OA16845A - Stable dosage forms of arterolane and piperaquine - Google Patents
Stable dosage forms of arterolane and piperaquine Download PDFInfo
- Publication number
- OA16845A OA16845A OA1201400016 OA16845A OA 16845 A OA16845 A OA 16845A OA 1201400016 OA1201400016 OA 1201400016 OA 16845 A OA16845 A OA 16845A
- Authority
- OA
- OAPI
- Prior art keywords
- dosage form
- active compound
- piperaquine
- solid oral
- stable solid
- Prior art date
Links
- 229950006717 piperaquine Drugs 0.000 title claims description 81
- UCRHFBCYFMIWHC-UHFFFAOYSA-N Piperaquine Chemical compound ClC1=CC=C2C(N3CCN(CC3)CCCN3CCN(CC3)C=3C4=CC=C(C=C4N=CC=3)Cl)=CC=NC2=C1 UCRHFBCYFMIWHC-UHFFFAOYSA-N 0.000 title claims description 80
- 239000002552 dosage form Substances 0.000 title claims description 49
- VXYZBLXGCYNIHP-UHFFFAOYSA-N Arterolane Chemical compound C1CC(CC(=O)NCC(C)(N)C)CCC21OC1(C3CC4CC(C3)CC1C4)OO2 VXYZBLXGCYNIHP-UHFFFAOYSA-N 0.000 title 1
- 229950007854 Arterolane Drugs 0.000 title 1
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- 238000000034 method Methods 0.000 claims abstract description 38
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Abstract
The field of the invention relates to stable oral dosage forms comprising spiro or dispiro 1,2,4-trioxolane antimalarials, or their pharmaceutically acceptable salts, prodrugs and analogues, and processes for their preparation.
Description
STABLE DOSAGE FORMS OF SPIRO AND DISPIRO 1,2,4-TRIOXOLANE ANTIMALARIALS
Field of the Invention
The field of the invention relates to stable oral dosage forms comprising spiro or dispiro 1,2,4-trioxolane antimalarials, or their pharmaceutically acceptable salts, prodrugs and analogues and processes for their préparation.
Backqround of the Invention
Malaria, the most common parasitic disease of humans, remains a major health and économie burden in most tropical countries. Large areas of Central and South America, Hispaniola (Haiti and the Dominican Republic), Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania are considered as malaria-risk areas. It leads to a heavy toll of illness and death, especially amongst children and prégnant women. According to the World Health Organization, it is estimated that the disease infects about 400 million people each year, and around two to three million people die from malaria every year. There are four kinds of malaria parasites that infect human: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.
Malaria spreads from one person to another by the bite of mosquito, Anopheles gambiae, which serves as vector. When a mosquito sucks the blood of human, sporozoites are transfused into the human body together with saliva of the mosquito. The sporozoites enter into the hépatocytes, reproduce asexually and finally enter into the blood stream. The parasites continue to multiply inside the red blood cells, untii they burst and release large number of merozoites. This process continues, destroying a signifïcant number of blood cells and causing the characteristic paroxysm (chills and fever) associated with the disease. In the red blood cells, some of the merozoites become male or female gamétocytes. These gamétocytes are ingested by the mosquito when it feeds on blood. The gamétocytes fuse in the vector’s gut; sporozoites are produced and are migrated to the vector’s salivary glands.
The clinical symptoms of malaria are generally associated with the bursting of red blood cells causing an intense fever associated with chills that can leave the infected individual exhausted and bedridden. More severe symptoms associated with repeat infections and/or infection by Plasmodium falciparum include anaemia, severe headaches, convulsions, delirium and, in some instances, death.
Quinine, an antimalarial compound that is extracted from the bark of cinchona tree, is one of the oldest and most effective drugs in existence. Chloroquine and mefloquine are the synthetic analogs of quinine developed in 1940's, which due to their effectiveness, ease of manufacture, and general lack of side effects, became the drugs of choice. The downside to quinine and its dérivatives is that they are short-actîng and hâve biffer taste. Further, they fail to prevent disease relapses and are also associated with side effects commonly known as “Chinchonism syndrome characterized by nausea, vomiting, dizziness, vertigo and deafness. However, in recent years, with the emergence of drug-resistant strains of parasite and insecticide-resistant strains of vector, the treatment and/or control of malaria is becoming difficult with these conventional drugs.
Malaria! treatment further progressed with the discovery of Artemisinin (qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone isolated from the plant Artemisia annua (Meshnick et al., Microbiol. Rev. 1996, 60, p. 301-315; Vroman et al., Curr. Pharm. Design, 1999, 5, p. 101-138; Dhingra et al., 2000,66, p. 279-300), and a number of its precursors, métabolites and semi-synthetic dérivatives which hâve shown to possess antimalarial properties. The antimalarial action of artemisinin is due to its reaction with iron in free heme molécules of the malaria parasite, with the génération of free radicals leading to cellular destruction. This initiated a substantial effort to elucidate its molecular mechanism of action (Jefford, dv. Drug Res. 1997, 29, p. 271-325; Cummtng et al., Adv. Pharmacol. 1997, 37, p. 254-297) and to identify novel antimalarial peroxides (Dong and Vennerstrom, Expert Opin. Ther. Patents 2001,11, p. 1753-1760).
Although the clînically useful artemisinin dérivatives are rapid acting and potent antimalarial drugs, they hâve several disadvantages including recrudescence, neurotoxicity, (Wesche et al., Antimicrob. Agents. Chemother. 1994, 38, p. 1813-1819) and metabolic instability (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41-43). A fair number of these compounds are quite active in vitro, but most suffer from low oral activity (White, Trans. R. Soc. Trop. Med. Hyg., 1994, 88, p. 41 43 and van Agtmael et al., Trends Pharmacol. Sci., 1999, 20, p. 199-205).
Further ail these artemisinin dérivatives are conventionally obtained from plant source and are therefore expensive. As the cultivation of the plant material is dépendent on many factors including the weather conditions, the supply source thus becomes finite and there are chances of varying yield and potency. This leads to quality inconsistencies and supply constraints. As malaria is more prévalent in developing countries, a switch to cheaper and effective medicine is highly désirable.
Thus there exists a need in the art to identify new peroxide antimalarial agents, especially those which are not dépendent on plant source and can be easily synthesized, are devoid of neurotoxicity, and which possess improved solubility, stability and pharmacokinetic properties.
Following that, many synthetic antimalarial 1,2,4-trioxanes (Jefford, Adv. Drug Res. 1997, 29, p. 271-325; Cumming et al., Adv. Pharmacol. 1997, 37, p. 254-297), 1,2,4,5-tetraoxanes (Vennerstrom et al., J. Med. Chem., 2000, 43, p. 2753-2758), and other endoperoxides hâve been prepared. Various patents/applications disclose means and method for treating malaria using Spiro or dispiro 1,2,4-trioxolanes for example, U.S. Patent Application No. 2004/0186168 and U.S. Patent Nos. 6,486,199 and 6,825,230. The présent invention relates to solid dosage forms of the various spiro or dispiro 1,2,4-trioxolanes antimalarial compounds disclosed in these patents/applications and are incorporated herein by reference.
