID and two other patents describe advantages in fixed dose combinations of tramadol and diclofenac, in particular. Thus also taking account the safety and efficacy profile of the NSAID class, where diclofenac is clinically associated with the second lowest relative risk,(11) and its potency substantially greater than several other agents, a fixed dose combination of tramadol, paracetamol and diclofenac, is proposed in this invention.
A vast number of receptors, biochemical transmitters and physiological processes are involved in the response and sensation of pain. Many pharmacological modalities target one specific site in order to attempt to reduce the pain symptom, and therefore do not provide satisfactorily adequate pain relief.
Nociceptive pain is pain that has a known or obvious source, such as trauma or arthritis. Neuropathic pain is defined by the International Association for the Study of Pain as pain that is initiated or caused by a primary lesion or dysfunction in the nervous system, and may be central or peripheral. Pain signals due to noxious stimuli such as inflammatory insults are converted into electrical impulses in the tissue nociceptors that are found within dorsal root ganglions. Nociceptive and neuropathic pain signals utilize the same pain pathways. The intensity, quality and location of the pain are conveyed to the sensory cortex from the somatosensory thalamus.
During persistent pain the inter-neurons in the dorsal horn release endogenous opioids in order to reduce the perceived pain. Exogenously administered opioids are thought to mimic the enkephalin and dynorphin effects of the p-opioid receptors in the brain and spinal cord. They act peripherally on injured tissue to reduce inflammation, on the dorsal horn to impede nociceptive signal transmission and at the supraspinal level, where they activate inhibitory pathways of spinal nociceptive processing. Opioids are powerful analgesic drugs that are used as an adjunctive treatment in addition to paracetamol or NSAIDs.
Tramadol [30% water solubility; pKa 9.41; elimination half-life (t1/2) 6 hours] is a weak μ- and κ-opioid receptor agonist and acts on the monoamine receptors of the autonomous nervous system preventing nor-adrenaline reuptake and displacing stored 5-HT. The synergy of its opioid and monoaminergic activity results in its analgesic activity in moderate to severe pain. It is clinically associated with fewer adverse events and a lower addictive potential, thought to be due to its binary mechanism of action, than the traditional opioids and is effective for various types of post-operative pain, In order to reduce the occurrence of adverse effects associated with opioid analgesics, they are often combined with non-opioid agents to reduce the amount of opioid needed to result in equivalent analgesia. Thus, tramadol is commonly prescribed in low-dose formulations in combination with paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs). The addition of a NSAID to tramadol may also result in synergistic anti-nociception.
Paracetamol [1.4% water solubility at 20° C.; pKa 9.5; elimination half-life (t1/2) 1 to 3 hours], a para-aminophenol derivative, has central anti-nociceptive effects involving serotonin and serotinergic descending inhibitory pathways. It is used for its analgesic and anti-pyretic properties in mild to moderate pain and fever, and as an adjunct to opioids in the management of severe pain. It is an agent known for its excellent antipyretic effectiveness and safety profile. Dependence and tolerance are not considered a limitation in the use of non-opiod analgesics, but there is a ceiling of efficacy, above which an increase in dose provides no further therapeutic effect. In rheumatic conditions the weak anti-inflammatory activity of paracetamol limits its contribution to pain management, usually requiring the anti-inflammatory effects of the NSAIDs. The addition of an NSAID to paracetamol has been shown to improve post-operative pain treatment.
Non-steroidal anti-inflammatory drugs, (such as diclofenac, a phenylacetic acid derivative), are anti-pyretic and analgesics with central and peripheral effects. They act by inhibiting cyclo-oxygenase (COX) enzymes and synthesizing prostaglandin E2 in traumatized and inflamed tissue, thereby increasing the threshold of activation of nociceptors. They exert anti-inflammatory effects due to their acidic character and extensive protein binding. The capillary leakage of plasma proteins and the acidic pH in the extracellular space of inflamed tissue, allows NSAIDs to concentrate in the injured tissue and exert their effects. As surgical trauma initiates peripheral inflammatory reactions that result in pain, NSAIDs are an effective post-operative option. Diclofenac [0.187% water solubility at pH 6.8; pKa 4.0; terminal plasma half-life (t1/2) 1 to 2 hours] is an analgesic, antipyretic and anti-inflammatory agent that is extensively used in the long-term symptomatic treatment of rheumatoid arthritis and osteoarthritis and for the short-term treatment of acute musculoskeletal injuries, post-operative pain and dysmenorrhoea.
