WO2002092056A1 - Compaction process for manufacture of sodium phenytoin dosage form - Google Patents
Compaction process for manufacture of sodium phenytoin dosage form Download PDFInfo
- Publication number
- WO2002092056A1 WO2002092056A1 PCT/IB2002/001425 IB0201425W WO02092056A1 WO 2002092056 A1 WO2002092056 A1 WO 2002092056A1 IB 0201425 W IB0201425 W IB 0201425W WO 02092056 A1 WO02092056 A1 WO 02092056A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- rollers
- blend
- excipient
- granulation
- sodium phenytoin
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
Definitions
- the present invention pertains to a method of manufacturing a dosage form of sodium phenytoin.
- the present invention pertains to a method of manufacturing an orally administered extended release sodium phenytoin capsules.
- a sustained release dosage form may be defined as a preparation which releases a drug, in vivo, at a considerably slower rate than is the case from an equivalent dose of a conventional (nonsustained release) dosage form.
- the objective of employing a sustained release product is to obtain a satisfactory drug response while at the same time, reducing the frequency of administration and maintaining bioequivalence to existing sodium phenytoin formulations.
- An example of a drug, which is popularly used in a sustained release form is chlo ⁇ heniramine maleate.
- the drug may be given as 4 mg doses every 4 hours or in sustained release form as one dose of 12 mg every 12 hours.
- compositions for the sequential or timed release of medicaments are well-known in the art.
- such compositions contain medicament particles, normally administered in divided doses 2 or 3 times daily, mixed with or covered by a material which is resistant to degradation or disintegration in the stomach and/or in the intestine for a selected period of time. Release of the medicament may occur by leeching, erosion, rupture, diffusion or similar actions depending upon the application of the material. In certain cases, . release of hydrophilic material from a formulation can be retarded by application of hydrophobic material. It is known that different pharmaceutical preparations of the same active ingredient will result in different bioavailabilities of the active ingredient to the mammal.
- Bioavailability or biological availability may be defined as the percentage of the drug liberated from the dosage form administered that becomes available in the body for biological effect. Different formulations of the same drug can vary in bioavailability to a clinically relevant extent and variation may even occur between batches of the same product due to subtle variations in . manufacturing procedures.
- Phenytoin 5,5-diphenyl-2,4-imidazolidinedione, is a well-known pharmaceutical agent having anti-convulsant and antiepileptic activity. Due to phenytoin's poor solubility in water, sodium phenytoin, which is much more soluble, is employed in the preparation of injectable solutions of the drug and in solid dosage forms.
- Sodium phenytoin has the following formula:
- phenytoin is the antiepileptic drug of choice for many types of epileptic seizures
- therapeutic drug monitoring is required because of the difficulty in maintaining an effective therapeutic plasma level of between 10 ⁇ g/mL and 20 ⁇ g/mL.
- phenytoin exhibits great variations in bioavailability following its oral administration to patients because of its poor water solubility.
- Kapseals® which are 100 mg extended sodium phenytoin capsules
- Kapseals® product in vivo performance is characterized by a slow and extended rate of absorption with peak blood concentrations expected in 4 to 12 hours.
- the sodium phenytoin microcapsules were prepared by mixing 80% (by weight) of the sodium phenytoin in a 10% (by weight) ethylcellulose solution in ethyl acetate. The suspension was stirred and n-pentane was added dropwise until a phase separation occurred and the microcapsules were obtained. The microcapsules were collected on filter paper, dried and stored. Karakasa et al.
- the salt might be easily transferred into free- phenytoin in the acidic fluids of the stomach.
- free-phenytoin is practically insoluble in water, its absorption' might be incomplete in the gastrointestinal tract.
- the volume of water penetrating into the ethylcellulose microcapsules might be minimal.
- most of the sodium phenytoin in the microcapsules might not be converted into free- phenytoin.
- enteric coated preparations as part of the process of manufacturing a dosage form does not alter a drug's (k abS ) value, they merely delay absorption.
- An enteric coating is designed to prevent absorption in the acidic environment of the stomach.
- the present invention meets the unfulfilled needs described above by providing a process for readily producing a formulation that has a given proportion of a required dose.
- the formulation exhibits bioequivalency to Dilantin® Kapseals® dosage forms.
- the present invention comprises the use of a roller compaction process to form consistent granules, which upon encapsulation provide a predictable dissolution profile.
