US20190142808A1 - Sustained-release preparation composition for animals - Google Patents

Sustained-release preparation composition for animals Download PDF

Info

Publication number
US20190142808A1
US20190142808A1 US16/307,544 US201716307544A US2019142808A1 US 20190142808 A1 US20190142808 A1 US 20190142808A1 US 201716307544 A US201716307544 A US 201716307544A US 2019142808 A1 US2019142808 A1 US 2019142808A1
Authority
US
United States
Prior art keywords
sustained
release
dissolution
zonisamide
tablet
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US16/307,544
Other languages
English (en)
Inventor
Teruaki Kuriyama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sumitomo Pharma Animal Health Co Ltd
Original Assignee
DS Pharma Animal Health Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by DS Pharma Animal Health Co Ltd filed Critical DS Pharma Animal Health Co Ltd
Assigned to DS PHARMA ANIMAL HEALTH CO., LTD. reassignment DS PHARMA ANIMAL HEALTH CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KURIYAMA, TERUAKI
Publication of US20190142808A1 publication Critical patent/US20190142808A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention provides a sustained-release composition intended for animal use.
  • the present invention relates to a novel sustained-release formulation of zonisamide.
  • the sustained-release technique in a formulation is first chosen. That is, such technique makes once-daily treatment possible by getting an active ingredient released gradually from a formulation in the gastrointestinal tract after administration, and getting the released active ingredient absorbed into the gastrointestinal tract over a long time.
  • sustained-release mechanism requires a formulation to move in the gastrointestinal tract over a long time.
  • a sustained-release formulation for dogs or the like.
  • the formulation is excreted before all the active ingredient is released, i.e., it is hard to obtain an useful bioavailability.
  • a sustained-release formulation having a fast release rate is tried to obtain an useful bioavailability, it is hard to control the release rate for such short time, that is, the release will eventually become burst-like, which is not different from a normal formulation. In this way, it has been difficult to realize a sustained-release formulation for dogs or the like.
  • epilepsy is one of chronic diseases whose symptom needs to be suppressed in pet animals such as dogs.
  • Epilepsy does not put someone into abnormal behavior in normal times, but once the attack of epilepsy starts, severe symptoms such as convulsion and faint could develop.
  • zonisamide As an antiepileptic drug intended for dogs, zonisamide has been already offered commercially, but zonisamide needs to be taken twice a day. Thus, it has been desired to develop a new drug formulation which makes possible once-a-day medication to reduce guardian's burden.
  • Non-Patent Literature 1 Package insert of CONSAVETM, DS Pharma Animal Health Co., Ltd.
  • the purpose of the present invention is to provide a sustained-release formulation intended for pet animals such as dogs and cats which have relatively short gastrointestinal tract.
  • a formulation comprising zonisamide which makes possible once-a-day medication to reduce guardian's burden, said zonisamide is an antiepileptic drug requiring twice-a-day medication.
  • the present inventors have extensively studied to reach the above purpose, i.e., to find an ideal formulation to complete the drug dissolution within a short time in a lenear release pattern (zero-order release) which is not burst-like release, and then have found that a drug composition comprising a drug, a sugar, a wax, and a water-soluble polymer can complete the dissolution of the whole of the drug within a given short time in pseudo zero-order release pattern, and have demonstrated that the drug composition succeeded in a sustained-release without lowering the bioavailability in an actual pharmacokinetic test with a dog. Based upon the new findings, the present invention has been completed.
  • the present invention can show as follows.
  • a sustained-release composition intended for animal use comprising (i) a drug, (ii) a sugar, (iii) a wax, and (iv) a water-soluble polymer.
  • a preferred example of the sugar includes isomalt, mannitol, and lactose, more preferably isomalt.
  • the sustained-release composition of Term 1 or 2 wherein the (iii) wax is one or more selected from hydrogenated castor oil, hydrogenated rapeseed oil, carnauba wax, stearic acid, and sodium stearyl fumarate.
