WO2000069420A1 - Compositions a administration buccale par poussees - Google Patents

Compositions a administration buccale par poussees Download PDF

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Publication number
WO2000069420A1
WO2000069420A1 PCT/IL2000/000271 IL0000271W WO0069420A1 WO 2000069420 A1 WO2000069420 A1 WO 2000069420A1 IL 0000271 W IL0000271 W IL 0000271W WO 0069420 A1 WO0069420 A1 WO 0069420A1
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Prior art keywords
vitamin
coating
microcapsules
composition according
hours
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PCT/IL2000/000271
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English (en)
Inventor
Yoseph Bornstein
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Coraltis Ltd.
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Priority to AU44280/00A priority Critical patent/AU4428000A/en
Publication of WO2000069420A1 publication Critical patent/WO2000069420A1/fr

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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • This invention relates in general to compositions for the delivery of bioactive agents to a subject.
  • a composition which delivers a bioactive agent in a pulsative manner and is intended for oral administration.
  • a bioactive agent is encapsulated within any of a number of protective wall materials, usually polymeric in nature.
  • the agent to be encapsulated can be coated with a single wall of polymeric material or can be homogeneously dispersed within a polymeric matrix.
  • the amount of agent inside the microcapsule can be varied as desired, ranging from either a small amount to as high as 95% or more of the microcapsule composition.
  • the diameter of the microcapsule can also be varied as desired, ranging from less than one 15 micrometer to as large as three millimeters or more.
  • EP 199362 and U.S. patents Nos. 4,900,556 and 4,921,757 describe a system for delayed and pulsed release of biologically active substances.
  • the active substance is entrapped in encapsulated liposomes which are stimulated by external factors or by including a phospholipase within the liposomes, at distinct intervals of 0 time to produce a pulsed release of the entrapped substance.
  • Vitamin C ascorbic acid
  • Vitamin C is an example of a bioactive agent, which its presence in the body is needed at substantial high concentrations but at the same time is not entirely absorbed when administered in a single dose.
  • Vitamin C is involved in a ⁇ reat number of biochemical reactions in the human body. Two of its major interactions are in potentiating the immune system and aiding the synthesis of the protein collagen, which is a very important substance that strengthens the blood vessels, the skin, the muscles and the bones. The clinical effects of metabolic reactions in which vitamin C is involved have been widely recognized and reported. For example, the free-radical scavenging effect is believed to enable the body to convert carcinogens to non-toxic derivatives which are eliminated in the urine and, consequently, to ameliorate the effects of smoking and exposure of the body to other environmental pollutants.
  • Vitamin C absorption by man has been studied, see for example Thielemann A. M. et al, in II Farmaco - Ed. Pr., vol. 43, 1988. According to this article, an increase in the absorption has been observed on administration of vitamin C in separate doses, compared with a single dose. Therefore, it was expected that a similar effect could be achieved by administering the vitamin in a slow release preparation. However, no statistical difference was observed with the urinary excretion of vitamin C between a slow release preparation and an aqueous solution of the same 1 gr. dose (Anderson T.W. et al., CMA Journal, 5,823,1975).
  • a composition for the oral delivery of a bioactive agent to a subject comprising three delivery forms of the bioactive agent, at least two of which being in the form of microcapsules having each an external coating encapsulating said agent, characterized in that the coating of the microcapsules of each form is different than that of the other form or forms, said agent being released in the digestive tract in essentially three release pulses.
  • the bioactive agent used in the compositions of the present invention is either one that its presence in the body is needed at substantial high concentrations but at the same time is not entirely absorbed when administered in a single dose or it is an agent that should be administered in a pulsative manner in order to ensure therapeutical activity .
  • a preferred bioactive agent is vitamin C.
  • the three release pulses of the bioactive agent are provided by the composition of the present invention, wherein the three delivery forms are microcapsules.
  • the coating of a first group of microcapsules is gastrosoluble, the coating of a second group of microcapsules is enterosoluble and the coating of the third group of microcapsules is enterosoluble but with dissolution properties in an intestinal or intestinal-like medium such that it releases the bioactive agent in the intestine at slower rate than the second group of microcapsules.