- the present invention comprises the use of a roller compaction process to form consistent granules which upon encapsulation provide a substantially consistent dissolution profile among various lots of dosage formulation blends comprising the same bulk substance sodium phenytoin.
- the process also produces a reliable and consistent product of sodium phenytoin. Therefore, standard application of this process provides a reliable manufacturing process of sodium phenytoin dosage forms as well as assuring consistent product performance.
- the present invention provides a process for the manufacture of a pharmaceutical product.
- the process comprises the steps of adding sodium phenytoin to a vessel or bowl of a blender and adding at least one excipient to the vessel. Next, the mixture is blended to form a blend.
- the resultant blend is transferred to a roller compactor and compacted between at least two rollers to form a compact with the excipient.
- the pressure imparted on the blend enhances the physical adhesion between the sodium phenytoin and the excipient.
- the compact is subsequently milled to form a granulation.
- the resultant granulation is then formed into the desired dosage form, such as capsules.
- the process comprises the steps of adding sodium phenytoin to a vessel of a blender; adding an excipient to the vessel; blending the sodium phenytoin and the excipient to form a first blend; compacting the first blend with sufficient force between at least two rollers to cause a portion of the sodium phenytoin to fracture and form a compact, wherein the rollers apply a force of between 1 and 20 kilo-Newtons (kN) to the first blend, the rollers rotate at a speed of between 1 and 20 rpm, and wherein the outer edge of said rollers are positioned between 0.5 mm and 5 mm apart at their closest point; milling the compact to form a granulation; and blending the granulation to form a second blend.
- kN kilo-Newtons
- the rollers apply a force of 2.5 kN, the rollers rotate at a speed of 10 rpm, and the outer edge of the rollers are positioned 3 mm apart at their closest point.
- the excipients include magnesium stearate, sugar and lactose monohydrate and the process includes the step of blending talc with the sodium phenytoin granulation.
- the talc may be included as one of the excipients initially mixed with the sodium phenytoin in the vessel.
- patients will benefit from such a formulation since many drugs, like sodium phenytoin, have narrow therapeutic windows, which could require multiple (three or more) daily dosings. . It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention.
- Figure 1 is a graphical representation showing dissolution of a mixture manufactured by the process of the present invention at various compaction forces using same roller gap and speed;
- Figure 2 is a graphical representation showing the dissolution profile of two sodium phenytoin formulations produced by the process of the present invention compared to the dissolution profile of a Dilantin® Kapseals® dosage form.
- the present invention comprises a roller compaction process, which is applied to a mixture of an active pharmaceutical ingredient and one or more excipients to form granules with consistent characteristics.
- the present invention is a process for the production of granules of the active pharmaceutical ingredient sodium phenytoin.
- the process of the present invention involves the use of a roller compaction device having variable rotation speed, force application, and gap width capabilities.
- a Gerteis Polygran dry roller compactor system having 100-mm knurled rollers, commercially available from Gerteis of Germany, is a preferred roller compaction device because the programmable logic control . systems of that roller compactor are relatively easy to operate.
- the roller compactor functions by uniformly applying pressure on a mixed powder blend by passing the blend between two counter-rotating rollers. The pressure imparted on the blend by the rollers compresses the powder into a compact, such as a sheet or ribbon, which is typically milled to produce granules.
- the process of the present invention relates to the discovery that some therapeutic agents, such as sodium phenytoin, can be formulated and processed to yield a dosage form providing sustained blood plasma concentrations of the active pharmaceutical ingredient. It will be understood by the skilled artisan that the effective amounts are released over an intended delivery time and for a desired blood plasma concentration. It has been found that the controlled application of pressure to a mixture of an active pharmaceutical ingredient and at least one excipient during roller . compaction yields a product that is relatively easy to produce yet exhibits sustained release properties in a reproducible manner. Further, in the case of sodium phenytoin, the product is bioequivalent to commercial Dilantin® Kapseals®.
- roller compacting a blend prepared in accordance with the current invention, the ingredients are forced into a state of intimate contact, mixing and adhesion.
- the particles undergo rearrangement, and it is believed that particle fracturing creates multiple surface sites, contact points and bonding sites between the active pharmaceutical ingredient and the excipient.
- the enhanced contact between the active pharmaceutical ingredient and excipient directly affects the dissolution properties of the active pharmaceutical ingredient.