  • the (iii) wax is one or more selected from hydrogenated castor oil, hydrogenated rapeseed oil, carnauba wax, stearic acid, and sodium stearyl fumarate.
  • a preferred example of the wax includes hydrogenated castor oil.
  • the (iv) water-soluble polymer is one or more selected from gum arabic, xanthane gum, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and methylcellulose (MC).
  • a preferred example of the water-soluble polymer includes gum arabic, hydroxypropylcellulose (HPC), and methylcellulose (MC), more preferably gum arabic, hydroxypropylcellulose (HPC), even more preferably gum arabic.
  • the sustained-release composition of any one of Terms 1-4 wherein the content of the (i) drug is 10 wt %-90 wt %, the content of the (ii) sugar is 5 wt %-90 wt %, the content of the (iii) wax is 0.5 wt %-70 wt %, and the content of the (iv) water-soluble polymer is 2 wt %-80 wt %.
  • the sustained-release composition of any one of Terms 1-4 wherein the content of the (i) drug is 15 wt %-80 wt %, the content of the (ii) sugar is 10 wt %-80 wt %, the content of the (iii) wax is 1 wt %-60 wt %, and the content of the (iv) water-soluble polymer is 4 wt %-70 wt %.
  • the sustained-release composition of any one of Terms 1-4 wherein the content of the (i) drug is 20 wt %-70 wt %, the content of the (ii) sugar is 15 wt %-70 wt %, the content of the (iii) wax is 1.5 wt %-50 wt %, and the content of the (iv) water-soluble polymer is 6 wt %-60 wt %.
  • the animal belonging to Carnivora includes, for example, a pet animal which likes eating meat on a routine basis, more specifically dogs and cats, more preferably dogs.
  • sustained-release composition of any one of claims 1 - 10 which further comprises a lubricant.
  • sustained-release composition of any one of claims 1 - 11 , wherein the dissolution rate in dissolution test of the composition shows a pseudo zero-order release for 1-9 hours.
  • the dissolution test herein is intended to the dissolution test shown in the examples below. Preferably, it shows a pseudo zero-order release for 1.5-6 hours, more preferably a pseudo zero-order release for 2-5 hours.
  • Normal quick-release formulations give a burst-like release in early dissolution.
  • normal sustained-release formulations give a controlled release rate depending on the size of tablet in early dissolution, but the release rate tends to delay gradually in late dissolution because the surface area of the tablet decreases and thereby the release rate in early dissolution cannot be maintained in late dissolution.
  • dissolution of membrane-controlled sustained-release formulations is generally controlled under favor of the concentration difference between inside and outside of the membrane, but the release rate thereof also tends to delay gradually in late dissolution because the concentration of the inside decreases.
  • the composition of the present invention does not produce a burst-like release in early dissolution and does not create a delay in late dissolution, that is, the present composition can realize pseudo zero-order release, which can make a drug therein dissolved at a constant rate independent of time course and make all the drug dissolved out in a given period.
  • the rate of the pseudo zero-order release can be controlled by adjusting the composition of each ingredient, the composition amount, and the mixing ratio. For example, it is possible to prepare a drug formulation which can complete the dissolution in about 3 hours or in another period, which means that it is possible to prepare any ideal compositions suitable for each animal type.
  • the above-mentioned effect of the present invention can be achieved through the difference of solubility in the type of additives, as follows: in early dissolution, an easily-dissoluble part in the tablet disintegrates/dissolves to make the drug at the surface of the table dissolved at a constant rate; as the dissolution progressed, the drug in the tablet inside is also dissolved; in late dissolution, hardly-dissoluble additives in the tablet gradually weaken, and in the end the whole tablet completely disintegrates to dissolve out all the drug.
  • the dissolution behavior is made to become pseudo zero-order release by suitably-specifying the composition of each ingredient, the composition amount, and the mixing ratio.
  • FIG. 1 shows results of Comparative examples 1-3 in the dissolution test using 2nd fluid for dissolution test (pH 6.8 buffer).