  • the three release pulses of the bioactive agent are provided by the composition of the present invention, wherein one delivery form of the bioactive ingredient is other than a microcapsule and is gastrosoluble, the remaining two delivery forms being microcapsules which have distinct dissolution properties in an intestinal or intestinal-like medium.
  • composition of the present invention comprises of different forms of a bioactive agent, designed so as to release the bioactive agent in the stomach and in the intestines at different time intervals.
  • bioactive agents are vitamins such as vitamin C, or drugs such as amoxycillin, ampicillin, tetracycline, nalidixic acid, cefaclor, cephalexin, clindamycin, erytromycin, verapamil, omeprazole, ciprofloxacin, famotidine, diclofenac sodium, nifedipine, ceftriaxone sodium, dilthiazem hydrochloride, captopril, lansoprazole, cefuroxime axetil, albuterol sulfate, metoprolol succinate or pentoxifylline.
  • a preferred bioactive agent is vitamin C and the invention will be further described with reference to vitamin C.
  • the gradual release of the active substance is achieved by using particles of the bioactive agent that have different solubilities in the gastrointestinal tract, i.e. by using in the same system gastrosoluble particles that are soluble under acidic conditions, together with enterosoluble particles.
  • the enterosoluble particles themselves should vary in their solubility in the intestines, so as to have one group of such particles that dissolves quickly in the intestinal fluid and a second group that dissolves at a slower rate. Therefore, according to a preferred embodiment, the system of the present invention contains a blend of three groups of particles: a group that releases vitamin C in the stomach, a second group that releases vitamin C quickly in the intestines and a third group that releases vitamin C slowly in the intestines.
  • microencapsulation technology To achieve pulse delivery of a bioactive agent, microencapsulation technology is used. This technology leads to the formation of individualized particles coated with an appropriate polymer.
  • the advantages gained by the encapsulation of a bioactive agent with a polymer are multi-fold and include: protection against humidity, chemical agents or extreme thermal conditions; taste and color masking; modification of the surface, improved fluidity and flowing properties of powders; controlled or prolonged release of drugs using predefined release mechanisms such as:
  • the gastrosoluble particles used in the composition of the present invention may be either encapsulated or not encapsulated in case that the bioactive material has a good solubility in the stomach.
  • Coating materials for the production of gastrosoluble microcapsules may be selected from commercially available acid-soluble coating materials such as acrylic resins (e.g. Eudragit ®E100) or methacrylic resins.
  • the enterosoluble coating materials that dissolve quickly in an intestinal or intestinal-like medium may be selected from: cellulose derivatives such as hydroxypropylmethylcellulose phthalate (e.g. HPMCP 55), hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose (e.g. Pharmacoat® 606), carboxymethyl ethyl cellulose (e.g. Duodcell® AQ), cellulose acetate phthalate, or other polymers such as polyvinyl acetate phthalate.
  • cellulose derivatives such as hydroxypropylmethylcellulose phthalate (e.g. HPMCP 55), hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose (e.g. Pharmacoat® 606), carboxymethyl ethyl cellulose (e.g. Duodcell® AQ), cellulose acetate phthalate, or other polymers such as polyvinyl acetate phthalate.
  • enterosoluble coating materials that have dissolution properties in an intestinal or intestinal-like medium such that release the bioactive agent in the intestine at a slower rate are copolymers of methacrylic acid and methyl methacrylate and/or methyl acrylate that are soluble under pH values higher than 7 (e.g. Eudragit® S, Eudragit® 4110D).
  • the release of vitamin C from microcapsules is dictated by the solubility of the coating materials in the gastrointestinal tract.
  • certain additives may affect the solubility and the coating properties of a certain coating material, such as for example surfactants, plasticizing agents and brittleness-inducing agents.
  • the plasticizing agents can be selected from commercially available agents, and preferred plasticizing agents are diethyl phthalate, dibutyl phthalate, triethyl citrate, polyethylene glycol, acetyl triethyl cytrate, dibutyl sebacate, or glyceryl triacetate.
  • the effective amount of the plasticizing agent varies between 2 and 20% of the total dry substance of the coating material.
  • a brittleness-inducing agent is defined as a dose agent which decreases the elasticity of the film which forms the coatings.
  • Examples of commercially available brittleness-inducing agents are talc, aerosil and magnesium stearate and effective amounts are 5 to 60% relative to the total dry substance of the coating material.