- one or more of the excipients form a drug dissolution inhibiting coating around the active pharmaceutical ingredient upon exposure to the pressure imparted by the roller compactor.
- the present invention comprises the use of a roller compaction process to form consistent granules which upon encapsulation provide a substantially consistent dissolution profile among various lots of dosage formulation blends comprising the same bulk substance sodium phenytoin.
- substantially consistent dissolution profile is intended to mean that the difference in the percentage dissolution of any two formulation batches of the same bulk substance sodium phenytoin is no greater than 15% when measured under the same conditions (e.g., temperature and time) by well-known methods in the art including those exemplified herein. More preferably, this difference is between 10% and 15%, even more preferably between 5 to 10%, yet even more preferably between 2% and 5%; most preferably between 0% and 2%.
- an active pharmaceutical ingredient is deposited in a vessel of a blender, such as a Patterson-Kelley® twin shell blender.
- sodium phenytoin is the active pharmaceutical ingredient.
- the percentages of the constituents shall mean weight percentages.
- the active pharmaceutical ingredient is present at about 25% to 75% of the overall weight of the final dose form.
- 35% to 50% is added to the vessel.
- excipients such as fillers and lubricants are deposited in the vessel of the blender with the active pharmaceutical ingredient, although the order of addition is not important and may be reversed.
- Multiple lubricants may be added to the mixture and are well-known in the art, such as stearic acid and magnesium stearate.
- the lubricant may be added in amounts of about 1% to about 10% of the overall weight of the mixture, preferably 2% to 5%.
- the present invention may also contain at least one filler as an excipient.
- suitable fillers are well-known in the art and typically comprise microcrystallirie cellulose, sorbitol, mannitol, confectioner's sugar, compressible sugar, glucose, lactose monohydrate, and talc.
- confectioner's sugar, lactose monohydrate, compressible sugar, or combinations thereof is added to about 25% to 75% of the overall weight of the mixture.
- Talc may be added to about 0.5% to 5% of the overall weight of the mixture.
- talc may be added to the vessel of the blender with the other fillers, talc may alternatively be added to the mixture just prior to an additional blending step, as described below.
- one or more of the ingredients are first deplumed before being added to the vessel, such as by passing the ingredients through a screen.
- the blender utilized in the processes of the invention is a twin shell blender
- this blender optionally comprises an intensifier bar.
- intensifier bar is intended a bar containing blades that rotate in a direction opposite to that of the twin shell. Utilization of such bars to improve agitation in the powder bed is well-known in the art.
- the blender is activated and the mixture is blended in the vessel of the blender.
- One such blender, described above, which may be used in the present invention is a Patterson-Kelley® blender.
- the powder mixture is deposited in the blender and blended for about 10 to 60 minutes at a speed of about 5 to 30 rpm.
- the resultant blend is subsequently transferred to a roller compactor in a known manner.
- the roller speed, roller gap width, and force of compaction are then adjusted and the blend is fed through the roller compactor in a known manner.
- the process of the present invention compresses the blend of sodium phenytoin and excipients into compacts by applying an optimal force to form the compact.
- the preferred force and other conditions can be selected to provide sufficient adhesion among constituents to permit a suitable dissolution profile.
- One skilled in the art can identify the factors empirically.
- the optimal force is typically between 1 and 20 kN. In such a compactor, the optimal force is preferably between 2 and 6 kN, even more preferably 2.5 kN.
- the rollers rotate at a speed of between 1 and 20 rpm. Preferably, the rollers rotate at a speed of between 5 and 15 rpm. Additionally, the outer edge of the rollers are positioned between 0.5 mm and 5 mm apart, with the outer edges of the rollers are preferably positioned between 2 mm and 4 mm apart at their closest point.
- the roller force is the most significant parameter, as described above and detailed in Example 3.
- This compact is subsequently fed to a mill, typically an oscillating mill, fitted with a screen.
- the screen has a hole diameter between 0.2 mm and 2 mm, most preferably about 1.0 mm. After passing through the mill and screen, the compact is converted into a granulation.
- the granulation is transferred to a blender and blended in a similar manner as described above to form a second blend.
- talc was not added prior to compaction with the other excipients, it may optionally be added prior to this second blending step.
- the resultant blend may be encapsulated in a known manner such as by using a
- Granules may be filled into the body of the capsule dosage form by tamping or dosing and the capsule may be subsequently sealed using a cap.