  • FIG. 2 shows results of Examples 1-3 in the dissolution test using 2nd fluid for dissolution test (pH 6.8 buffer).
  • FIG. 3 shows results of Examples 4 and 5 in the dissolution test using 2nd fluid for dissolution test (pH 6.8 buffer).
  • FIG. 4 shows results of Examples 6-8 in the dissolution test using 2nd fluid for dissolution test (pH 6.8 buffer).
  • FIG. 5 shows results of Examples 9 and 10 in the dissolution test using 2nd fluid for dissolution test (pH 6.8 buffer).
  • FIG. 6 shows results of Examples 11-13 in the dissolution test using 2nd fluid for dissolution test (pH 6.8 buffer).
  • FIG. 7 shows results of Examples 14-16 in the dissolution test using 2nd fluid for dissolution test (pH 6.8 buffer).
  • FIG. 8 shows results of Examples 17-19 in the dissolution test using 2nd fluid for dissolution test (pH 6.8 buffer).
  • FIG. 9 shows results of Example 20 in the dissolution test using pH 1.2, pH 4.0, pH 6.8 buffers and water as the test media.
  • FIG. 10 shows the concentration-variations of zonisamide in plasma in Test 1 wherein quick-release zonisamide tablet 100 mg ⁇ 1 tablet (100 mg single) was administered.
  • FIG. 11 shows the concentration-variations of zonisamide in plasma in Test 1 wherein sustained-release zonisamide tablet 50 mg ⁇ 4 tablets (200 mg single) was administered.
  • FIG. 12 shows a simulation of the concentration-variations of zonisamide in plasma in Test 1 wherein sustained-release 200 mg tablet is repeatedly administered once a day.
  • FIG. 13 shows a simulation of the concentration-variations of zonisamide in plasma in Test 1 wherein quick-release 100 mg tablet is repeatedly administered twice a day.
  • FIG. 14 shows a simulation of the concentration-variations of zonisamide in plasma in Test 1 wherein quick-release 200 mg tablet is repeatedly administered once a day.
  • the drug used herein includes drugs for a chronic disease in a pet animal such as dogs, which can suppress its symptom through the daily administration. It includes, for example, antiepileptic agents such as zonisamide and imepitoin, medicaments for treating heart failure such as pimobendan and alacepril, and prokinetic agents such as mosapride; preferably it is antiepileptic agents, particularly zonisamide. In the present invention, however, it should not be construed to be limited to these drugs. Any drugs may be used herein as long as they are drugs intended for animal use for suppressing a symptom of a chronic disease through the daily administration.
  • the amount of a drug in the present invention may be chosen from 10 wt %-90 wt % per the whole weight of its formulation, and preferably 15 wt %-80 wt %, more preferably 20 wt %-70 wt %.
  • the sugar used herein should not be limited as long as it is a normal sugar used as a pharmaceutical additive, and it includes, for example, one or more selected from isomalt, mannitol, lactose, sucrose, glucose, and sorbitol; preferably isomalt, mannitol, and lactose; more preferably isomalt.
  • isomalt includes Galen IQ720 (HIGUCHI INC.), Galen IQ721 (HIGUCHI INC.), Galen IQ800 (HIGUCHI INC.), Galen IQ810 (HIGUCHI INC.), and Isomalt Powder for direct tableting (MICROFOODS JAPAN).
  • the amount of a sugar in the present invention may be chosen from 5 wt %-90 wt % per the whole weight of its formulation, and preferably 10 wt %-80 wt %, more preferably 15 wt %-70 wt %.
  • the wax used herein should not be limited as long as it is a normal wax used as a pharmaceutical additive, and it includes, for example, one or more selected from hydrogenated castor oil, hydrogenated rapeseed oil, carnauba wax, stearic acid, and sodium stearyl fumarate; preferably hydrogenated castor oil.
  • hydrogenated castor oil includes Libriwax 101 (FREUND CORPORATION)
  • hydrogenated rapeseed oil includes Libriwax 103 (FREUND CORPORATION)
  • carnauba wax includes Polidhing wax 105 (FREUND CORPORATION)
  • stearic acid includes stearic acid provided by Mallinckrodt Pharmaceuticals
  • sodium stearyl fumarate includes PRUV (Kimura Sangyo Co., Ltd).
  • the amount of a wax in the present invention may be chosen from 0.5 wt %-70 wt % per the whole weight of its formulation, and preferably 1 wt %-60 wt %, more preferably 1.5 wt %-50 wt %.
  • the water-soluble polymer used herein should not be limited as long as it is a normal water-soluble polymer used as a pharmaceutical additive, and it includes, for example, one or more selected from gum arabic, xanthane gum, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), and methylcellulose (MC); preferably gum arabic, hydroxypropylcellulose (HPC), methylcellulose (MC); more preferably gum arabic, hydroxypropylcellulose (HPC); even more preferably gum arabic.