The administration of NSAIDs with opioids has been shown to reduce post-operative opioid consumption, allow an earlier return of post-operative bowel function and reduce the incidence of bladder spasm. In the management of severe visceral pain, analgesia seems less amenable to NSAID therapy but combination with opioids may achieve good results. The fixed combination of tramadol and paracetamol in Tramacet™ (Janssen-Cilag Ltd.) has proved to be a therapeutic advantage and the efficacy of both these active pharmaceutical ingredients seems to benefit from the addition of a NSAID according to the above-cited research. U.S. Pat. No. 5,516,803 describes the super-additive advantage gained by combining tramadol and a NSAID and two other patents describe advantages in fixed dose combinations of tramadol and diclofenac, in particular, Thus also taking account the safety and efficacy profile of the NSAID class, where diclofenac is clinically associated with the second lowest relative risk, and its potency substantially greater than several other agents, an oral rate-modulated, site-specific pharmaceutical dosage form comprising a fixed dose combination of tramadol, paracetamol and diclofenac, is proposed,
The acronym “API” when used in this specification is intended to refer to an active pharmaceutical ingredient and to its synonym, a pharmaceutically active ingredient.
It is an object of this invention to provide a multi-configured pharmaceutical dosage form and, more particularly, to provide a multi-layered tablet pharmaceutical dosage form or various multi-unit formulations suitable for the rate-modulated delivery of single or multiple pharmaceutical compositions.
In accordance with this invention there is provided a pharmaceutical dosage form for the delivery of at least one active pharmaceutical ingredient (API) or the pharmaceutically active salts and isomers thereof, to a desired absorption location of the human or animal body in a predetermined rate-modulated manner.
There is also provided for the desired absorption location of the human or animal body to be the gastrointestinal tract and for the pharmaceutical dosage form to be orally ingestible and, preferably, in the form of a tablet or capsule.
There is further provided for the dosage form to be in the form of a multilayered tablet preferably three layers, and for each layer to include an API, or the pharmaceutically active salts and isomers thereof, preferably tramadol, paracetamol and diclophenac, which is deliverable to a desired absorption location of the gastrointestinal tract. Alternatively there is provided for the dosage form to be in the form of a capsule and for the API or APIs, preferably tramadol, paracetamol and diclophenac, or the pharmaceutically active salts and isomers thereof, so be formed into discrete granules which are located within the capsule.
There is further provided for the or each API to be integrated, preferably by mixing or blending, into a platform formed from at least one and preferably a matrix of polymers and, where appropriate, excipients which, in use, inhibit release of an API in a region of the gastrointestinal tract other than the desired absorption location and facilitate release of the API in a rate controlled manner when in the desired absorption location.
There is further provided for the or each API, or the pharmaceutically active salts and isomers thereof, to be mixed with one or more excipients having a known chemical interaction such as crosslinking, dissolution rate of pH dependency, erodibility and/or swellability so that, in use, the or each API, or the pharmaceutically active salts and isomers thereof, can be released over a desired period of time, preferably in a rate-controlled manner which may be rapid alternatively slowly.