- the compaction force plays a major role on the dissolution . of sodium phenytoin. Specifically, it was found that the greater the amount of force applied to the blend fed to the roller compactor, the lower the dissolution rate at constant speed and gap. Thus, adjusting the pressure applied to a blend of active ingredient and excipient fed to the roller compactor can reproducibly control the dissolution profile of sodium phenytoin in a dosage form.
- the dosage form prepared in a manner according to the present invention has a similar release profile when compared to Dilantin® Kapseals® dosage forms.
- a blend of sodium phenytoin and excipients was provided in the amounts described in Table 1. The mixture was blended for 10 minutes in a Patterson- Kelly®.
- EXAMPLE 2 To determine the extent to which the force of compaction plays on dissolution o granules produced by the process of the present invention, the roller gap and roller speed process parameters were held constant, as detailed below. Table 2 provides the dissolution data of a portion of the blend described in Example 1 compressed at varying roller forces. The percent of drug dissolved was determined using standard protocols well-known in the art. Specifically, a USP dissolution test was used for each of the sodium phenytoin formulations. Specifically, this test involves placing each capsule in 900 mL of water, which was maintained at 37°C ⁇ 0.5°C and stirred at 50 rpm. Samples were collected at 30, 60, and 120 minutes and tested for the amount of sodium phenytoin dissolved.
- roller force clearly plays the predominant role in determining dissolution profile of the drug product produced in this invention.
- a comparison of the dissolution data from runs 1, 3, and 7 confirm that an increase in roller force reduces the dissolution rate.
- statistical analysis reveals that the roller gap width and speed do not affect the dissolution rate to the same extent.
- EXAMPLE 4 The process parameters of the invention were further tested using various preparations of the bulk substance sodium phenytoin. Unless otherwise indicated, all procedures and parameters were according to those described above. The ingredients and the weight ratios shown in Table 1 was kept the same, with the optional substitution of confectioner's sugar for compressible sugar. This data is summarized below in Tables 4-10 and shows that substantially consistent dissolution profiles are achieved for a given sodium phenytoin bulk drug substance. Three sodium phenytoin bulk drug substances (I, ⁇ , and HI) were evaluated with the present invention.
Landscapes
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2003-7014779A KR20030096392A (en) | 2001-05-15 | 2002-04-25 | Compaction Process for Manufacture of Sodium Phenytoin Dosage Form |
IL15851802A IL158518A0 (en) | 2001-05-15 | 2002-04-25 | Compaction process for manufacture of sodium phenytoin dosage form |
EP02722623A EP1392246A1 (en) | 2001-05-15 | 2002-04-25 | Compaction process for manufacture of sodium phenytoin dosage form |
CA002446957A CA2446957A1 (en) | 2001-05-15 | 2002-04-25 | Compaction process for manufacture of sodium phenytoin dosage form |
MXPA03009805A MXPA03009805A (en) | 2001-05-15 | 2002-04-25 | Compaction process for manufacture of sodium phenytoin dosage form. |
HU0304078A HUP0304078A2 (en) | 2001-05-15 | 2002-04-25 | Compaction process for manufacture of sodium phenytoin dosage form |
BR0209644-7A BR0209644A (en) | 2001-05-15 | 2002-04-25 | Compaction process for the manufacture of a sodium phenytoin dosage form |
JP2002588974A JP2004531548A (en) | 2001-05-15 | 2002-04-25 | Compression method for the production of sodium phenytoin dosage form |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US29097001P | 2001-05-15 | 2001-05-15 | |
US60/290,970 | 2001-05-15 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002092056A1 true WO2002092056A1 (en) | 2002-11-21 |
WO2002092056A8 WO2002092056A8 (en) | 2003-10-23 |
Family
ID=23118256