  • polyvinylpyrrolidone PVP
  • polyvinyl alcohol PVA
  • polyethylene glycol PEG
  • dextran pullulan
  • pectin and the like may be also used as the water-soluble polymer of the present invention.
  • gum arabic includes Gum Arabic spray (NIPPON FUNMATSU YAKUHIN Co., LTD.) and Arabic kohl SS (SAN-EI YAKUHIN BOEKI CO., LTD);
  • xanthane gum includes xanthane gum provided by DSP GOKYO FOOD & CHEMICAL CO., LTD.;
  • hydroxypropylcellulose includes HPC-LFP (NIPPON SODA CO., LTD.), HPC-SSL (NIPPON SODA CO., LTD.), HPC-L(NIPPON SODA CO., LTD.), HPC-M (NIPPON SODA CO., LTD.), and HPC-H (NIPPON SODA CO., LTD.);
  • hydroxypropylmethylcellulose includes HPMC and TC5-R (Shin-Etsu Chemical Co., Ltd.); and
  • methylcellulose includes SM-4, SM-15, SM-25, SM-100, SM-400, SM-1500, SM-4000, 605H
  • the amount of a water-soluble polymer in the present invention may be chosen from 2 wt %-80 wt % per the whole weight of its formulation, and preferably 4 wt %-70 wt %, more preferably 6 wt %-60 wt %.
  • composition of the present invention may comprise a general additive for drug product unless the zero-order release behavior is adversely affected, said additive includes, for example, lubricant, carrier, binder, flavor, buffer, thickener, colorant, stabilizer, emulsifier, dispersant, suspending agent, and preservative.
  • Widely-used lubricant herein includes light anhydrous silicic acid, magnesium stearate, and sodium stearyl fumarate; and in more detail, light anhydrous silicic acid includes Aerosil 200 (NIPPON AEROSIL CO., LTD); magnesium stearate includes magnesium stearate (vegetable grade) (Taihei Chemical Industrial Co., Ltd.); and sodium stearyl fumarate includes PRUV (Kimura Sangyo Co., Ltd).
  • the animal in “for animal use” is intended for Carnivora that have relatively short gastrointestinal tract, which include, for example, pet animals such as dogs and cats, preferably dogs. However, it should not be limited to these animals, and it may be used for other animals.
  • the “sustained-release composition” in the present invention is intended to be an oral solid formulation which includes, for example, a tablet, a capsule, and a granule, preferably a tablet.
  • the tablet may be film-coated.
  • the “sustained-release composition” in the present invention can be prepared in a standard manner of formulation production.
  • the tablet includes a plain tablet.
  • the production of a tablet includes, for example, mixing each ingredient in an appropriate mixer, and tableting the mixture with a tableting machine using a suitable punch.
  • a tablet may be also prepared as follows; wet-granulating a portion or all of ingredients in a granulator, adding the other ingredients to the granulated mixture and mixing it if the other ingredients exist, and tableting it with a tableting machine.
  • the “zero-order release” in the present invention means that the dissolution rate in a dissolution test increases linearly with time, and for example, if 100% dissolution is established in 100 minutes, 25%, 50%, and 75% dissolutions are established in 25, 50, and 75 minutes, respectively.
  • the zero-order release means that a formulation product does not give a burst-like release in early dissolution, and complete the dissolution sharply in late dissolution, and the pseudo zero-order release shows a similar dissolution behavior to it.
  • the prepared powder is tableted with a hydraulic tableting machine wherein the diameter of the punch is 6 mm and the tableting pressure is 5 kN.
  • Comparative Comparative Comparative example 1 example 2 example 3 Ingredient mg mg mg zonisamide 50 50 50 isomalt (Galen IQ720) — 49.5 — hydrogenated castor oil — — 10 magnesium stearate 0.25 0.5 0.3 total 50.25 100 60.3 Total amount of actual 20.1 g 20 g 12.6 g production
  • the dissolution test with each test tablet was carried out according to Dissolution Test ⁇ 6.10> in the Japanese Pharmacopoeia 16th Edition (Paddle Method 100 rpm, Dissolution Medium: 2nd fluid for dissolution test (pH 6.8 buffer)).
  • the assay of the active ingredient (zonisamide) in the test sample was carried out according to Liquid Chromatography (HPLC) ⁇ 2.01> in the Japanese Pharmacopoeia 16th Edition, and the detailed condition of the assay was based on the assay of “zonisamide” in the Japanese Pharmaceutical Codex (2002).