There is further provided for the polymer or polymers used in the pharmaceutical dosage form to be one or more of: a standard hydrophilic polymer or polymers, a hydrophilic swellable and/or erodible polymer or polymers, a standard hydrophobic polymer or polymers, a hydrophobic swellable and/or erodible polymer or polymers, and, preferably, one or more polymers selected from the group consisting of:: hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyethylene oxide (PEO), polyvinyl alcohol (PVA), sodium alginate, pectin, ethylcellulose (EC), poly(lactic) co-glycolic acids (PLGA), polylactic acids (PLA), polymethacrylates, polycaprolactones, polyesters and polyamides, and for the polymer or polymers to be mixed with a co-polymer or used alone in the pharmaceutical dosage form.
There is also provided for the polymer or polymers to impart, to the API, or the pharmaceutically active salts and isomers thereof, in use, a phasic drug release profile and thus a time-controlled release of the or each API, preferably tramadol and paracetamol, or the pharmaceutically active salts and isomers thereof, which is released first and which is absorbed in the operatively upper regions of the gastrointestinal tract and zero-order release kinetics for an API, preferably diclofenac, or the pharmaceutically active salts and isomers thereof, which is released second and which is absorbed in a lower portion of the gastrointestinal tract.
There is further provided for the polymer or polymers to provide, in use, first-order release kinetics of one or more APIs, preferably tramadol and paracetamol, or the pharmaceutically active salts and isomers thereof, from a first outer layer or a tabletised dosage form having three layers and zero-order release kinetics of an API, preferably tramadol and paracetamol, or the pharmaceutically active salts and isomers thereof, from a second outer layer of the tabletised dosage form.
There is further provided for the polymer or polymers to provide, in use, first-order release kinetics of the or each APIs, preferably tramadol and paracetamol, or the pharmaceutically active salts and isomers thereof, from one or both outer layers of the tabletised dosage form which has three layers.
There is also provided for the pharmaceutically active composition/s to be from among an analgesic combination, preferably paracetamol, tramadol and diclofenac, and for each or a combination of at least two of the pharmaceutically active composition/s to be incorporated into at least one tablet-like layer that is mixed with various polymeric permutations and pharmaceutical excipients that are able to control the release of the said pharmaceutically active composition/s, or alternatively have the same alternating polymeric permutations and pharmaceutical excipients in each layer. The said pharmaceutically active composition/s may, for example, in the case of paracetamol and tramadol, or may not demonstrate synergistic therapeutic activity.
There is further provided for the dosage form to include a number of pharmaceutically active compositions which are selected to provide a treatment regimen for a specific condition or conditions such as, for example, a circulatory disorder in which case the dosage form could have three layers, the first layer containing, as a pharmaceutically active composition, a cholesterol medication, the second layer containing, as a pharmaceutically active composition, an antihypertensive and the third layer containing, as a pharmaceutically active composition, a blood thinning agent, preferably aspirin and for each of these pharmaceutically active compounds to be released, in use, with a desired release kinetic profile.
The invention extends to a method of manufacturing a pharmaceutical dosage form as described above comprising mixing a polymer in various concentrations, a pharmaceutical excipient, preferably a desired crosslinking agent and a lubricant, such as, for example, magnesium stearate, and at least one API or the pharmaceutically active salts and isomers thereof, to form at least one of layer of a number, preferably three, of layers in the pharmaceutical dosage form, for the or each layer to be dimensioned and configured so that, in use an API is released therefrom over a desired period of time and preferably in a rate-controlled manner which may be rapid alternatively slowly as a result of variations in the polymeric materials employed, pharmaceutical excipients, chemical interactions such as crosslinking that may be in situ, and/or diffusion path-lengths created,
There is also provided for the pharmaceutical dosage form to have at least one outer layer and, in addition to this, a middle or inner layer of rate-modulating polymeric material, preferably selected from the group consisting of polyethylene oxide and alginates, and at least one crosslinking reagent, preferably ,zinc gluconate, to provide, in use, zero-order release kinetics of an API, preferably diclofenac, or the pharmaceutically active salts and isomers thereof.