  • the encapsulation of a bioactive agent may be carried out by various known methods, for example spray-drying, spray-coating, solvent emulsion evaporation or extraction, prilling, extrusion or supercritical C0 2 .
  • the spray-coating technique is especially preferred, since it is easily scaled up and is well adapted to obtain microparticles whose diameter ranges between 100 and 500 ⁇ m.
  • a typical process for the preparation of encapsulated bioactive agents, for example of vitamin C includes the steps of placing vitamin C particles in a fluidized hot air and carrying out spray-coating onto the vitamin C particles, using a polymer solution/dispersion so as to produce a microcapsule wall at the surface of vitamin C.
  • the air temperature depends on the polymer solvent evaporation temperature.
  • the polymer solution/dispersion is kept under continuous stirring and pumped up to the spray nozzle at the bottom of the fluidized air bed.
  • the polymer solution may be sprayed in a number of separate periods, and between each spraying the particles are cured. After the last curing step, the vitamin C microcapsules are harvested.
  • compositions of the present invention may normally be for pharmaceutical and/or nutritional use and in a solid form, e.g. with the microparticles/microcapsules inco ⁇ orated in a unit dose such as tablets, capsules, including hard gelatine capsules, caplets, chewable tablets, tongue tablets, as a mixture in a sachet, or in any adequate nutritive form, for example bars, cereals, etc.
  • the composition of the present invention may further comprise one or more food additives or ingredients which strengthen or boost the immune system or other body functions, as for example propolis, echinacea, minerals, amino acids, ginseng, antioxidants, etc.
  • Fig. 1 - a graph showing the stability profile of 2g/L vitamin C solutions versus time at 37°C, in an acidic or neutral medium
  • Fig. 3 - a graph showing the in vitro release profile of vitamin C recorded for batch B for 2 hours in an acidic medium and then 6 hours in a neutral medium
  • Fig. 4 - a graph showing the release profile of batch D, HPMCP 55 + 25% talc for 2 hours in an acidic medium, 6 hours in a neutral medium
  • Fig. 6 - a graph showing the in vitro release profile of batch H (Eudragit ® 4110D + 10% talc), for 2 hours in an acidic medium, and 6 hours in a neutral medium
  • Fig. 7 - a graph showing the in vitro release profile of batch I, (Eudragit ® 41 10D + 25% talc) for 2 hours in an acidic medium, 6 hours in a neutral medium
  • Fig. 12 - a histogram showing the amount of vitamin C released versus time for the PDS 3 containing 800 mg. of vitamin C
  • Fig. 13 - a graph showing the release profile of vitamin C recorded for PDS 4 for two hours in an acidic medium and 6 hours in a neutral medium
  • Fig. 14 - a histogram showing the amount of vitamin C released versus time for the PDS 4 containing 800 mg. of vitamin C
  • Fig. 15 - a graph showing the release profile of vitamin C recorded for PDS 5 for two hours in an acidic medium and 6 hours in a neutral medium
  • Fig. 16 - a histogram showing the amount of vitamin C released versus time for the PDS 5 containing 800 mg. of vitamin C
  • Fig. 17 - a graph showing the release profile of vitamin C recorded for PDS 6 for two hours in an acidic medium and 6 hours in a neutral medium
  • Fig. 18 - a histogram showing the amount of vitamin C released versus time for the PDS 6 containing 800 mg. of vitamin C
  • Fig. 19 - a graph showing the in vitro release profile of a Twinlab® tablet (C- 1000 Tabs) EXPERIMENTAL
  • the measurement of vitamin C content in the microcapsules was performed using a UV spectrophotometer.
  • a known amount of microcapsules was ground so as to break the capsule wall and release the vitamin C.
  • the ground microcapsules were introduced in the appropriate dissolution medium chosen to mimic either a gastric or an enteric medium.
  • the amount of vitamin C was measured using a UV spectrophotometer. Stability of vitamin C in the dissolution medium was preliminary checked.
  • the measurement of vitamin C released from the particles at given time intervals was performed using a UV spectrophotometer.
  • Vitamin C profile in the neutral medium For the development of the pulse-delivery system, the release profile of vitamin C from microcapsules was recorded successively for 2 hours in the acidic medium and 6 hours in the neutral solution.