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2002/001425 WO2002092056A1 (en) | 2001-05-15 | 2002-04-25 | Compaction process for manufacture of sodium phenytoin dosage form |
Country Status (16)
Country | Link |
---|---|
US (1) | US20030083360A1 (en) |
EP (1) | EP1392246A1 (en) |
JP (1) | JP2004531548A (en) |
KR (1) | KR20030096392A (en) |
CN (1) | CN1527700A (en) |
AR (1) | AR034332A1 (en) |
BR (1) | BR0209644A (en) |
CA (1) | CA2446957A1 (en) |
CZ (1) | CZ20033116A3 (en) |
HU (1) | HUP0304078A2 (en) |
IL (1) | IL158518A0 (en) |
MX (1) | MXPA03009805A (en) |
PL (1) | PL366728A1 (en) |
RU (1) | RU2262922C2 (en) |
WO (1) | WO2002092056A1 (en) |
ZA (1) | ZA200308353B (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004054550A1 (en) * | 2002-12-16 | 2004-07-01 | Ranbaxy Laboratories Limited | An extended release pharmaceutical composition of phenytoin sodium |
WO2004075826A2 (en) * | 2003-02-28 | 2004-09-10 | Ranbaxy Laboratories Limited | Extended release, multiple unit dosage forms of phenytoin sodium and processes for their preparation |
WO2018106107A1 (en) * | 2016-12-06 | 2018-06-14 | Kopsky David Jos | Topical phenytoin for use in the treatment of peripheral neuropathic pain |
US10668089B2 (en) | 2006-06-21 | 2020-06-02 | Opko Ireland Global Holdings, Ltd. | Method of treating and preventing secondary hyperparathyroidism |
US11007204B2 (en) | 2006-02-03 | 2021-05-18 | Opko Renal, Llc | Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 |
US11007205B2 (en) | 2014-08-07 | 2021-05-18 | Eirgen Pharma Ltd. | Adjunctive therapy with 25-hydroxyvitamin D and articles therefor |
US11147799B2 (en) | 2016-12-06 | 2021-10-19 | Jan Marius Keppel Hesselink | Topical pharmaceutical composition containing phenytoin and a (co-) analgesic for the treatment of chronic pain |
US11154509B2 (en) | 2007-04-25 | 2021-10-26 | Eirgen Pharma Ltd. | Methods for controlled release oral dosage of a vitamin D compound |
US11173168B2 (en) | 2016-03-28 | 2021-11-16 | Eirgen Pharma Ltd. | Methods of treating vitamin D insufficiency in chronic kidney disease |
US11253528B2 (en) | 2013-03-15 | 2022-02-22 | Eirgen Pharma Ltd. | Stabilized modified release Vitamin D formulation and method of administering same |
US11672809B2 (en) | 2010-03-29 | 2023-06-13 | Eirgen Pharma Ltd. | Methods and compositions for reducing parathyroid levels |
US11752158B2 (en) | 2007-04-25 | 2023-09-12 | Eirgen Pharma Ltd. | Method of treating vitamin D insufficiency and deficiency |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060034910A1 (en) * | 2004-08-09 | 2006-02-16 | Sanjay Patel | Pharmaceutical composition for extended release of phenytoin sodium |
FI20080348A0 (en) * | 2008-02-15 | 2008-05-09 | Atacama Labs Oy | A novel pharmaceutical formulation |
CA2694516A1 (en) * | 2007-07-31 | 2009-02-05 | Cargill, Incorporated | Direct compressible dextrose |
CN102125522B (en) * | 2010-01-15 | 2013-01-16 | 复旦大学附属华山医院 | P-glycoprotein monoclonal antibody modified phenytoin targeting nanopreparation and preparation method thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000050014A2 (en) * | 1999-02-23 | 2000-08-31 | Mylan Pharmaceuticals, Inc. | Phenytoin sodium pharmaceutical compositions |
-
2002
- 2002-04-25 PL PL02366728A patent/PL366728A1/en not_active Application Discontinuation
- 2002-04-25 JP JP2002588974A patent/JP2004531548A/en active Pending
- 2002-04-25 BR BR0209644-7A patent/BR0209644A/en not_active IP Right Cessation
- 2002-04-25 RU RU2003133299/15A patent/RU2262922C2/en not_active IP Right Cessation
- 2002-04-25 KR KR10-2003-7014779A patent/KR20030096392A/en not_active Application Discontinuation
- 2002-04-25 CA CA002446957A patent/CA2446957A1/en not_active Abandoned
- 2002-04-25 HU HU0304078A patent/HUP0304078A2/en unknown
- 2002-04-25 EP EP02722623A patent/EP1392246A1/en not_active Withdrawn
- 2002-04-25 CZ CZ20033116A patent/CZ20033116A3/en unknown
- 2002-04-25 IL IL15851802A patent/IL158518A0/en unknown
- 2002-04-25 CN CNA028098951A patent/CN1527700A/en active Pending
- 2002-04-25 WO PCT/IB2002/001425 patent/WO2002092056A1/en not_active Application Discontinuation
- 2002-04-25 MX MXPA03009805A patent/MXPA03009805A/en not_active Application Discontinuation
- 2002-05-13 AR ARP020101738A patent/AR034332A1/en unknown
- 2002-05-14 US US10/145,063 patent/US20030083360A1/en not_active Abandoned
-
2003
- 2003-10-27 ZA ZA200308353A patent/ZA200308353B/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000050014A2 (en) * | 1999-02-23 | 2000-08-31 | Mylan Pharmaceuticals, Inc. | Phenytoin sodium pharmaceutical compositions |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004054550A1 (en) * | 2002-12-16 | 2004-07-01 | Ranbaxy Laboratories Limited | An extended release pharmaceutical composition of phenytoin sodium |
WO2004075826A2 (en) * | 2003-02-28 | 2004-09-10 | Ranbaxy Laboratories Limited | Extended release, multiple unit dosage forms of phenytoin sodium and processes for their preparation |
WO2004075826A3 (en) * | 2003-02-28 | 2005-04-28 | Ranbaxy Lab Ltd | Extended release, multiple unit dosage forms of phenytoin sodium and processes for their preparation |
US11911398B2 (en) | 2006-02-03 | 2024-02-27 | Opko Renal, Llc | Treating Vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 |
US11007204B2 (en) | 2006-02-03 | 2021-05-18 | Opko Renal, Llc | Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 |
US10668089B2 (en) | 2006-06-21 | 2020-06-02 | Opko Ireland Global Holdings, Ltd. | Method of treating and preventing secondary hyperparathyroidism |
US11154509B2 (en) | 2007-04-25 | 2021-10-26 | Eirgen Pharma Ltd. | Methods for controlled release oral dosage of a vitamin D compound |
US11752158B2 (en) | 2007-04-25 | 2023-09-12 | Eirgen Pharma Ltd. | Method of treating vitamin D insufficiency and deficiency |
US11672809B2 (en) | 2010-03-29 | 2023-06-13 | Eirgen Pharma Ltd. | Methods and compositions for reducing parathyroid levels |
US11253528B2 (en) | 2013-03-15 | 2022-02-22 | Eirgen Pharma Ltd. | Stabilized modified release Vitamin D formulation and method of administering same |
US11007205B2 (en) | 2014-08-07 | 2021-05-18 | Eirgen Pharma Ltd. | Adjunctive therapy with 25-hydroxyvitamin D and articles therefor |
US11738033B2 (en) | 2014-08-07 | 2023-08-29 | Eirgen Pharma Ltd. | Adjunctive therapy with 25-hydroxyvitamin D and articles therefor |
US11173168B2 (en) | 2016-03-28 | 2021-11-16 | Eirgen Pharma Ltd. | Methods of treating vitamin D insufficiency in chronic kidney disease |
US11147799B2 (en) | 2016-12-06 | 2021-10-19 | Jan Marius Keppel Hesselink | Topical pharmaceutical composition containing phenytoin and a (co-) analgesic for the treatment of chronic pain |
US11285099B2 (en) | 2016-12-06 | 2022-03-29 | Topical Innovations B.V. | Topical phenytoin for use in the treatment of peripheral neuropathic pain |
AU2017371467B2 (en) * | 2016-12-06 | 2023-06-01 | Jan Marius KEPPEL HESSELINK | Topical phenytoin for use in the treatment of peripheral neuropathic pain |
WO2018106107A1 (en) * | 2016-12-06 | 2018-06-14 | Kopsky David Jos | Topical phenytoin for use in the treatment of peripheral neuropathic pain |
Also Published As
Publication number | Publication date |
---|---|
RU2003133299A (en) | 2005-04-10 |
MXPA03009805A (en) | 2005-03-07 |
CN1527700A (en) | 2004-09-08 |
CA2446957A1 (en) | 2002-11-21 |
JP2004531548A (en) | 2004-10-14 |
HUP0304078A2 (en) | 2004-04-28 |
CZ20033116A3 (en) | 2004-09-15 |
BR0209644A (en) | 2004-07-06 |
WO2002092056A8 (en) | 2003-10-23 |
ZA200308353B (en) | 2004-07-08 |
EP1392246A1 (en) | 2004-03-03 |
PL366728A1 (en) | 2005-02-07 |
AR034332A1 (en) | 2004-02-18 |
US20030083360A1 (en) | 2003-05-01 |
IL158518A0 (en) | 2004-05-12 |
RU2262922C2 (en) | 2005-10-27 |
KR20030096392A (en) | 2003-12-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2563440C (en) | Orally disintegrating tablets and methods of manufacture | |
EP0747050B2 (en) | Pharmaceutical compositions containing irbesartan | |
AU596183B2 (en) | Controlled release bases for pharmaceuticals | |
KR930007245B1 (en) | Process for preparing controlled-release preparation | |
AU737738B2 (en) | Pharmaceutical preparation comprising clodronate as active ingredient and silicified microcrystalline cellulose as excipient | |
EP1392246A1 (en) | Compaction process for manufacture of sodium phenytoin dosage form | |
NZ201008A (en) | Oral preparations containing dipyridamole and at least 5 molar equivalents of orally acceptable acidic excipient | |
JPH01250314A (en) | Gradual release agent | |
WO2001032183A2 (en) | Pharmaceutical compositions comprising oxcarbazepine | |
IE880584L (en) | Pharmaceutical tablet, pharmaceutical granulate and process¹for their preparation | |
AU2010213594A1 (en) | Delayed release, oral dosage compositions that contain amorphous CDDO-Me | |
KR20100126266A (en) | Pharmaceutical compositions | |
CA2632375A1 (en) | Diclofenac formulations and methods of use | |
US20030138496A1 (en) | Drug delivery system for enhanced bioavailability of hydrophobic active ingredients | |
WO2009013306A1 (en) | Improved pharmaceutical composition containing dihydropyridine calcium channel antagonist and method for the preparation thereof | |
WO2006115770A2 (en) | Orally disintegrating pharmaceutical tablet formulations of olanzapine | |
NZ239567A (en) | Sustained release pharmaceutical dosage form: capsule containing minitablets each containing an active agent in a sustained release xanthan gum matrix | |
WO2013082706A1 (en) | Disintegrant-free delayed release doxylamine and pyridoxine formulation and process of manufacturing | |
WO2007007182A2 (en) | Solid and liquid dosage forms of an antiepileptic agent | |
WO2005046648A1 (en) | Extended release pharmaceutical dosage forms comprising alpha-2 agonist tizanidine | |
WO2009043914A1 (en) | Multi particulate matrix system containing galantamine | |
Chaudhary et al. | Recent Development in Floating Drug Delivery System: An Overview | |
AU2002253480A1 (en) | Compaction process for manufacture of sodium phenytoin dosage form | |
CN104922084B (en) | Sodium ibuprofen tablet and method for preparing pharmaceutical composition containing sodium ibuprofen | |
KR20040047920A (en) | Solid pharmaceutical formulation for a piperazine urea derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: P-903/03 Country of ref document: YU |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
WWE | Wipo information: entry into national phase |
Ref document number: 02112499 Country of ref document: CO |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 158518 Country of ref document: IL |
|
CFP | Corrected version of a pamphlet front page | ||
CR1 | Correction of entry in section i |
Free format text: IN PCT GAZETTE 47/2002 UNDER (72, 75) REPLACE "FESSEHAIE, MEBRAHTU, GHEBRETENSAE ¢US/US!" BY "FESSEHAIE, MEBRAHTU, GHEBRETENSAE ¢ER/US!"; GADIRAJU, SRINIVAS, RAJU ¢US/US!" BY "GADIRAJU, SRINIVAS, RAJU ¢IN/US!" AND "GHEBRE-SALLASSIE, ISSAC" BY "GHEBRE-SELLASSIE ISAAC" |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002253480 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2003/009805 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200308353 Country of ref document: ZA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 01000/MUMNP/2003 Country of ref document: IN Ref document number: 1000/MUMNP/2003 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002722623 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2446957 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 028098951 Country of ref document: CN Ref document number: PV2003-3116 Country of ref document: CZ Ref document number: 1020037014779 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002588974 Country of ref document: JP |
|
WWP | Wipo information: published in national office |
Ref document number: 2002722623 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: PV2003-3116 Country of ref document: CZ |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2002722623 Country of ref document: EP |
|
WWR | Wipo information: refused in national office |
Ref document number: PV2003-3116 Country of ref document: CZ |