  • the dissolution tests of Examples 1-20 shown below were carried out in the same manner. As for Example 20, additional dissolution tests were also carried out with 1st fluid for dissolution test (pH 1.2 buffer), pH 4.0 buffer, and water as dissolution medium.
  • FIG. 1 The result of the dissolution tests with the test tablets is shown in FIG. 1 .
  • Comparative example 1 which was a tablet substantially-consisting of zonisamide exhibited a considerable sustained-release property, but the tablet hardness thereof was real 0 N (newton), which means that it had no quality for practical tablets.
  • Comparative example 2 which was a formulation-type comprising zonisamide and a sugar exhibited an extremely rapid dissolution rate. However, the tablet hardness thereof became practicable by adding a sugar to zonisamide.
  • Comparative example 3 which was a formulation-type comprising zonisamide and a wax exhibited an extremely late dissolution rate.
  • the weighed hydrogenated castor oil and magnesium stearate are screened with 30-mesh-screen, and the screened ingredients are mixed with the other ingredients in a polyethylene bag.
  • the prepared powder is tableted with a hydraulic tableting machine wherein the diameter of the punch is 7 mm and the tableting pressure is 6 kN.
  • Example 1 Example 2
  • Example 3 Ingredient mg mg mg zonisamide 50 50
  • 14 14 magnesium stearate 0.7 0.7 0.7 total 140
  • 140 Total amount of actual 28 g 28 g 28 g production
  • Example 1 In this test, the quantitative influence of hydrogenated castor oil which was added as a wax was studied in formulation-types comprising isomalt+hydrogenated castor oil+gum arabic as additives.
  • the formulation prepared in Example 1 substantially exhibited a targeted zero-order release property in three hours.
  • the property of the present formulation is to complete almost 100% dissolution of a drug at the end of the zero-order release. It is for preventing the shortfall of gastrointestinal absorption in dogs because their gastrointestinal tract has a restricted length.
  • the concept of the present invention was accomplished in Example 1.
  • the weighed hydrogenated castor oil and magnesium stearate are screened with 30-mesh-screen, and the screened ingredients are mixed with the other ingredients in a polyethylene bag.
  • the prepared powder is tableted with a hydraulic tableting machine wherein the diameter of the punch is 7 mm and the tableting pressure is 6 kN.
  • Example 4 Ingredient mg mg zonisamide 50 50 isomalt (Galen IQ720) 61.3 54.3 hydrogenated castor oil 7 7 gum arabic 21 28 magnesium stearate 0.7 0.7 total 140 140 Total amount of actual 28 g 28 g production
  • gum arabic which was added as a water-soluble polymer was studied in formulation-types comprising isomalt+hydrogenated castor oil+gum arabic as additives. There was not so big difference in the dissolution results of Examples 2, 4, and 5 which had different amounts of gum arabic. It is thought that gum arabic as a water-soluble polymer serves as a dissolution regulator which can make the dissolution (of a tablet comprising a sugar and a wax) a natural zero-order release by easing an extreme variation.
  • Each ingredient listed in the table below is weighed.
  • the weighed carnauba wax, stearic acid, sodium stearyl fumarate, and magnesium stearate are screened with 30-mesh-screen, and the screened ingredients are mixed with the other ingredients in a polyethylene bag.
  • the prepared powder is tableted with a hydraulic tableting machine wherein the diameter of the punch is 7 mm and the tableting pressure is 6 kN.
  • Example 6 Example 7 Example 8 Ingredient mg mg mg zonisamide 50 50 50 isomalt (Galen IQ720) 69.7 65.3 65.3 carnauba wax 5.6 — — stearic acid — 10 — sodium stearyl fumarate — — 10 gum arabic 14 14 14 magnesium stearate 0.7 0.7 0.7 total 140 140 140 Total amount of actual 28 g 28 g 28 g production
  • HPC LFP and HPC SSL hydroxypropylcellulose
  • HPC SSL hydroxypropylcellulose
  • hydrogenated castor oil hydrogenated castor oil
  • magnesium stearate screened with 30-mesh-screen, and the screened ingredients are mixed with the other ingredients in a polyethylene bag.
  • the prepared powder is tableted with a hydraulic tableting machine wherein the diameter of the punch is 7 mm and the tableting pressure is 6 kN.
  • Example 9 Ingredient mg mg zonisamide 50 50 isomalt (Galen IQ720) 69.7 61.3 hydrogenated castor oil 5.6 5.6 hydroxypropylcellulose (HPC LFP) 14 — hydroxypropylcellulose (HPC SSL) — 14 magnesium stearate 0.7 0.7 total 140 140 Total amount of actual production 28 g 28 g