There is also provided for the outer layers of the dosage form to include a rate-modulating polymeric material, preferably polymeric material from among the group consisting of hydroxyethylcellulose, sodium starch glycollate, pregelatinised starch, powdered cellulose, maize starch and magnesium stearate, to provide, in use, first-order release kinetics of one or more APIs, preferably tramadol and paracetamol, or the pharmaceutically active salts and isomers thereof.
There is further provided for the dosage form to be tabletised and for the or each polymer to be selected to provide, in use, selected delivery profiles of the or each API from each tabletised layer, preferably in a zero-order manner from a central layer, and phasic release from two outer tablet-like layers if the said pharmaceutical dosage form comprises a total of three layers thus providing, in use, therapeutic blood levels similar to those produced by individual multiple smaller doses.
There is also provided for the API or APIs to be a combination of analgesics, preferably paracetamol, tramadol and diclofenac, and for each or a combination of at least two of the APIs to be incorporated into at least one tablet-like layer that is mixed with various polymeric permutations and pharmaceutical excipients that are able to control the release of the said pharmaceutically active composition's, or alternatively have the same alternating polymeric permutations and pharmaceutical excipients in each layer. The said pharmaceutically active composition/s may or may not demonstrate synergistic therapeutic activity.
The above and additional features of the invention will now be described and exemplified below with reference to the following non-limiting examples in which:
PEO and Iginate/calcium chloride in the outer layers at pH 6.8 over 24 hours.
and in the following tables in which:
Table 1: provides data on the dissolution study conditions;
Table 2: shows data of chromatographic conditions for combined API analysis; and
Table 3: shows the formulae studied using APIs in a 1:2 ratio with cellulose polymers.
The examples begin with the methods employed to develop an innovative pharmaceutical dosage form for facilitating the treatment of mild to moderate pain that promotes patient compliance and simplifies prescribing without increasing the side-effects of the drugs according to the invention and also endeavours to illustrate the apparent improvements on previous studies performed in an attempt to address the delivery of pharmaceutical active composition/s for the treatment and management of pain and more particularly of polymers, excipients and dosage forms according to the invention,
The suitability of a high performance liquid chromatographic (HPLC) method was confirmed by performing linearity plots for the combined APIs, Stock solutions of the active pharmaceutical ingredients were made. A 25%, 50%, 75%, 100% and 125% solution of APIs paracetamol, tramadol hydrochloride and diclofenac potassium was produced. Samples were processed by gradient elution techniques using a Waters 2695 Alliance Separations Module and Waters 2996 Photo Diode Array detector.
Initial dissolution characteristics of the combined APIs paracetamol, tramadol hydrochloride and diclofenac potassium; individual and combined cellulose and ethylene oxide-based polymers were determined by producing experimental batches of tablets. These were produced on a Manesty Single Punch Type F3 machine by direct compression and wet granulation techniques into monolithic matrix and multi-layered systems, as shown in
Dissolution studies were conducted using a USP rotating paddle method (Hanson Virtual Instruments SR8 Plus Dissolution Test Stations) at 50 rpm in phosphate buffer pH 6.8 (900 mL, 37° C.±0.5° C.) for each formulation employing an autosampler (Hanson Research Auto Plus Maximiser and AutoPlus™ MultiFill™). Samples of 1.6 mL were withdrawn over a period of 12 to 20 hours and analysed via HPLC, Release profiles in simulated gastric fluid pH 1.2 without pepsin over a period of four hours were determined to identify any site-specific release induced by the polymers, The dissolution studies were performed under the conditions described in Table 1.
The assay method developed displayed superior resolution of the API combinations and the linearity plots produced indicated that the method was sufficiently sensitive to detect the concentrations of each API over the concentration ranges studied (R2=0.99 for paracetamol, tramadol hydrochloride and diclofenac potassium). The chromatographic conditions are mentioned in Table 2.
Initially paracetamol and tramadol hydrochloride showed good resolution from one another but it seemed that diclofenac potassium was retained for a longer period on the column, due to its base properties, when a run time of ten minutes was used. To overcome this, the gradient run time was increased to 14 minutes and the concentration of the organic modifier increased.