Active compounds representing various Spiro and dispiro 1,2,4-trioxolane dérivatives possess excellent potency, efficacy against Plasmodium parasites, and a lower degree of neurotoxicity, in addition to their structural simplicity and ease of synthesis. Furthermore, these compounds hâve half-lives which are believed to permit short-term treatment regimens comparing favorably to other artemisinin-like drugs. In general, the therapeutic dose of trioxolane dérivative may range between about 0.1-1000 mg/kg/day, in particular between about 1-100 mg/kg/day. The foregoing dose may be administered as a single dose or may be divided into multiple doses. For malaria prévention, a typical dosing schedule could be, for example, 2.0-1000 mg/kg weekly beginning 1-2 weeks prior to malaria exposure, continued up to 1-2 weeks post-exposure.
Monotherapy with artemisinin (natural or synthetic) class of drugs might cure the patients within 3 days, however perceiving the potential threat of the malarial parasite developing résistance towards otherwise very potent artemisinin class of drugs, WHO had strictly called for an immédiate hait to the provision of single-drug artemisinin malaria pills. Combination therapy in case of malaria retards the development of résistance, improve efficacy by lowering recrudescence rate, provides synergistic effect, and increase exposure of the parasite to the drugs.
Artemsinin based combinations are available in the market for a long time. Artemetherlumafentrine (Co-artem®) was the first fixed dose antimalarial combination containing an artemisinin dérivative and has been known since 1999. This combination has passed extensive safety and efficacy trials and has been approved by more than 70 regulatory agencies. Co-artem® is recommended by WHO as the first line treatment for uncomplicated malaria.
Other artemisinin based combinations include artesunate and amodiaquine (Coarsucam®), and dihydroartemisin and piperaquine (Eurartesim®). Unfortunately, ail the available artemisinin based combinations hâve complicated dosage regimens making it difficult and inconvénient for a patient to comply completely with the total prescribed duration. For example, the dosage regimen of Co-artem® for an adult having body weight of more than 35 kg includes 6 doses over three days. The first dose comprises four tablets initially, the second dose comprises four tablets after eight hours, the third to sixth doses comprise four tablets twice for another two days; making it a total of 24 tablets. The dosage regimen of Coarsucam® for an adult having body weight of more than 36 kg or âge above 14 years includes three doses over three days; each dose comprises two tablets; making it a total of six tablets. The dosage regimen of Eurartesim® for an adult having body weight between 36 kg - 75 kg includes 3 doses over three days, each dose comprises of three tablets, making it a total of nine tablets.
It is évident that the available artemisinin-based combinations hâve a high pill burden on patients as they need to consume too many tablets. As noted above, this may increase the possibility of missing a few doses, and, consequently, could resuit in reduced efficacy due to noncompliance and may even lead to development of résistance for the drug.
Therefore, there Is an urgent and unmet need for anti-malarial combinations with a simplified daily dosing regimen that reduces the pill burden and would increase patient compliance.
Apart from simplifying the regimen, there are certain limitations for formulators developing formulations with trioxolones, the first being their susceptibility to dégradation in presence of moisture that results in reduced shelf lives. Another is their bitter taste, which can resuit in poor compliance of the regimen or sélection of another, possibly less effective, therapeutic agent.
We hâve now discovered that a stable antimalarial oral solid dosage form comprising spiro or dispiro 1,2,4-trioxolanes can be prepared by controlling the water content below a certain criticaI limit. Further, the bitter taste can be masked by applying a film coating layer to the solid dosage form.
Summary of the Invention
In one general aspect there is provided a stable solid oral dosage form that includes a therapeutically effective amount of a compound having the structural Formula I,
Formula I and ils enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvatés, wherein:
Rj and R2 are same or different and are selected from hydrogen, substituted or unsubstituted linear or branched alkyl, aryl, and alkaryl groups and substituted or unsubstituted alicyclic groups that are optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromatic or heterocyclic groups that may be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and a halogen, and further providing that the spirocyclohexyl rings attaching R-i and R2 are optionally interrupted by one or more oxygen, sulfur, or nitrogen atoms; and one or more pharmaceutically acceptable excipients, wherein not more than
5% w/w total related substances are formed on storage at 40°C ± 2°C and 75% ± 5% relative humidity over a period of 6 months.
Embodiments of the solid oral dosage form may include one or more of the following features. For example, the dosage form may include one or more of other antimalarial drugs. The other antimalarial drugs may include quinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin, tétracycline, DB 289 (pafuramidine maleate), clindamycin, or their salts and dérivatives thereof. In particular, piperaquine, lumefantrine and DB 289 may be used.
In another general aspect, there is provided a method of treatment of malaria. The method includes administering a solid dosage form that includes a therapeutîcally effective amount of a compound of structural Formula I; and one or more pharmaceutically acceptable excipients, wherein not more than 5% w/w total related substances are formed on storage at 40°C ± 2°C and 75% ± 5% relative humidity over a period of 6 months.
In another aspect, there is provided a method of treatment of malaria, wherein the method includes administering a solid dosage form that includes a therapeutîcally effective amount of a compound of structural Formula I, formulated using a dry or non-aqueous process.
In another aspect, there is provided a stable solid oral dosage form, wherein the dosage form includes a therapeutîcally effective amount of a compound of structural Formula I; at least one other antimalarial drug selected from lumefantrine, piperaquine, or DB 289; and one or more pharmaceutically acceptable excipients.
Embodiments of the oral dosage form may include one or more of the following features. For example, the water content of the dosage form may not be more than 6,5% w/w.
In another general aspect, there is provided a stable oral solid dosage form comprising cisadamantane-2“Spiro-3'“8'-[[[(2'-amino-2,-methylpropyl) aminojcarbonyl]- methyl]-1 ',2',4'trioxaspiro[4.5]decane hydrogen maleate; piperaquine; and one or more pharmaceutically acceptable excipients.
In another general aspect, there is provided a stable solid oral dosage form comprising;
(a) cis-adamantane-2-spiro-3,-8,-[[[(2'-amino-2,-methylpropyl)amino]carbonyl]-methyl]T,2',4'-trioxaspiro[4.5]decane hydrogen maleate (Active compound I);
(b) piperaquine; and (c) one or more pharmaceutically acceptable excipients wherein the dosage form is prepared by a dry process.
In another general aspect, there is provided a stable solid oral dosage form comprising;
(a) Active compound I; and (b) piperaquine wherein the total drug content is within the range of from about 25% to about 85% w/w based on the total weight of the dosage form.
In another general aspect, there is provided a stable solid oral dosage form comprising;
(a) Active compound I in an amount of from about 5% to about 25%; and (b) piperaquine in an amount of from about 40% to about 80%, w/w based on the total weight of the dosage form.
In another general aspect, there is provided a stable solid oral dosage comprising;
(a) Active compound I in an amount of from about 5% to about 25%; and (b) piperaquine in an amount of from about 40% to about 80% wherein the total drug content does not exceed 85% w/w based on the total weight of the dosage form.
In another general aspect, there is provided a stable solid oral dosage of Active compound I and piperaquine; wherein the dosage form has dissolution performance such that more than 70% w/w of the Active compound I dissolves within 45 minutes, in a pH 4.5 acetate buffer with 2% tween 80, in USP type II apparatus.
In another general aspect, there is provided a stable solid oral dosage form comprising;
(a) Active compound I and (b) piperaquine; in a weight ratio of about 1:1 to about 1:10.
In another general aspect, there is provided a stable oral solid dosage form comprising Active compound I présent in a dose range of about 100 to about 300 mg and piperaquine présent in a dose range of about 700 mg to about 850 mg.
In another general aspect, there is provided a stable solid oral dosage form comprising;
(a) Active compound I in an amount of from about 5% to about 25%;
(b) piperaquine in an amount of from about 40% to about 80%;
(c) diluent in an amount of from about 10% to about 40%;
(d) disintegrant in an amount of from about 1% to about 10%; and (e) lubricant in an amount of from about 1 % to about 5%; w/w based on the total weight of the dosage form.
In another general aspect, there is provided a stable solid oral dosage form comprising;
(a) Active compound I;
(b) piperaquine;
(c) microcrystalline cellulose;
(d) crospovidone; and (e) magnésium stéarate.
In another general aspect there is provided a stable oral solid dosage comprising;
(a) Active compound I in an amount of from about 5% to about 25%;
(b) piperaquine in an amount of from about 40% to about 80%; and (c) microcrystalline cellulose in an amount of from about 10% to about 40%; w/w based on the total weight of the dosage form.
ln another general aspect, there is provided a stable solid oral dosage form comprising Active compound I and microcrystalline cellulose in a weight ratio of about 1:1 to about 1:5.
The pharmaceutically acceptable excipients may be selected from the group consisting of binders, diluents, glidants/lubricants, disintegrants, surfactants and coloring agents.
The solid dosage form may be in the form of a tablet, capsule, pellet, pill, granule or powder, Particularly the dosage form is a tablet or a capsule. More particularly, the dosage form is a tablet.
ln another general aspect, there is provided a stable solid oral dosage form, wherein the dosage form is processed and stored at a température below 27°C and relative humidity 50%.
Embodiments of the process may include one or more of the following features. For example, the dosage form is formulated using a dry or non-aqueous process. The non-aqueous process may include a non-aqueous granulating liquid selected from éthanol, isopropyl alcohol, acetone, or dichloromethane for preparing the binder solution. The dry process may include direct compression or dry granulation. Dry granulation may be compaction or slugging. ln particular, the dry granulation may be compaction for example, dry roller compaction.
In another general aspect, there is provided a process for the préparation of a stable solid oral dosage form, comprising the steps of;
(a) blending Active compound I, piperaquine, and one or more intragranular excipients;
(b) milling, grinding or sieving the blend by roller compaction to form granules;
(c) blending the granules with one or more extragranular excipients;
(d) compressing the blend into tablets or filling into capsules.
ln another general aspect, there is provided a process for the préparation of a stable solid oral dosage form, comprising the steps of;
(a) blending Active compound I, piperaquine, and one or more intragranular excipients;
(b) granulating the blend by slugging;
(c) blending the granules with one or more extragranular excipients;
(d) compressing the blend into tablets or filling into capsules.
In another general aspect, there is provided a process for the préparation of a stable solid oral dosage form, comprising the steps of;
(a) blending Active compound I, piperaquine, and one or more pharmaceutically acceptable excipients; and (b) dîrectly compressing the blend into tablets or filling into capsules.
In another general aspect, there is provided a process for the préparation of a stable solid oral dosage form, comprising the steps of;
(a) granulating a blend of one or more excipients;
(b) drying the excipient granules;
(c) blending excipient granules with Active compound I and piperaquine; and (d) compressing the blend into tablets or filling into capsules.
The tablet may be coated with layer(s) of one or more film forming polymers.
ln another general aspect, there is provided a method of treatment of malaria. The method includes administering a stable oral solid dosage form comprising;
(a) Active compound I;
(b) piperaquine; and (c) one or more pharmaceutically acceptable excipients wherein the dosage form is prepared by a dry process.
ln another general aspect, there is provided a stable solid oral dosage form comprising;
(a) 150 mg of Active compound I and (b) 750 mg of piperaquine wherein the dosage form is administered once a day for three days.
ln another general aspect, there is provided a method of treating malaria comprising administering a stable solid oral dosage form comprising;
(a) 150 mg Active compound I and (b) 750 mg of piperaquine wherein the dosage form is administered once a day for three days.
The details of one or more embodiments are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and daims.
Detailed Description of the Invention
We hâve now discovered that stable solid oral dosage forms of Spiro or dispiro 1,2,4trioxolane antimalarials can be prepared which do not dégradé significantly and provide acceptable shelf life.
The term stable as used herein refers to chemical stability of active compound in solid dosage forms against décomposition occurring during shelf life due to hydrolysis, wherein not more than 5% w/w total related substances are formed on storage at 40°C ± 2°C and 75% ± 5% relative humidity over a period of 6 months.
The présent invention provides stable solid oral dosage forms of the active compound, by using excipients having low water content and manufactured using dry or non-aqueous formulation processes.
The term active compound as used herein includes spiro or dispiro 1,2,4-trioxolane compound of structural Formula I
wherein Ri and R2 are same or different and are selected from hydrogen, substituted or unsubstituted linear or branched alkyl, aryl, and alkaryl groups and substituted or unsubstîtuted alicyclic groups that are optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromatic or heterocyclic groups that may be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and a halogen, and further providing that the spirocyclohexyl rings attaching R, and R2 are optionally interrupted by one or more oxygen, sulfur, or nitrogen atoms. ln particular, it includes compounds of Formula I, wherein RJs hydrogen, for example, compounds of structural Formula II.
ΙΟ
Formula II
Active compound includes one or more of the various spiro and dispiro trioxolane dérivatives disclosed in U.S. Application No. 2004/0186168 and U.S. Patent Nos. 6,486,199 and 6,825,230, which are incorporated herein by reference. These trioxolanes are relatively sterically hindered on at least one side of the trioxolane heterocycle which provides better in vivo activity, especially with respect to oral administration. Particularly, spiro and dispiro 1,2,4-trioxolanes dérivatives possess excellent potency and efficacy against Plasmodium parasites, and a lower degree of neurotoxicîty.
The term “Active compound Γ herein means cis-adamantane-2-spiro-3'-8'-[[[(2’-amino-2’methylpropyl)amino]carbonyl]-methyl]-r,2',4'-trioxaspiro[4.5]decane hydrogen maleate. The Active compound I may be présent in an amount of from about 5% to about 25%, w/w based on the total dosage form.
Further, perceiving the potential threat of the malarial parasite developing résistance towards otherwise very potent artemisinin class of drugs, WHO has called for an immédiate hait to the provision of single-drug artemisinin malaria pills. In the case of malaria, combination therapy has been applied since around 1990. However, this strategy is being hampered because the Plasmodium parasite has developed résistance, as a resuit of monotherapy, to certain components of currently applied combination drugs. Combination therapy is expected to retard the development of résistance, improve efficacy by lowering recrudescence rate, provide synergistic effect, and increase exposure of the parasite to the drugs.
Embodiments of the solid oral dosage of the présent invention further include one or more of antimalarial drugs. The antimalarial drugs may include quinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin, tétracycline, DB 289 (pafuramidine maleate), clindamycin, or their salts and dérivatives thereof. In particular, piperaquine, lumefantrine and DB 289 may be used; however piperaquine remains the preferred one.
Sélection of combination as an antimalarial therapy is based on certain attributes. Synthetic artemisinin dérivatives exhibit their action by their reaction with the iron in free heme molécules in the malaria parasite with the génération of free radicale leading to cellular destruction. On the other
II hand bisquinoline dérivatives such as piperaquine interfère with the détoxification of haemin in the digestive vacuole of the parasite to non-toxic malaria pigment, so that haemin can generate free radicale and membrane damage follows. The unrelated mode of action of the two drugs wouîd provide improved therapy, and treatment against ail stages of parasites including gamétocytes. Additionally, since synthetic artemisinin dérivatives are very efficacious and highly potent, these would thereby treat the symptoms quickly, exhibiting fast recovery rates. The combination of synthetic artemisinin dérivatives and bisquinoline dérivatives such as piperaquine provide a short duration of treatment.
Piperaquine is a bisquinoline compound that has antimalarial activity against both P. vivax and P. falciparum, including strains of chloroquine résistant P, falciparum. The tolerability, efficacy, pharmacokinetic profile, low cost and longer-acting piperaquine makes it a very perfect candidate for use in combination with short and rapidly acting Active compound I. Piperaquine of the présent invention includes piperaquine phosphate. Piperaquine may be présent in an amount of from about 40% to about 80%, w/w based on the total dosage form.
The total drug content of the oral dosage forms of the présent invention is within the range of about 25% to about 85%, and in particular does not exceed 85% w/w based on the total dosage form.
The oral dosage forms of the présent invention comprise Active compound I and piperaquine in a weight ratio of about 1:1 to about 1:10.
The oral dosage forms of the présent invention comprise Active compound I présent in a dose range of about 100 mg to about 300 mg and piperaquine présent in a dose range of about 700 mg to about 850 mg.
The oral dosage forms of the présent invention comprise Active compound I présent in a unit dose of 100 mg, 150 mg or 250 mg and piperaquine présent in a unit dose of 750 mg.
The oral dosage forms of the présent invention comprise Active compound I in a unit dose of about 100 mg and piperaquine présent in a unit dose of about 750 mg.
The oral dosage forms of the présent invention comprise Active compound I in a unit dose of about 150 mg and piperaquine présent in a unit dose of about 750 mg
The oral dosage forms of the présent invention comprise Active compound I in a unit dose of about 200 mg and piperaquine présent in a unit dose of about 750 mg
The dosage regimen of the présent invention includes administering a fixed dose combination of 150 mg Active compound I and 750 mg of piperaquine once a day for three days.
The dose of Active compound I herein means dose équivalent to Active compound I free base.
The dosage regimen of the présent invention inciudes three doses over three days. The first dose is administered immediateîy on diagnosis, the second dose about 24 hours after the first dose, and the third dose about 24 hours after the second dose.
The dosage regimen of the présent invention is suitable for ail patients aged from 12 to 65 years and thus éliminâtes the need for calculating dose based on individual weight parameters. In the existing artemisinin based combinations, the dose is calculated with respect to the individual weight of the patient and in many cases the tablets are scored to adjust the dose. However, the dosage regimen of this combination is surprisingly simple and effective both for patients and for prescribers.
Solid dosage form as used herein is selected from a group consisting of tablets or coated tablets, capsules, pellets, pills, granules and powders. A particularly suitable solid dosage form is that of tablets.
Further, it has been observed through exhaustive expérimentation that when the active compound is formulated into dosage forms, including liquid as well as solid dosage forms, it gets degraded by hydrolysis. The dégradation may be due to water associated with the excipients or added during the course of processing. Thus, liquid oral dosages forms such as aqueous syrups, suspensions or solutions having desired shelf life could not be successfully prepared. Further, préparation of solid oral dosage forms of active compound using techniques involving use of water such as wet granulation, spray drying, or extrusion-spheronization processes resulted in dosage forms with wavering stabiîity results. However, acceptable stability results were obtained when the solid dosage forms were formulated using appropriate excipients with low water content and a process in which water was absent, such as dry granulation, direct compression or non-aqueous granulation. In case where excipients were granulated using water, the excipient granules were dried appropriately before blending with the active compound as such or with active compound containing granules, and processed into solid dosage forms of acceptable stability.
The rôle of excipients and water content was evaluated by conducting compatibility studies of the active compound with various excipients in different proportions, and evaluating the extent of dégradation by forced dégradation at 60°C over the period of 2 weeks and at 50°C for 4 weeks. The water content was analyzed using Karl Fischer method and the total related substances (% w/w) were determined by HPLC method. The results of the study are represented below in Table 1.
Table 1: Compatibility studies of active compound (Active compound I) with various excipients
Excipient | Drug: Excipient | Water (%w/w) | Total Related Substance (Percent w/w) | ||
Initial | After 4 weeks/ 50°C | After 2 weeks/ 60°C | |||
Croscarmellose sodium | 1:0.5 | 0.59 | 0.09 | 0.34 | 0.35 |
Cross povidone | 1:0.5 | 3.49 | 0.13 | 0.40 | 0.68 |
Sodium starch glycolate | 1:0.5 | 1.43 | 0.13 | 0.43 | 0.89 |
Hydroxypropyl methylcellulose 5cps | 1:0.5 | 1.22 | 0.17 | 0.70 | 1.05 |
Polyvinyl pyrrolidone K 30 | 1:0.5 | 3.02 | 0.00 | 0.33 | 0.79 |
Sodium lauryl sodium | 1:0.5 | 0.79 | 0.15 | 0.92 | 1.59 |
Opadry® | 1:0.5 | 0.46 | 0.17 | 1.85 | 0.96 |
Titanium dioxide | 1:0.5 | 0.18 | 0.16 | 0.57 | 0.93 |
Talc | 1:0.1 | 0.12 | 0.15 | 0.63 | 0.90 |
Mg. Stéarate | 1:0.1 | 0.46 | 0.13 | 0.65 | 0.86 |
Aérosol | 1:0.1 | 0.27 | 0.14 | 0.66 | 0.86 |
Polyethylene glycol 400 | 1:0.1 | 0.88 | 0.14 | 0.66 | 0.68 |
Microcrystalline cellulose | 1:2 | 3.69 | 0.19 | 0.70 | 0.74 |
Starch | 1:2 | 4.73 | 0.08 | 0.60 | 0.74 |
Dicalcium phosphate | 1:2 | 2.01 | 0.07 | 0.77 | 1.32 |
Pearlitol | 1:2 | 0.02 | 0.14 | 0.72 | 0.77 |
Micro crystalline cellulose | 1:10 | 4.94 | 0.39 | 0.78 | 1.02 |
Starch | 1:10 | - | 0.07 | 0.60 | 4.13 |
Dicalcium phosphate | 1:10 | 2.14 | 0.17 | 0.61 | 6.07 |
Pearlitol | 1:10 | 0.52 | 0.14 | 0.46 | 0.70 |
The study clearly indicates the importance of use of excipients having low water or moisture content in stabilizing solid dosage forms of the active compound. In the présent invention, we hâve discovered that the use of excipients having water content less than 6.5% w/w surprisingly increases the stability of the active compound, and thus provides reasonably long shelf lives. Starch was found to be incompatible with the active compound when used In higher amounts. Further, lactose was also found to be incompatible due to dégradation by other mechanisms such as Maillard reaction, and dicalcium phosphate was not preferred due to an increase in related substances at 60°C. Microcrystalline cellulose, however, gave the most satisfactory results.
The stable solid oral dosage forms of the présent invention may further comprise one or more pharmaceutically acceptable excipients, which include ail physiologically inert excipients used in the art for the préparation of solid dosage forms. Examples include binders, diluents, glidants/lubricants, disintegrants, surfactants, coloring agents, and the like. The excipients may be used either intragranularly or extragranularly, or both. The weight ratio of active compound and excipients in the dosage forms may vary from about 1.5:1 to about 1:30.
Examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arable, ethyl cellulose, polyvinyl alcohol, pullulan, agar, tragacanth and sodium alginate, or mixtures thereof.
Examples of diluents include cellulose powdered, microcrystalline cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, mannitol, sorbitol, sucrose, sugar compressible, and sugar confectioners, in particular microcrystalline cellulose. The diluents may be présent in an amount from about 10% to about 40% w/w based on the total weight of the dosage form. Further the weight ratio of Active compound I to microcrystalline cellulose may vary from about 1:1 to about 1:5.
Examples of disintegrants include clays, celluloses, alginates, gums, cross-linked polymers (such as cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose), sodium starch glycolate, low-substituted hydroxypropyl cellulose and soy polysaccharides, in particular crospovidone. The disintegrant may be présent in an amount from about 1% to about 10% w/w based on the total weight of the dosage form.
Examples of lubricants or glidants include talc, magnésium stéarate, calcium stéarate, stearic acid, colloïdal silicon dioxide, magnésium carbonate, magnésium oxide, calcium silicate, microcrystalline cellulose, minerai oil, waxes, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium laurylsulfate, sodium stearyl fumarate, and hydrogenated vegetable oils, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, în particular magnésium stéarate. The lubricant may be présent in an amount from about 1% to about 5%, w/w based on the total weight of the dosage form.
Examples of surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in sweetener compositions. These include polyethoxylated fatty acids and its dérivatives, for example polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4-150 mono dilaurate, polyethylene glycol—20 glyceryl stéarate; alcohol—oil transestérification products, for example polyethylene glycol—6 corn oil; polyglycerized fatty acids, for example polyglyceryl-6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides, for example glyceryl ricinoleate; sterol and sterol dérivatives; sorbitan fatty acid esters and its dérivatives, for example polyethylene glycol-20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phénols, for example polyethylene glycol-20 cetyl ether, polyethylene glycol—10-100 nonyl phénol; sugar esters, for example sucrose monopalmitate; polyoxyethylene-polyoxypropylene block copolymers known as poloxamer; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, and palmitoyl carnitine.
The coloring agents include any FDA approved colors for oral use.
The solid dosage forms may further be coated with one or more functional and/or nonfunctional layers comprising film-forming polymers, and other coating additives.
Examples of film-forming polymers include cellulose dérivatives such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzed polyvinyl alcohol, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; and methacrylic acid polymers such as Eudragit® RL and RS. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry®, may also be used for coating.
The coating additives comprise one or more of plasticizers, glidants or flow regulators, opacifiers and lubricants.
The pharmaceutical acceptable excipients and/or film formtng polymers and coating additives may be selected to provide an immediate-release profile or a modified release profile.
Solid dosage forms of Active compound I may be prepared by densifying Active compound I and one or more excipients, and processing into solid dosage forms. Densification may be carried out using any conventional method known in the art. In particular, granulation or extrusionspheronization may be used.
In one of the embodiments, stable oral tablets of Active compound I may be prepared by a process comprising the steps of blending Active compound I and intragranular portion of a diluent, lubricant, and disintegrant; passing the blend through a roller compacter to form a compact mass; reducing the compact mass into granules of suitable size; blending the granules with extragranular portion of a lubricant, disintegrant, and diluent in a double cône blender; and finally compressing into tablets using suitable tooling.
In another embodiment, stable oral tablets of Active compound I may be prepared by a process comprising the steps of blending Active compound I and intragranular portion of a diluent, lubricant, and disintegrant; compressing the blend in a heavy tabletting press to form slugs; reducing the slugs into granules of suitable size; blending the granules with extragranular portion of a lubricant, disintegrant, and diluent in a double cône blender; and finally compressing into tablets using suitable tooling.
In another embodiment, stable oral capsules of Active compound I may be prepared by a process comprising the steps of blending Active compound I and intragranular portion of a diluent, lubricant, and disintegrant; passing the blend through a roller compacter to form a compact mass; reducing the compact into granules of a suitable size; blending the granules with extragranular portion of a lubricant in a double cône blender; and finally filling into capsules of a suitable size.
In another embodiment, stable oral capsules of Active compound I may be prepared by a process comprising the steps of blending Active compound I and intragranular portion of a diluent, lubricant, and disintegrant; compressing the blend in a heavy tabletting press te form slugs; reducing the slugs into granules of a suitable size; blending the granules with extragranular portion of lubricant in a double cône blender; and finally filling into capsules of a suitable size.
In another embodiment, stable oral tablets of Active compound I may be prepared by a process comprising the steps of blending Active compound I, a diluent, a lubricant and a disintegrant; and directly compressing into tablets using suitable tooling.
In another embodiment, stable oral capsules of Active compound I may be prepared by a process comprising the steps of blending Active compound I, a diluent, and a lubricant; and filling into capsules of a suitable size.
In another embodiment, stable oral tablets of Active compound I may be prepared by a process comprising the steps of blending Active compound I and intragranular portion of a diluent, and disintegrant; wet granulating the blend with a non aqueous granulating fluid or a solution/dispersion of pharmaceutically acceptable excipients in the non-aqueous granulating fluid; drying and reducing the granules to a suitable size, blending the granules with extragranular portion of a lubricant, disintegrant and diluent in a double cône blender; and finally compressing into tablets using suitable tooling.
In yet another embodiment, stable oral capsules of Active compound I may be prepared by a process comprising the steps of blending Active compound I and intragranular portion of diluent, and disintegrant; wet granulating the blend with a non aqueous granulating fluid or a solution/dispersion of pharmaceutically acceptable excipients in the non-aqueous granulating fluid; drying and reducing the granules to a suitable size; blending the granules with extragranular portion of lubricant in a double cône blender; and finally filling into capsules of a suitable size.
Examples of non-aqueous granulating fluid include organic solvents such as methanol, éthanol, isopropyl alcohol, dichloromethane, acetone, or mixtures thereof.
In yet another embodiment, tablets prepared by any of the above described processes may further be coated with film-forming polymers and one or more coating additives, using techniques well known in the art such as spray coating in a conventional coating pan or a fluidized bed processor or dip coating. Alternatively, coating can also be performed using a hot melt technique.
The coating layers over the tablet may be applied as a solution/dispersion of coating components in a suitable solvent. Examples of solvents used for preparing a solution/dispersion of the coating ingrédients include methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water and the like, and mixtures thereof.
ln still another embodiment, one or more of another antimalarial drug selected from piperaquine, lumefantrine, and DB 289 (pafuramidine maleate) may be added in the blend comprising active compound, in any of the embodiments above.
The dosage form of the présent invention is processed and stored at a température below 27°C and relative humidîty 50%.
The invention described herein is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
EXAMPLES
Example 1:
Ingrédients | Percent w/w |
Intragranular | |
Maleate sait of a compound of Formula II (active compound) [Active compound I] | 43.2 |
Microcrystalline Cellulose | 46.67 |
Magnésium stéarate | 0.75 |
Extragranular | |
Microcrystalline Cellulose | 5.63 |
Croscarmellose sodium | 3.0 |
Magnésium stéarate | 0.75 |
Total Percentage | 100% |
Coating | |
Opadry® OY SS 58910 white | 2.5 |
Water | q.s |
Total weight | 615 |
Water content | <6.55% w/w |
Procedure:
1. Active compound I and intragranular portion of microcrystalline cellulose were sieved through sieve BSS #44 and mixed together in a double cône blender to form a uniform blend.
2. To the blend of step 1, intragranular portion of sifted magnésium stéarate was added and blended for about 5 minutes.
3. The blend of step 2 was compacted in a roller compactor and was sifted through sieve BSS #22 to form granules.
4. Extragranular portion of microcrystalline cellulose, croscarmellose sodium and magnésium stéarate were sieved through sieve BSS # 44 and blended with the granules of step 3.
5. The blend of step 4 was compressed using suitable size punches to obtain compressed tablets.
6. The tablets as obtained from step 5 were coated with Opadry® using conventional coating techniques.
The tablets prepared as per Example 1 were subjected to stability studies at 25°C/ RH 60%,
30°C/RH 65% and 40°C/RH 75% over a period of 6 months. The results are summarized in Table
2. The results of in vitro drug release analyzed at predetermined time periods are given in Table 3.
Table 2: Total related substances* (Percent w/w)
Storage Condition | Initial | 1 month | 2 months | 3 months | 6 months |
25°C and 60% relative humidity | 0.11 | - | - | 0.27 | 0.28 |
30°C and 65% relative humidity | 0.11 | 0.37 | 0.27 | 0.29 | 0.34 |
40°C and 75% relative humidity | 0.11 | 0.55 | 0.67 | 1.40 | 1.82 |
* % Total Related Substance should not be more than 5% w/w.
Table 3: Percentage (%) of ln vitro drug release in USP II apparatus* (media: 2% tween 80 in water, 900ml 75 rpm, in 45 min)
Storage Condition | Initial | 1 month | 2 months | 3 months | 6 months |
25°C and 60% relative humidity | 93 | - | - | 101 | 95 |
30°C and 65% relative humidity | 93 | 98 | 93 | 94 | 96 |
Température 40°C and 75% relative humidity | 93 | 98 | 96 | 92 | 94 |
*The in vitro drug release (%w/w) should not be less than 70% (Q) of the labeled amount dissolved in 45 minutes.
As évident from the above studies, the tablets prepared by the process of the présent invention in which water is absent shows acceptable shelf stability.
Example 2:
Ingrédients | Percent w/w |
Maleate sait of a compound of Formula II (active compound) [Active compound I] | 44.33 |
Microcrystalline Cellulose | 51.17 |
Magnésium stéarate | 1.5 |
Croscarmellose sodium | 3.0 |
Total weight | 600 mg |
Water content | <6.5% |
Procedure:
1, Active compound I, microcrystalline cellulose, croscarmellose sodium and magnésium stéarate were sifted through steve BSS #44.
2. Sifted Active compound I, microcrystalline cellulose, and croscarmellose sodium were mixed in a double cône blenderfor about 15 minutes to form a uniform blend.
3. To the blend of step 2, sifted magnésium stéarate was added and mixed for about 5 minutes.
4. The blend obtained in step 3 was directly compressed using suitable size capsule shape 10 punches to obtain compressed tablets.
Examples 3 and 4:
Ingrédients | Example 3 Percent w/w | Example 4 Percent w/w |
Intragranular | ||
Maleate sait of a compound of Formula II (active compound) [Active compound I] | 7.68 | 13.80 |
Piperaquine phosphate | 61.80 | 55.50 |
Microcrystalline Cellulose | 20.39 | 21.15 |
Magnésium stéarate | 0.44 | 0.39 |
Crospovidone | 2.21 | 1.99 |
Extragranular | ||
Microcrystalline Cellulose | 4.32 | 3.99 |
Crospovidone | 2.11 | 1.99 |
Magnésium stéarate | 1.05 | 1.19 |
2I
Total percentage | 100% | 100% |
Coating | ||
Opadry® O2B53782 orange | 2.5 | 2.5 |
Water | q.s | q.s |
Total weight (mg) | 1332.5 | 738 |
Water content | <6.55% w/w | <6.55% w/w |
Procedure:
1. Active compound I, piperaquine phosphate and intragranular portion of microcrystalline cellulose and crospovidone were sieved through sieve BSS # 44 and mixed together in a double cône blenderto form a uniform blend.
2. To the blend of step 1, intragranular portion of sifted magnésium stéarate was added and blended for about 5 minutes.
3. The blend of step 2 was compacted in a roller compacter and was sifted through sieve BSS # 18 to form granules.
4. Extragranular portion of microcrystalline cellulose and crospovidone were sieved through sieve BSS # 44 and blended with the granules of step 3.
5. Extragranular portion of magnésium stéarate was sieved through sieve BSS # 44 and blended with the blend of step 4 in a double cône blender for about 5 minutes.
6. The blend of step 5 was compressed using suitable size punches te obtaln compressed tablets.
7. The tablets as obtained from step 6 were coated with Opadry® using conventional coating techniques and weight built of up to 2.5% w/w.
The tablets prepared as per the Example 3 & 4 were subjected to stability studies at 40°C/RH 75% over a period of 3 months, as represented in Table 4.
Table 4: Percent total related substances* (%w/w)
Ingrédient | Initial | 1 month | 2 months | 3 months | |
Maleate sait of a compound of Formula II [Active compound I] | Example 3 | 0.19 | 0.27 | 0.44 | 0.54 |
Example 4 | 0.25 | 0.32 | 0.45 | 0.54 |
Piperaquine phosphate | Example 3 | 1.16 | 1.1 | 1.11 | 1.16 |
Example 4 | 1,15 | 1.03 | 1.13 | 1.16 |
* % Total related substance should not be more than 5% w/w.
Example 5:
Ingrédients | Percent w/w |
Intragranular | |
Active compound I | 14.60 |
Piperaquine phosphate | 56.30 |
Microcrystalline Cellulose | 16.70 |
Magnésium stéarate | 0.43 |
Crospovidone | 2.15 |
Extragranular | |
Microcrystalline Cellulose | 4.30 |
Crospovidone | 2.15 |
Magnésium stéarate | 0.97 |
Coating | |
Opadry® O2B53782 orange | 2.40 |
Water | q.s |
Total weight (mg) | 1332.0 |
Water content | <6.55% w/w |
5 Procedure:
1. Active compound I, piperaquine phosphate and intragranular portion of microcrystalline cellulose and crospovidone were sieved through sieve BSS # 44 and mixed together.
2. To the blend of step 1, intragranular portion of sifted magnésium stéarate was added and blended for about 5 minutes.
3. The blend of step 2 was compacted and compacts were sifted through sieve BSS # 18 to form granules.
4. Extragranular portion of microcrystalline cellulose and crospovidone were sieved through sieve BSS # 44 and blended with the granules of step 3.
5. Extragranular portion of magnésium stéarate were sieved through sieve BSS # 44 and blended with the blend of step 4 in a double cône blender for about 5 minutes.
6. The blend of step 5 was compressed using suitable size punches to obtain compressed tablets.
7. The tablets as obtained from step 6 were coated with Opadry® using conventional coating techniques and weight built of up to 2.4%w/w.
Table 5: Percentage (% w/w) of In vitro drug release of Active compound I, from example 5, in USP II apparatus* (media: 2% tween 80 in water, 900ml, 75 rpm)
Time (minutes) | (Percent w/w) |
15 | 88 |
30 | 87 |
45 | 90 |
*The in vitro drug release (% w/w) should not be less than 70% (Q) of the labeled amount dissolved in 45 minutes.
A Phase II, double blind, parallel group, randomized, dosefindîng study was performed to détermine the safety and efficacy of three dose levels (50 mg, 100 mg and 200 mg) of Active compound I administered for three days in patients with uncomplîcated P. falciparum malaria. Preliminary data showed that the mean parasite clearance time for the patient on 50 mg was 52 hours, and ail the 3 patients who were followed up for 28 days showed reappearance of parasites. Patients receiving 100 mg had a parasite clearance time of 46.6 hours and 5 of total 6 patients showed reappearance of parasites. Patients receiving 200 mg had a parasite clearance time of 30.4 hours and 4 out of 5 patients showed adéquate clinical and parasitological response (ACPR) at day 28. Only 1 patient showed reappearance of parasites. The results obtained so far indicate that Active compound I was a short-acting drug and produced rapid clearance of parasites. The relatively high rate of recrudescence with Active compound I after three days of monotherapy highlighted the need to combine the drug with a long-acting drug.
Piperaquine phosphate was chosen as a partner drug and a Phase I double blind, randomized, parallel group, placebo controlled study was conducted in young healthy male subjects to investigate the safety, tolerability and pharmacokinetic profile of Active compound I and piperaquine phosphate after co-administration of multiple oral doses. The study comprised of three cohorts. Cohort I received an oral daily dose of 100 mg of Active compound I and 750 mg of piperaquine phosphate, Cohort II received an oral daily dose of 200 mg of Active compound I and 750 mg of piperaquine phosphate and Cohort III received an oral daily dose of 200 mg of Active compound I and 1000 mg of piperaquine phosphate. Ail three doses were administered once daily for three days in each cohort. No drug related adverse event was observed up to dose levels of 200 mg Active compound I and 750 mg of piperaquine phosphate. However, somnolence and vomiting were reported in dose level of 200 mg Active compound I and 1000 mg of piperaquine phosphate. Systemic exposures to Active compound I after repeated dosing was not appreciably different to that after single dose, hence no accumulation was observed for Active compound I upon 3 days repeated dosing of Active compound I - piperaquine phosphate combination. Exposures of Active compound I increased in a dose-proportional manner upon doubling the dose from 100 mg to 200 mg, when the dose of piperaquine phosphate was kept constant (Table 6).
Comparative Bioavailability Study of fixed-dose combination of Active compound 1150 mg + piperaquine phosphate 750 mg and co-pack formulations.
A single-dose, two-treatment, parallel design study comparing the bioavailability of fixed dose combination tablets of Active compound 1150 mg + piperaquine phosphate 750 mg with coadministered Active compound 1150 mg and piperaquine phosphate 750 mg was conducted as an open label, balanced, randomized, single-dose, two-treatment, parallel design in 36 healthy, adult, human, male subjects under fasting conditions. The pharmacokinetic parameters are presented in Tables 7 and 8. The results of this study suggested that the pharmacokinetics of Active compound I remained unaltered when administered in fixed-dose combination with piperaquine phosphate as compared to their co-administration as individual tablets.
Table 6: Géométrie mean pharmacokinetic parameters of Active compound I (free base) following multiple oral co-adminlstration of Active compound I and piperaquine phosphate to young healthy male subjects (n=6).
Cohor t Study | Tmax (h) | Cm„x (ng/ml) | Ti,2 (h) | AUCq-24 (ng.h/ml) | AUCo-t (ng.h/ml) | Ro | |||||
Day 1 | Day 3 | Day 1 | Day 3 | Day 1 | Day 3 | Day 1 | Day 3 | Day 1 | Day 3 | ||
1 | 3.1 1 | 4.4 2 | 73.63 | 78.87 | 3.6 0 | 3.8 6 | 540.18 | 623.74 | 547.82 | 637.36 | 1.1 5 |
II | 4.5 6 | 5.3 1 | 164.2 0 | 148.5 1 | 4.6 9 | 5.8 6 | 1388.1 8 | 1527.6 3 | 1458.6 1 | 1683.3 0 | 1.1 0 |
III | 4.2 9 | 4.0 6 | 180.9 9 | 163.0 4 | 5.1 4 | 5.4 6 | 1573.1 9 | 1772.5 3 | 1670.8 9 | 1940.1 0 | 1.1 3 |
Ro=Degree of accumulation calculated as (AUC0.24(Day 3)/AUC0.24 (Day 1))
Table 7: Géométrie mean pharmacokinetic parameters of Active compound I (free base) following administration of fixed-dose combination (FOC) and co-pack formulations of Active compound I and piperaquine phosphate to young healthy male subjects.
Tmax (h) | Cmax (ng/ml) | AUCq.24 (ng.h/ml) | AUC0.t (ng.h/ml) | T1/2 (h) | |||||
FDC | Co· pack | FDC | Copack | FDC | Copack | FDC | Copack | FDC | Copack |
3.38 | 3.84 | 127.73 | 116.98 | 1143.01 | 1100.39 | 1146,70 | 1113.48 | 3.98 | 3.91 |
FDG: Fixed-dose combination tablet of Active compound 1150 mg and piperaquine phosphate 750 10 mg as one tablet (n=16); Co-pack: Three Active compound I 50 mg tablets and one piperaquine phosphate 750 mg tablet as individual tablets (n=17), AUCo-t= AUC 0 to last measurable concentration (sampling up to 96 h).
Table 8: Géométrie mean pharmacokinetic parameters of piperaquine following administration of fixed-dose combination (FDC) and co-pack formulations of Active 15 compound I and piperaquine phosphate to young healthy male subjects.
TmaK (h) | CmaK(ng/ml) | AUCq.24 (ng.h/ml) | AUCo.t (ng.h/ml) | ||||
FDC | Co-pack | FDC | Co-pack | FDC | Co-pack | FDC | Co-pack |
4.59 | 4.46 | 92.68 | 95.90 | 728.79 | 915.19 | 1431.48 | 1747.66 |
FDC: Fixed-dose combination tablet of Active compound 1150 mg and piperaquine phosphate 750 mg as one tablet (n=16); Co-pack: Three Active compound I, 50 mg tablets and one piperaquine phosphate 750 mg tablet as individual tablets (n=17), AUC0.t= AUC 0 to last measurable concentration (sampling up to 96 h).
While several particular compositions hâve been described, it will be apparent that various modifications and combinations of the compositions detailed in the text can be made without departing from the spirit and scope of the invention.
Claims (24)
- We Claim:1. A stable solid oral dosage form comprising:(a) ciS'adamantane^-spiro-S'-e'-K^’-aminote'-methylpropylJaminojcarbonylj-methyl]r,2',4'-trioxaspiro[4.5]decane hydrogen maleate (Active compound I);(b) piperaquine; and (c) one or more pharmaceutically acceptable excipients; wherein the dosage form is prepared by a dry process.
- 2. The stable solid oral dosage form according to claim 1, wherein the dosage form comprises:(a) Active compound I in an amount of from about 5% to about 25%; and (b) piperaquine in an amount from about 40% to about 80%, w/w based on the total weight of the dosage form.
- 3. The stable solid oral dosage form according to claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of binders, diluents, glidants/lubricants, disintegrants, surfactants and coloring agents.
- 4. The stable solid oral dosage form according to claim 3, wherein the diluent is microcrystalline cellulose.
- 5. The stable solid oral dosage form according to claim 1, wherein the dosage form has dissolution performance such that, more than 70% w/w of the Active compound I dissolves within 45 minutes, in a pH 4.5 acetate buffer with 2% tween 80, in USP type II apparatus.
- 6. The stable solid oral dosage form according to claim 1, wherein the Active compound I and piperaquine are présent in a weight ratio of from about 1:1 to about 1:10.
- 7. The stable solid oral dosage form according to claim 1, wherein the Active compound I is présent in a dose range of about 100 mg to about 300 mg and piperaquine présent in a dose range of about 700 mg to about 850 mg.
- 8. The stable solid oral dosage form according to claim 1, wherein the dosage form comprises:(a) Active compound I in an amount of from about 5% to about 25%;(b) piperaquine in an amount of from about 40% to about 80%;(c) diluent in an amount of from about 10% to about 40%;(d) disintegrant in an amount of from about 1% to about 10%; and (e) lubricant in an amount of from about 1% to about 5%, w/w based on the total weight of the dosage form.
- 9. The stable solid oral dosage form according to claim 1, wherein the dosage form comprises:(a) Active compound I;(b) piperaquine;(c) microcrystalline cellulose;(d) crospovidone; and (e) magnésium stéarate.
- 10. The stable solid oral dosage form according to claim 1, wherein the dosage form comprises:(a) Active compound I in an amount of from about 5% to about 25%:(b) piperaquine in an amount of from about 40% to about 80%, and (c) microcrystalline cellulose in an amount of from about 10% to about 40%; w/w based on the total weight of the dosage form.
- 11. The stable solid oral dosage form according to claim 1, wherein the dosage form comprises Active compound I and microcrystalline cellulose in a weight ratio of from about 1:1 to about 1:5.
- 12. The stable solid oral dosage fomn according to claim 1, wherein the dosage form is selected from a group consisting of tablet, capsule, pill, granule and powder.
- 13. The stable solid oral dosage form according to claim 12, wherein the tablet is coated with one or more functional and or non-functional coating layers comprising film-forming polymers and coating additives.
- 14. The stable solid oral dosage form according to claim 13, wherein the coating additives comprise one or more of plasticizers, glidants or flow regulators, opacifiera and lubricants.
- 15. The stable solid oral dosage form according to claim 1, wherein the dosage form is processed and stored at a température below 27°C and relative humidity 50%.
- 16. The stable solid oral dosage form according to claim 1, wherein the dry process comprises direct compression or dry granulation.
- 17. The stable solid oral dosage form according to claim 1, wherein the dosage form is prepared by a process comprising the steps of:(a) blending Active compound I, piperaquine, and one or more intragranular excipients;(b) milling, grinding or sieving the blend by roller compaction to form granules;(c) blending the granules with one or more extragranular excipients; and (d) compressing the blend into tablets or filling into capsules.
- 18. The stable solid oral dosage form according to claim 1, wherein the dosage form is prepared by a process comprising the steps of:(a) blending Active compound I, piperaquine, and one or more intragranular excipients;(b) granulating the blend by slugging;(c) blending the granules with one or more extragranular excipients; and (d) compressing the blend into tablets or filling into capsules.
- 19. The stable solid oral dosage form according to claim 1, wherein the dosage form is prepared is prepared by a process comprising the steps of:(a) blending Active compound I, piperaquine, and one or more pharmaceutically acceptable excipients; and (b) directly compressing the blend into tablets or filling into capsules.
- 20. The stable solid oral dosage form according to claim 1, wherein the dosage form is prepared by a process comprising the steps of:(a) granulating a blend of one or more excipients;(b) drying the excipient granules;(c) blending excipient granules with Active compound I and piperaquine; and (d) compressing the blend into tablets or filling into capsules.
- 21. A stable solid oral dosage form comprising:(a) 150 mg of Active compound I and (b) 750 mg of piperaquine, wherein the dosage form is administered once a day for three days.
- 22. The stable solid oral dosage form according to claim 21, wherein the first dose of the dosage form is administered immediately on diagnosis, the second dose about 24 hours after the first dose, and the third dose about 24 hours after the second dose.
- 23. A stable oral solid dosage form for the treatment of malaria comprising:(a) Active compound I;(b) piperaquine; and (c) one or more pharmaceutically acceptable excipients wherein the dosage form is prepared by a dry process.
- 24. A stable solid oral dosage form for the treatment of malaria comprising:(a) 150 mg Active compound I and (b) 750 mg of piperaquine wherein the dosage form is administered once a day for three days.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/183,119 | 2011-07-14 | ||
IN2703/DEL/2011 | 2011-09-19 | ||
IN2156/DEL/2012 | 2012-07-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
OA16845A true OA16845A (en) | 2016-01-07 |
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