  • HPC hydroxypropylcellulose
  • each ingredient listed in the table below is weighed.
  • the weighed hydrogenated castor oil and magnesium stearate are screened with 30-mesh-screen, and the screened ingredients are mixed with the other ingredients in a polyethylene bag.
  • the prepared powder is tableted with a rotary tableting machine wherein the diameter of the punch is 6 mm and the tableting pressure is 5 kN.
  • the prepared powder is tableted with a hydraulic tableting machine wherein the diameter of the punch is 6 mm and the tableting pressure is 5 kN.
  • Example 11 Example 12
  • Example 13 Ingredient mg mg mg zonisamide 50 50 50 50 lactose (SUPER TAB 11SD) 38.5 38 34.5 hydrogenated castor oil 1 1.5 5 gum arabic 10
  • 10 10
  • the termination points of the zero-order release were controlled at around 3 hours in Examples 11-12, and at a little later in Example 13.
  • the termination point of the zero-order release was able to be controlled by adjusting the amount of hydrogenated castor oil used herein.
  • Example 14 Each ingredient listed in the table below is weighed.
  • the weighed hydrogenated castor oil and magnesium stearate are screened with 30-mesh-screen, and the screened ingredients are mixed with the other ingredients in a polyethylene bag.
  • Example 14 the prepared powder is tableted with a hydraulic tableting machine wherein the diameter of the punch is 6 mm and the tableting pressure is 5 kN.
  • Example 15 and 16 the prepared powder is tableted with a hydraulic tableting machine wherein the diameter of the punch is 7 mm and the tableting pressure is 6 kN.
  • Example 14 Example 15 Example 16 Ingredient mg mg mg zonisamide 50 50 50 isomalt (Galen IQ800) 36 — — isomalt (Isomalt Powder for — 69.7 — direct tableting) D-mannitol — — 66.3 (PEARLITOL 100SD) hydrogenated castor oil 3.5 5.6 9 gum arabic powder 10 14 14 magnesium stearate 0.5 0.7 0.7 Total 100 140 140 Total amount of actual 20 g 28 g 28 g production
  • Each ingredient listed in the table below is weighed.
  • the weighed hydrogenated castor oil and magnesium stearate are screened with 30-mesh-screen, and the screened ingredients are mixed with the other ingredients in a V blender.
  • the prepared powder is tableted with a hydraulic tableting machine wherein the diameter of the punch is 7 mm, 9 mm, or 12 mm, for 50 mg, 100 mg, or 200 mg tablet, respectively, and the tableting pressure is 6 kN, 9 kN, or 14 kN, for 50 mg, 100 mg, or 200 mg tablet, respectively.
  • Example 17 Example 18 Example 19 Ingredient mg mg mg zonisamide 50 100 200 isomalt (Galen IQ720) 69 138 276 hydrogenated castor oil 5.6 11.2 22.4 gum arabic 14 28 56 light anhydrous silicic acid 0.7 1.4 2.8 magnesium stearate 0.7 1.4 2.8 Total 140 280 560 Total amount of actual 280 g 280 g 280 g production
  • Formulations comprising isomalt+hydrogenated castor oil+gum arabic as additives in which the tablet size varied between 50 mg tablet-200 mg tablet were prepared. Each terminate time in the dissolution tests was controlled to about three hours.
  • Example 20 Each ingredient listed in the table below is weighed.
  • the weighed hydrogenated castor oil and magnesium stearate are screened with 30-mesh-screen, and the screened ingredients are mixed with the other ingredients in a polyethylene bag.
  • the prepared powder is tableted with a rotary tableting machine wherein the diameter of the punch is 7 mm and the tableting pressure is 6 kN.
  • Example 20 Ingredient mg zonisamide 50 isomalt (Galen IQ720) 69.7 hydrogenated castor oil 5.6 gum arabic 14 magnesium stearate 0.7 Total 140 Total amount of actual production 280 g
  • the result of the dissolution tests with the test tablet is shown in FIG. 9 .
  • Example 20 Using the tablet of Example 20, the dissolution tests were carried out with pH 1.2 buffer, pH 4.0 buffer, pH 6.8 buffer, and water as the dissolution medium.
  • the rapid-release commercial tablet of zonisamide or the sustained-release tablet prepared herein was orally administered to a dog, and each pharmacokinetics (hereinafter, mentioned as “PK”) was tested.
  • PK pharmacokinetics
  • a rapid-release tablet of 100 mg zonisamide (which is equivalent of the commercial product tablet) used as a reference drug was prepared, and the rapid-release tablet was administered to 4 beagle dogs which were fasted for at least 16 hours before the administration (100 mg ⁇ 1 tablet per one dog), with 10 mL of water. 30 minutes, 1, 2, 3, 4, 6, 9, 12, 24, 36, 48, and 72 hours after the administration, every about 2 mL of blood was collected as whole blood.