As evident in
The calibration curves or linearity plots produced indicate that the method is sufficiently sensitive to detect concentrations of each of the three APIs over the concentration ranges studied. All three APIs gave linear response over the tested range. The coefficient of determination, R2 or the proportion of variability in the data set is as mentioned previously. As each value is close to one, it provides assurance that the degree of goodness of fit of the linear model is satisfactory.
A series of experiments were performed in order to assess the pharmaceutical dosage form and attain the desired drug release profiles. These experiments are discussed hereunder.
Initial dissolution characteristics of the combination of the three APIs and individual polymers were determined by producing small batches of tablets each with a different polymer. The tablets were produced using direct compression on a Manesty Single Punch Type F3 compression machine (England) fitted with 22×9mm caplet-shaped punches. The ratio of polymer to actives was kept at 2:1 with 0.5% magnesium stearate added to ensure sufficient lubrication during compression. The ingredients were blended by hand in a polyethylene bag for three minutes prior to compression. The formulae are presented in Table 3 below. The dissolution profiles obtained for each API are displayed in
A cellulose and polyethylene oxide-based formulation was subjected to monolithic and layered tableting technology, with the three APIs demonstrating markedly different behaviour dependent solely upon their location within the dosage unit, Diclofenac potassium demonstrated both first-order and zero-order kinetics, when compressed as a monolithic matrix or layered dosage form respectively.
Various pectin, alginate and eudragit polymers that displayed desired in vitro crosslinking activity with metallic salts, were incorporated into the dosage form, to determine the effects of these polymers on the release characteristics of the combined APIs. Paracetamol and tramadol hydrochloride still showed first-order release while potassium diclofenac retained its zero-order release curve as evidenced in the release profiles in
The concentration of HEC and HPC in paracetamol/tramadol layers 1 and 2 were halved to 90.6 mg and 181.25 mg respectively in the first formulation in this series (
The first experiment in this series involved reducing HEC in layer 1 to 22.6 mg and HPC in layer 2 to 45.31 mg (
This formulation reduced the HEC in layer 1 to 27.10 mg and the HPC in layer 2 to 54.36 mg while the PEO in layer 3 was increased to 100 mg. The alginate in layer 3 remained at 12.5 mg.
The polymer concentration in layer 1 and 2 was increased by a factor of two (HEC54.38 mg and HPC=108.72 mg) to slow the release rate slightly and make it more site specific and the PEO was increased to 200 mg/tablet to improve zero-order release. Dissolutions were performed over a period of 12 hours. The first experiment increased PEO to 200 mg per tablet, with layer 3 being blended and layers 1 and 2 granulated (
The quantity of polyethylene oxide in the diclofenac potassium layer was increased to 300 mg, 400 mg, and 500 mg to see the effect on the zero-order diclofenac profile. The 200 mg polyethylene oxide experiment was repeated with the lower molecular weight material (WSR301). The 200 mg and 400 mg experiment were run over both 8 hours and 24 hours to visualise the release effect over a 24 hour period.
The incorporation of assorted cellulose-based polymers on the typical release response of combinations of paracetamol, diclofenac potassium and tramadol hydrochloride resulted in each API displaying slight differences in their release response to the cellulose polymers implying possible rate modulating activity. The release profiles of each API obtained with various cellulose-based polymers were similar despite differing solubilities, indicating that the polymers were influential in controlling drug release.
A cellulose and polyethylene oxide-based formulation was subjected to monolithic and layered tableting technology, with the three APIs demonstrating markedly different behaviour dependent solely upon their location within the dosage unit. Diclofenac potassium demonstrated both first-order and zero-order kinetics, when compressed as a monolithic matrix or layered dosage form respectively.
Various pectin, alginate and eudragit polymers that displayed desired in vitro crosslinking activity with metallic salts were incorporated into the dosage form, to determine the effects of these polymers on the release characteristics of the combined APIs. Paracetamol and tramadol hydrochloride showed first-order release while diclofenac potassium retained its zero-order release curve.