  • Figure 1 shows the stability profile of two citrate buffer solution and two acidic media containing 2g/L Vitamin C versus time at 37 C. The measurement has been performed successively for two different samples, so as to check the reproductibility of each assay.
  • the batch A produced in this experiment is based on Vitamin C coated with a gastrosoluble polymer: Eudragit ®E.
  • the in vitro release profile of this batch is shown in Fig. 2.
  • Figure 2 shows the in vitro release profile of Vitamin C recorded in an acidic medium. The measurement has been performed successively for two different samples, so as to check the reproducibility of the assay. From Fig.2 it can be noticed that all the Vitamin C contained in the microcapsules is solubilized rapidly (15 min. ) in an acidic medium. The Eudragit ® ElOO coating allows a rapid vitamin C dissolution in an acidic medium. II.3 Vitamin C coated with an entersoluble polymer
  • the coating solution composition has been fixed as follows:
  • the polymer solution has been sprayed in 4 separate periods. Between each spraying step, the particles have been cured for half an hour, so as to form a continuous polymer film on the Vitamin C particles.
  • the reference of this batch is batch B. In vitro release profile
  • Figure 3 shows the in vitro release profile of vitamin C recorded for batch B for 2 hours in an acidic medium and then 6 hours in a neutral medium. The measurement has been performed successively for two different samples, so as to check the reproductibility of the assay.
  • Fig. 3 shows that 55% of the vitamin C contained in the mircrocapsules is solubilized after two hours in an acidic medium. The remaining vitamin C contained in the microcapsules is rapidly solubilized in the neutral medium.
  • the batch seems to be relatively homogeneous.
  • the release profile is quite similar for two different samples taken from the same batch.
  • talc was added.
  • the polymer solution (5mL/min flow rate) has been sprayed in four separate periods, at a spraying pressure of 1 bar. Between each spraying step, the particles have been cured for half an hour, so as to form a continuous polymer film on the vitamin C particles (weight of vitamin C - 500 g).
  • the coating solution composition is presented in Table 5 : Table 5
  • the polymer solution (5.5 mL/min flow rate) has been sprayed in five separate periods, at a spraying pressure of 1 bar. Between each spraying step, the particles have been cured for half and hour, so as to form a continuous polymer film on the Vitamin C particles (weight of vitamin C - 500 g).
  • Figure 4 shows the release profile of vitamin C recorded for batch D (HPMCP55 and 25% talc) for 2 hours in an acidic medium and 6 hours in a neutral medium. The measurement has been performed successively for two different samples, so as to check the reproductibility of the assay.
  • the Eudragit® 4110D dispersion formulation prepared is shown in Table 5: Table 5
  • This dispersion was sprayed onto the Vitamin C particles already coated with stearic acid.
  • the process parameters selected for the trials are presented in Table 6.
  • the polymer solution has been sprayed in 6 steps. Between each spraying step, the particles have been cured for half an hour so as to favor the formation of a continuous polymer film on the vitamin C particles.
  • In vitro release profile
  • the first polymer tested is the pH-independent coating polymer Eudragit® RS30D.
  • the second polymer is Eudragit ® 4110D blended with talc to increase the release time of Vitamin C.
  • Coating material Eudragit ® RS30D
  • Eudragit ® RS30D is an aqueous dispersion of a copolymer of an amino alkyl methacrylate monomer and acrylic and methacrylic esters.
  • the polymer dispersion (10 mL/min flow rate) was sprayed in four separate periods at a spraying pressure of 1 bar. Between each spraying step, the particles have been cured for half an hour, so as to form a continuous polymer film on the Vitamin C particles (weight of vitamin C - 500 g).
  • Figure 5 shows the in vitro release profile of vitamin C recorded for this batch (batch G) for 2 hours in an acidic medium and 5 hours in a neutral medium. The measurement has been performed successively for two different samples, so as to check the reproductibility of the assay.
  • Coating materials Eudragit ® 4110D and 10% talc
  • the polymer dispersion was sprayed in four separate periods. Between each spraying step, the particles have been cured for half an hour so as to form a continuous polymer film on the Vitamin C particles.
  • Figure 6 shows the release profile of vitamin C recorded for batch H for 2 hours in an acidic medium and 6 hours in a neutral medium. The measurement has been performed successively for two different samples, so as to check the reproductibility of the assay.