  • the dogs were fed. After that, the dogs were fed once a day at a fixed time.
  • the plasma was divided from each collected blood, and the drug concentration of each plasma was measured by liquid chromatography (HPLC).
  • the same beagle dogs were given 2-week washout period, and then the sustained-release tablet of 50 mg zonisamide prepared in Example 20 was administered to the beagle dogs which were fasted for at least 16 hours before the administration (50 mg ⁇ 4 tablets per one dog), with 10 mL of water. 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 after the administration, every about 2 mL of blood was collected as whole blood.
  • the dogs were fed as is the case with the rapid-release tablet test.
  • the drug concentration was also measured by liquid chromatography (HPLC) as is the case with the rapid-release tablet test.
  • the concentration-variations of zonisamide in plasma for 24 hours are shown in FIGS. 10 and 11 (in which the data were meanscores from each four dogs).
  • maximum plasma concentration (Cmax), time-to-maximum plasma concentration (Tmax), area under the plasma concentration-time curve (AUC ⁇ ), elimination rate constant of plasma concentration (Kel), half-life (T1/2), and mean retention time (MRT) were estimated from the concentration-variations.
  • the relative availability was estimated from the AUC ratio of the sustained-release tablet and the rapid-release tablet.
  • the Tmax and other parameters of the sustained-release tablet are delayed, compared with the rapid-release tablet.
  • the relative ratio of AUC is 1.05, which means that the relative bioavailability of the drug in the sustained-release tablet does not decrease.
  • FIG. 12 a simulation of the concentration-variations of zonisamide in plasma wherein sustained-release tablet of 200 mg zonisamide is administered once a day is shown in FIG. 12
  • FIG. 13 a simulation of the concentration-variations of zonisamide in plasma wherein rapid-release tablet of 100 mg zonisamide is administered twice a day as a reference drug is shown in FIG. 13
  • FIG. 14 a simulation of the concentration-variations of zonisamide in plasma wherein rapid-release tablet of 200 mg zonisamide is administered once a day as another reference drug is shown in FIG. 14 .
  • the elimination rate constant ke (h-1) and the absorption rate constant ka (h-1) were estimated, the plasma level in a steady state wherein the drug is repeatedly administered was estimated, and the maximum plasma level (CSS, max), minimum plasma level (CSS, min), and AUCSS, 0-24 h, in a steady state were estimated.
  • the diurnal variation (DVSS, 24 h) of the plasma level in a steady state was estimated from CSS, max/CSS, min, in which the criterion of sustained release property is 2.0 or lower.
  • the relative availability in a steady state wherein the drug is repeatedly administered was estimated. The results are shown in the table below.
  • sustained- rapid-release rapid-release release tablet tablet tablet once a day twice a day once a day
  • the ratio between AUC SS,0-24 h (in a steady state, for 24 hours) wherein the sustained-release tablet of 200 mg zonisamide is administered once a day and AUC SS,0 24 h wherein the rapid-release tablet of 100 mg zonisamide is administered twice a day was 1.15. This result indicates that the bioavailability of the sustained-release tablet does not decrease, compared with the rapid-release tablet.
  • the ratio of the diurnal variation in plasma level in a steady state of the simulation, DV SS,24 h (CSS, max /C SS, min ), is 1.53 for the rapid-release tablet of 100 mg zonisamide administered twice a day, 2.62 for the rapid-release tablet of 200 mg zonisamide administered once a day, and 1.90 for the sustained-release tablet of 200 mg zonisamide once a day.
  • the criterion of diurnal variation of the present formulation is 2.0 or lower, as mentioned above.
  • the present invention has accomplished the purpose of sustained release because the ratio is lower than the criterion.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US16/307,544 2016-06-09 2017-06-08 Sustained-release preparation composition for animals Abandoned US20190142808A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2016-115580 2016-06-09
JP2016115580 2016-06-09
PCT/JP2017/021258 WO2017213208A1 (ja) 2016-06-09 2017-06-08 動物用徐放性製剤組成物