In order to establish the potential site-specific release potential of the polymeric dosage form, formulations consisting of cellulose, polyethylene oxide and alginate polymers were subjected to dissolution studies in simulated gastric fluid pH 1.2 without pepsin. Typical results from these studies, shown in
An additional number of experimental formulations were run based on the previous formulation containing 400 mg PEO. In formulation A the HEC in layer 1 was reduced to 5.12% and PEO included at 15.37% in order to keep the proportion of polymer in layer 1 constant. Layer 2, the other outer layer, was adjusted to include 8.5% HPC and 25.5% PEO. The diclofenac layer remained unchanged in this experimental series. Formulation B displayed the dissolution profile when alginate and zinc gluconate, as well as the PEO, were included in layers 1 and 2 and formulation C calcium chloride instead of zinc gluconate was used as the metallic cross-linker. Formulation D was the same as that for C but with the calcium chloride concentration halved. It was also necessary to determine the effect of having 100% of the paracetamol in the one outer layer and 100% of the tramadol HCl in the second outer layer. Formulation E explored this with the original concentrations of HEC and HPC used in combination with paracetamol and tramadol HCl respectively and formulation F was used to display the effect of including PEO in these outer layers. Formulation G and H were performed to display the effect of the addition of alginate and zinc gluconate and alginate and calcium chloride respectively to these layers. The dissolution profiles are displayed below in
The assay method developed displayed superior resolution of the API combinations and the linearity plots produced indicated that the method was sufficiently sensitive to detect the concentrations of each API over the concentration ranges studied (R2=0.99 for paracetamol and R2=0.99 for tramadol hydrochloride). The dissolution profiles obtained with cellulose and ethylene oxide-based polymers displayed flexible yet rate-modulating drug release kinetics for each API. Typical first-order release kinetics was obtained from the monolithic configurations over a period of 20 hours. in addition, the application of multi-layered tableting technology allowed for the attainment of both prolonged first-order (n≧5) and desirable zero-order (n>0.9) release kinetics.
In addition to the above description, this invention also provides for the delivery of a wide range of other drugs within various drug classes that may or may not be administered as a combination or as a fixed dose combination, which includes but not limited to, anti-inflammatory agents, analgesic agents, anti-histamines, local anesthetics, bactericides and disinfectants, vasoconstrictors, haemostatics, chemotherapeutics, antibiotics, cosmetics, antifungals, vasodilators, antihypertensives, anti-emetics, antimigraine, anti-arrhythmics, anti-asthmatics, antidepressants, peptides, vaccines, hormones, anti-proton pumps, H-receptor blockers or lipid-lowering agents. Examples of potential drug combinations may include but are not limited to, [Antiretrovirals], [neomycin and bacitracin]; [amoxicillin and clavulanic acid]; [imipenem and cilastatin]; [sulfamethoxazole and trimethoprim]; [isoniazid and ethambutol]; [rifampicin and isoniazid]; [rifampicin, isoniazid and pyrazinamide]; [thiacetazone and isoniazid]; [benzoic acid and salicylic acid]; [ethinylestradiol and levonorgestrel]; [ethinylestradiol and levonorgestrel]; [ethinylestradiol and norethisterone]; [levodopa and carbidopa]; [ferrous salt and folic acid]; [sulfadoxine and pyrimethamine]; [lidocaine and epinephrine]; [oral rehydration salts: sodium chloride, trisodium citrate dehydrate, potassium chloride, and glucose]; [lipid-lowering agents and antihypertensives]; [sodium alendronate, colecalciferol, and calcium gluconate]; [furosemide, potassium chloride, and carvedilol]; [colchicine, diclofenac, and prednisolone].
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| Number | Date | Country | Kind |
|---|---|---|---|
| 2008/07122 | Aug 2008 | ZA | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13059803 | Apr 2011 | US |
| Child | 14863659 | US |