  • Vitamin C contained in the microcapsules is totally solubilized after three hours in the neutral medium. Hence, it appears that the dissolution of Vitamin C particles in neutral medium has been extended over a longer period of time.
  • the coating dispersion composition has been fixed as follows: Table 10
  • the polymer dispersion was sprayed in four separate periods. Between each spraying step, the particles have been cured for half an hour so as to form a continuous polymer film on the vitamin C particles.
  • Figure 7 shows the release profile of Vitamin C recorded for batch I for 2 hours in an acidic medium and 6 hours in a neutral medium. The measurement has been performed successively for two different samples, so as to check the reproductibility of the assay.
  • Vitamin C without any coating was used for the first batch, if no specific coating is required to enhance stability of the product during the storage period.
  • the appropriate coating material was an entersoluble polymer: HPMCP55, blended with 25% talc. This composition, at a 35% coating ratio, makes it possible to release 32% of vitamin C in two hours in an acidic medium and the remaining Vitamin C as a single dose pulsed in the neutral medium. The talc ratio could even be adjusted to restrict the dissolution of vitamin C in the acidic medium.
  • the third batch was the slow and sustained release form of vitamin.
  • the coating composition elaborated is made of the polymer Eudragit® 4110D with
  • the talc ratio could even be adjusted to extend the dissolution time of vitamin C contained in the microcapsules.
  • composition of the three batches to be prepared is as follows:
  • Figure 8 shows the in vitro release profile of the three batches proposed.
  • Figure 9 shows the release profile of Vitamin C recorded for this first PDS for two hours in an acidic medium and 6 hours in a neutral medium. The measurement was performed successively for two different samples, so as to check the reproductibility of the assay.
  • Second system (1,2,3,) Figure 10 shows the release profile of vitamin C recorded for the second PDS for two hours in an acidic medium and 6 hours in a neutral medium. The measurement has been performed successively for two different samples, so as to check the reproductibility of the assay.
  • Vitamin C contained in the system is solubilized after one hour and a half in the neutral medium. Once again, the second pulse does not appear in the release profile. The content of batch 2 in the blend must be more increased.
  • Figure 11 shows the release profile of vitamin C recorded for the third PDS for two hours in an acidic medium and 6 hours in a neutral medium. The measurement was performed successively for two different samples, so as to check the reproductibility of the assay.
  • Figure 12 shows a histogram which displays the amount of vitamin C released versus time for the PDS 3 containing 800 mg. of vitamin C. This figure confirms the achievement of a pulse-delivery system with three steps: vitamin C released immediately in the stomach (30 min.), vitamin C released immediately in the intestines (150 min) and vitamin C released in the intestines slowly (210-240 min).
  • Figure 13 shows the release profile of vitamin C recorded for the fourth PDS for two hours in an acidic medium and six hours in a neutral medium. The measurement was performed successively for two different samples, so as to check the reproductibilty of the assay.
  • FIG. 13 shows a histogram which displays the amount of vitamin C released versus time for PDS 4 containing 800 mg. of vitamin C. This figure confirms the achievement of a pulse-delivery system with three steps: vitamin C released immediately in the stomach (30 min.), vitamin C released immediately in the intestines (150 min) and vitamin C released in the intestines slowly (300 min.). The ratio of the different batches in the system should be adjusted to obtain three equivalent pulses, and more particularly to increase the third one.
  • Figure 16 shows a histogram which displays the amount of vitamin C released versus time for PDS 5 containing 800 mg. of vitamin C. This figure confirms the achievement of a pulse-delivery system with three steps: vitamin C released immediately in the stomach (30 min), vitamin C released immediately in the intestines (150 min) and vitamin C released in the intestines slowly (210-240 min.). The ratio of the different batches in the system can once again be adjusted to obtain three equivalent pulses, and more particularly to decrease the first one.
  • Figure 18 shows a histogram which displays the amount of vitamin C released versus time for PDS 6 containing 800 mg of vitamin C. This figure confirms the achievement of a pulse-delivery system with three steps: vitamin C released immediately in the stomach (30 min.), vitamin C released immediately in the intestines (150 min) and vitamin C released in the intestines slowly (210 min.).
  • This PDS is the most efficient one, three pulses clearly appear in the release profile and all the vitamin C contained in this system is solubilized within about 6 hours.
  • a Twinlab ® tablet (C- 1000 TABS, manufactured by TWIN LABORATORIES INC., Ronkonkoma, New York), was evaluated for two hours in an acidic medium and six hours in a neutral medium.
  • a Twinlab ® tablet (weight: 1300 mg.) contains 1000 mg. vitamin C.
  • Figure 19 shows the release profile recorded. It can be observed that the vitamin C contained in the tablet is solubilized almost linearly versus time over a period of more than 8 hours. This tablet gives a sustained release of vitamin C, but not a pulse-delivery effect.

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Abstract

L'invention concerne une composition destinée à administrer buccalement un agent bioactif à un sujet. Ladite composition comprend trois formes d'administration de l'agent bioactif, au moins deux d'entre elles se présentant sous forme de microcapsules qui ont chacune un enrobage externe encapsulant l'agent. Ledit agent bioactif est libéré dans le conduit digestif en trois poussées de libération, étant donné que l'enrobage des microcapsules de chaque forme est différent de celui de l'autre ou des autres formes.
PCT/IL2000/000271 1999-05-14 2000-05-12 Compositions a administration buccale par poussees WO2000069420A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU44280/00A AU4428000A (en) 1999-05-14 2000-05-12 Pulse-delivery oral compositions

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IL129964 1999-05-14
IL12996499 1999-05-14

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WO2000069420A1 true WO2000069420A1 (fr) 2000-11-23

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WO2003053420A1 (fr) * 2001-12-20 2003-07-03 Pharmacia Corporation Formulations de clindamycine a liberation prolongee, a impulsions multiples
FR2850577A1 (fr) * 2003-02-03 2004-08-06 Ethypharm Sa Particules enrobees a gout masque, leur procede de preparation et comprimes orodispersibles contenant lesdites particules
WO2004066974A1 (fr) * 2003-01-30 2004-08-12 Ethypharm Particules presentant un enrobage de masquage du gout, procede de preparation associe et comprimes orodispersibles contenant lesdites particules enrobees
WO2004084870A1 (fr) * 2003-03-28 2004-10-07 Sigmoid Biotechnologies Limited Forme posologique solide s'administrant par voie orale qui contient des microcapsules sans soudure
WO2005023229A1 (fr) * 2003-09-03 2005-03-17 Boehringer Ingelheim International Gmbh Capsule contenant des pellets de principe actif presentant differents profils de liberation
WO2006035417A2 (fr) * 2004-09-27 2006-04-06 Sigmoid Biotechnologies Limited Preparations de dihydropyrimidine
EP2215936A1 (fr) 2009-02-09 2010-08-11 Stichting Top Institute Food and Nutrition Récipient de boisson et procédé pour la distribution pulsée d'un arôme
CN103462916A (zh) * 2013-09-12 2013-12-25 山东天力药业有限公司 一种维生素c咀嚼片及其制备方法
US8911777B2 (en) 2007-04-04 2014-12-16 Sigmoid Pharma Limited Pharmaceutical composition of tacrolimus
US8951570B2 (en) 2007-04-26 2015-02-10 Sigmoid Pharma Limited Manufacture of multiple minicapsules
US9220681B2 (en) 2012-07-05 2015-12-29 Sigmoid Pharma Limited Formulations
US9278070B2 (en) 2009-05-18 2016-03-08 Sigmoid Pharma Limited Composition comprising oil drops
EP3042648A1 (fr) 2014-12-23 2016-07-13 Hermes Arzneimittel GmbH Granules directs a agent actif retarde
FR3046088A1 (fr) * 2015-12-28 2017-06-30 Capsulae Microcapsule comprenant une membrane issue d'une microencapsulation par coacervation complexe, et procede d'obtention
US9821024B2 (en) 2010-11-25 2017-11-21 Sigmoid Pharma Limited Immunomodulatory compositions
US9878036B2 (en) 2009-08-12 2018-01-30 Sigmoid Pharma Limited Immunomodulatory compositions comprising a polymer matrix and an oil phase
US10434138B2 (en) 2013-11-08 2019-10-08 Sublimity Therapeutics Limited Formulations
US10993987B2 (en) 2014-11-07 2021-05-04 Sublimity Therapeutics Limited Compositions comprising Cyclosporin

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