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2017/021258 A-371-Of-International WO2017213208A1 (ja) 2016-06-09 2017-06-08 動物用徐放性製剤組成物

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/867,773 Division US11173148B2 (en) 2016-06-09 2020-05-06 Zero-order release preparation composition for animals

Publications (1)

Publication Number Publication Date
US20190142808A1 true US20190142808A1 (en) 2019-05-16

Family

ID=60578667

Family Applications (2)

Application Number Title Priority Date Filing Date
US16/307,544 Abandoned US20190142808A1 (en) 2016-06-09 2017-06-08 Sustained-release preparation composition for animals
US16/867,773 Active US11173148B2 (en) 2016-06-09 2020-05-06 Zero-order release preparation composition for animals

Family Applications After (1)

Application Number Title Priority Date Filing Date
US16/867,773 Active US11173148B2 (en) 2016-06-09 2020-05-06 Zero-order release preparation composition for animals

Country Status (5)

Country Link
US (2) US20190142808A1 (de)
EP (1) EP3470065A4 (de)
JP (1) JP6359234B2 (de)
CN (1) CN109310640A (de)
WO (1) WO2017213208A1 (de)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070148237A1 (en) * 2005-11-28 2007-06-28 Orexigen Therapeutics, Inc. Sustained-release formulation of zonisamide
US20170360715A1 (en) * 2014-12-17 2017-12-21 Empros Pharma Ab Modified release composition of orlistat and acarbose for the treatment of obesity and related metabolic disorders

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54163823A (en) 1978-06-12 1979-12-26 Dainippon Pharmaceutical Co Antiiepileptic agent based on 33sulphamoylmethyll 1*22benzisoxazole
JPS6124516A (ja) 1984-07-12 1986-02-03 Fujisawa Pharmaceut Co Ltd 持続性錠剤
JPH0688899B2 (ja) * 1985-07-05 1994-11-09 藤沢薬品工業株式会社 持続性錠剤
JP2000119181A (ja) * 1998-10-06 2000-04-25 Kureha Chem Ind Co Ltd エスクレチン及びその誘導体の放出制御経口製剤
US6489350B1 (en) 1999-09-15 2002-12-03 Elan Pharmaceuticals, Inc. Methods for treating neuropathic pain using heteroarylmethanesulfonamides
JP2006507251A (ja) 2002-09-13 2006-03-02 エーザイ株式会社 振せんの治療方法
DE102008022520A1 (de) 2008-05-07 2009-11-12 Bayer Animal Health Gmbh Feste Arzneimittelformulierung mit verzögerter Freisetzung
FR2934156B1 (fr) * 2008-07-23 2010-09-24 Virbac Medicament appetissant a administration orale sous forme solide
MX2012009798A (es) * 2010-02-24 2012-09-12 Pfizer Composiciones veterinarias.
CN102949365A (zh) * 2011-08-31 2013-03-06 瑞普（天津）生物药业有限公司 一种宠物用恩诺沙星缓释片及其制备方法
CA2987114A1 (en) * 2015-06-03 2016-12-08 Triastek, Inc. Method of 3d printing oral dosage forms having a drug in a compartment sealed by an erodible plug

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070148237A1 (en) * 2005-11-28 2007-06-28 Orexigen Therapeutics, Inc. Sustained-release formulation of zonisamide
US20170360715A1 (en) * 2014-12-17 2017-12-21 Empros Pharma Ab Modified release composition of orlistat and acarbose for the treatment of obesity and related metabolic disorders

Also Published As

Publication number Publication date
JP6359234B2 (ja) 2018-07-18
CN109310640A (zh) 2019-02-05
EP3470065A1 (de) 2019-04-17
US20200323826A1 (en) 2020-10-15
US11173148B2 (en) 2021-11-16
EP3470065A4 (de) 2020-03-18
WO2017213208A1 (ja) 2017-12-14
JPWO2017213208A1 (ja) 2018-07-19

Similar Documents

Publication Publication Date Title
US20220265624A1 (en) Sustained release aminopyridine composition
US8545886B2 (en) Extended release tablet formulations of flibanserin and method for manufacturing the same
US20110218216A1 (en) Extended release pharmaceutical composition of donepezil
JP4463875B2 (ja) 医薬組成物
ES2525005T3 (es) Formulación de liberación prolongada que contiene una cera
ES2281313T3 (es) Composiciones farmacéuticas que comprenden lercanidipino
JP2020180123A (ja) デフェラシロクスの経口製剤
EP3323413B1 (de) Pharmazeutische zusammensetzung mit celecoxib und tramadol
KR102479497B1 (ko) 바레니클린 서방성 제제 및 이의 제조 방법
US11173148B2 (en) Zero-order release preparation composition for animals
US20070112075A1 (en) Stable pharmaceutical formulations containing escitalopram and bupropion
US20100310652A1 (en) Coated extended release pharmaceutical compositions of levetiracetam
US20220241222A1 (en) Atomoxetine hydrochloride extended release compositions and methods of use
ZA200605290B (en) Pharmaceutical compositions comprising lercanidipine
US11285152B2 (en) Stable oral pharmaceutical composition of imatinib
JP2015514799A (ja) サルサレートの遅延放出性医薬組成物
JP2016098230A (ja) 末梢血管疾患を有する患者における間欠跛行の症状を軽減するために用いられるキノリノン誘導体シロスタゾールの新規製剤
JP2016098230A5 (de)
JP2023157789A (ja) グアンファシン含有徐放性製剤

Legal Events

Date Code Title Description
AS Assignment

Owner name: DS PHARMA ANIMAL HEALTH CO., LTD., JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:KURIYAMA, TERUAKI;REEL/FRAME:047692/0453

Effective date: 20181126

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: ADVISORY ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION