EP1301174A1 - Bioadhäsive mikrokugeln mit schneller freisetzung für die sublinguale arnzeimittelverabreichung - Google Patents
Bioadhäsive mikrokugeln mit schneller freisetzung für die sublinguale arnzeimittelverabreichungInfo
- Publication number
- EP1301174A1 EP1301174A1 EP01945570A EP01945570A EP1301174A1 EP 1301174 A1 EP1301174 A1 EP 1301174A1 EP 01945570 A EP01945570 A EP 01945570A EP 01945570 A EP01945570 A EP 01945570A EP 1301174 A1 EP1301174 A1 EP 1301174A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- microspheres
- microspheres according
- solution
- proximate
- acrylic polymers
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
Definitions
- the present invention refers to fast release bioadhesive microspheres for the sublingual administration of proximate principles, processes for the preparation of the same and pharmaceutical formulations including said microspheres.
- proximate principles i.e. by the absorption of these through the mucous of the sublingual area
- sublingual administration is particularly suitable in cases in which a rapid onset of the therapeutic action is desired or for drugs subjected to wide hepatic metabolization.
- the main difficulty met in the sublingual administration of proximate principles is the short time these remain at the site of absorption, because of the continuous production and deglutition of saliva. If, in fact, the medicine dissolves slowly or is unable to penetrate the sublingual mucous, it is quickly removed before significant absorption takes place.
- Bioadhesive formulations have in fact been recently developed, namely tablets and gels, made up of a bioadhesive matrix able to adhere to the mucous of the sublingual cavity and disintegrate slowly, thus maintaining the medicine in situ for a sufficient time period to obtain adequate absorption.
- These formulations are nevertheless characterized by a slow release of the proximate principle and are therefore unsuitable should one wish to obtain a rapid onset of the therapeutic action. Therefore the need is felt to develop new formulations equipped with bioadhesive characteristics and which allow a ready release and hence rapid sublingual absorption, also of poorly hydrosoluble drugs.
- a new fast release formulation for the sublingual administration of proximate principles has now been surprisingly found.
- the inventors have in fact found that when a proximate principle is dispersed in non-crystalline form in a microparticle system made up of a bioadhesive polymer in microsphere form, with a mean diameter of less than 50 ⁇ and preferably less than 30 ⁇ , its dissolution speed is greater than that observed when the same proximate principle is in pure form.
- the aforesaid microspheres also show excellent adhesive capacities to the mucous. They therefore find particular utility in the sublingual administration of proximate principles, also poorly hydrosoluble ones.
- the present invention refers to fast release bioadhesive microspheres for sublingual administration of at least one proximate principle characterized in that they have a mean diameter of less than 50 ⁇ and preferably less than 30 ⁇ and contains said proximate principle dispersed in non-crystalline form in a bioadhesive polymer micromatrix of a molecular weight suitable for obtaining a fast release.
- the polymer is dispersed in the matrix in non-crystalline form.
- microspheres of the present invention preferably contain at least one proximate principle in an amount usually of between 5 and 80%, preferably between 15 and 50% and a bioadhesive polymer in an amount of between 20 and 95%, preferably between 35 and 85%.
- the microspheres of the invention can contain any proximate principle.
- the microspheres can contain hormones, vitamins, drugs that act on the cardiovascular and respiratory system, antimigraine, anaesthetics, myorelaxants, antihistamines, analgesics, antiinflammatories, antipyretics, hypnotic sedatives, stimulants of the nervous system, antiepileptic, antiparkinson, anticoagulants, hormonal antagonists, antimicrobial, antibiotics, peptide type drugs and vaccines. They are particularly suitable for the administration of poorly hydrosoluble proximate principles, of which increasing their solubility is desirable.
- the proximate principle is selected from the group including oxicam, dihydropyridines, benzodiazepines, steroids, alkaloids.
- piroxicam dihydropyridines
- benzodiazepines benzodiazepines
- steroids alkaloids
- nifedipine clonazepam and clobetasole
- morphine particularly preferred.
- the bioadhesive polymer has a molecular weight suitable for obtaining a fast release and is selected from the group including derivatives of cellulose, starches, gums, scleroglucans, chitosans, vinyl, ethylene and acrylic polymers and copolymers and their derivatives.
- cellulose such as, for example, hydroxypropylmethyleellulose at different degrees of substitution characterized by a viscosity of a 2% solution in water of less than 4000 cp, among which for instance Methocel E5 ® , Methocel E50 ® and Methocel F50 ® , polyvinylpyrrolidone having a molecular weight of less than 1000000 Da.
- Another group of polymers particularly preferred are the sodium or potassium salts of acidic acrylic polymers with a molecular weight of between 100000 and
- the acidic acrylic polymers usable to prepare the aforesaid salts are preferably selected from the group consisting of: a) copolymers of methacrylic acid and methyl methacrylate; b) copolymers of methacrylic acid and ethyl methacrylate, c) terpolymers of methacrylic acid, methyl methacrylate and methyl acrylate;
- the particularly preferred acidic acrylic polymers belonging to class (a) are those commercially available under the EUDRAGIT ® trademark and particularly the Eudragit S-100, with a mean molecular weight of around 135,000, and in which the free carboxylic groups and ester groups ratio is around 1 :2; and the Eudragit L-
- the preferred acidic acrylic polymers belonging to class (b) are still the Eudragit and particularly the Eudragit L-100-55 with a mean molecular weight of 250000 Da and in which the ratio between free carboxylic groups : ester groups is around 1: 1.
- Preferred acidic acrylic polymers belonging to class (c) are still the Eudragit and particularly the EUDRAGIT FS 30D, consisting of an aqueous dispersion of the terpolymer at 30% in weight, that contains only 10 to 12% of units of methacrylic acid.
- the sodium and potassium salts of the acidic acrylic polymers usable in the microspheres subject of the invention are preferably prepared with a process that includes the following steps: i) a 5% solution in weight of the acidic acrylic polymer is prepared to which sodium or potassium carbonate is added in an amount able to impart neutrality to the aqueous solution; ii) the solution obtained in the previous stage is dried by nebulization with the spray drying technique.
- the microspheres of the present invention also contain pharmaceutically acceptable excipients such as, for instance, wetting and solubilizing agents and diluents in amounts preferably between 2 and 20%.
- the solubilizing agents are preferably surfactants, among which are particularly preferred polysorbates, esters and ethers of polyethylene glycols, polyhydroxylated castor oil and sodium lauryl sulphate.
- the present invention also refers to processes for the production of the aforesaid microspheres.
- the microspheres of the invention can be produced through processes usually used in the art such as, for example, coprecipitation, emulsion formation and evaporation of the solvent, spray congealing and spray drying, using conditions that lead to the attainment of the proximate principle dispersed in non- crystalline form.
- Particularly preferred for the production of the microspheres of the invention are spray drying techniques.
- the preparation of the microspheres of the invention envisages the following stages:
- the proximate principle is dissolved in a solution or suspension of the bioadhesive polymer
- the resulting mixture is nebulized through the standard nozzle of a nebulizer at a flow speed of between 5 and 60 ml/min and at an incoming air temperature of between 50° and 130°C.
- the aforesaid solution or suspension contains a concentration of one of the aforesaid polymers of between 0.5 and 20% p/v.
- Solvents that can be used for the preparation of said solution or suspension are, for instance, water, ethanol, isopropanol, methylene chloride, butanol, cyclohexane, hexane, acetone or mixtures of these.
- the aforesaid proximate principle is added to said solution or suspension of the polymer in such an amount as to obtain a concentration of between 0.1 and 20% p/v.
- the polymer solution or suspension also contains one or more of the aforesaid pharmaceutically acceptable excipients at concentrations of between 0.5 and 20% p/v and preferably between 1 and 10% p/v.
- microspheres of the present invention present considerable advantages compared to the conventional formulations used sublingually. In fact, at the same time, they allow close contact between the proximate principle and the mucous and a high release speed, also for poorly hydrosoluble drugs, thus increasing the bioavailability and onset speed of the action of the proximate principle.
- microspheres of the present invention can be used as such, in the form of powders, or used for the preparation of pharmaceutical forms suitable for sublingual administration such as, for instance, tablets, capsules and sprays. Therefore, an additional aim of the present invention are pharmaceutical formulations for sublingual administration of proximate principles including the aforesaid microspheres usually together with pharmaceutically acceptable excipients. Among these are particularly preferred are formulations suitable for the administration of said microspheres in dispensers for mono or multidose powders.
- the invention will now be illustrated in detail by the following examples, to be considered as illustrative and non-limiting, of the invention.
- nifedipine microspheres Four solutions in methylene chloride/ethanol were prepared (90/10 v/v) having the following formulations:
- the solutions were then nebulized through the standard nozzle (1mm internal diameter) of an SD04 nebulizer (Lab-Plant LTD, West Yorkshire, United Kingdom) with a flow speed of 20 ml/min, maintaining an incoming air temperature of 60°C and an outgoing air temperature of 40°C.
- the microspheres obtained had a mean diameter of 20 ⁇ , determined by the light scattering method, and a proximate principle content of more than 98% of the theoretical content.
- the microspheres were analyzed using scanning calorimetry using a DSC 2010 apparatus (TA Instruments, United States), with a heating range from 30° to 225°C, scanning speed of 10°C/min and under continuous flow of nitrogen.
- the thermogram obtained shows the absence of thermal events in the temperature range considered and particularly at the melting temperature of nifedipine, at 173°C.
- Piroxicam 2.5%, polyvinylpyrrolidone having a molecular weight of 30000 Da, 2.5%.
- the solutions were then nebulized through the standard nozzle (1mm internal diameter) of an SD04 nebulizer (Lab-Plant LTD, West Yorkshire, United Kingdom) with a flow speed of 20ml/min maintaining an incoming air temperature of 60°C and at an outgoing air temperature of 40°C.
- the microspheres obtained had a mean diameter of 20 ⁇ determined using the light scattering method, and a proximate principle content of more than 98% of the theoretical content.
- the microspheres were also analyzed by scanning calorimetry using a DSC 2010 apparatus (TA Instruments, United States), with a heating range from 30° to 225°C, scanning speed of 10°C/min and under continuous flow of nitrogen.
- the thermogram obtained shows the absence of thermal events in the temperature range considered and particularly at the melting temperature of piroxicam, at
- both microspheres are characterized by a piroxicam dissolution speed which is greater than that of pure piroxicam.
- the microspheres thus obtained had a mean diameter of 20 ⁇ , determined by the light scattering method, and a proximate principle content of more than 98% of the theoretical content.
- the microspheres were also analyzed through scanning calorimetry using a DSC 2010 apparatus (TA Instruments, United States), with a heating range from 30° to 225°C, scanning speed of 10°C/min and under continuous flow of nitrogen.
- the thermogram obtained shows the absence of thermal events in the temperature range considered and particularly at the melting temperature of clonazepam.
- the dissolution speed of the clonazepam microspheres prepared in Example 5 was assessed, compared with the dissolution speed of the pure clonazepam in micronized form, with the paddle mixer method, described in the F. U. X.
- 60 mg of microspheres or 9 mg of pure clonazepam were placed in a container thermostatically set at 37°C ⁇ 0.5°C in 900 ml of distilled water containing 0.15% sodium lauryl sulphate and kept under agitation at a speed of 100 rpm.
- the amount of clonazepam in the solution was continuously determined spectrophotometrically at a wavelength of 252 nm.
- the following table shows the mean of the results obtained from three determinations, expressed as a percentage of proximate principle dissolved at different time ranges:
- microspheres obtained had a mean diameter of 20 ⁇ , determined by the light scattering method, and they had a proximate principle content of more than 98% of the theoretical content.
- the dissolution speed of the clobetasol microspheres prepared in Example 7 was assessed, compared with the dissolution speed of the pure clobetasol in micronized form, with the paddle mixer method described in the F. U. X.
- 48 mg of microspheres or 7.2 mg of pure clobetasol were placed in a container thermostatically set at 37°C ⁇ 0.5°C in 500 ml of distilled water containing 0.5%
- the amount of clobetasol in the solution was continuously determined spectrophotometrically at a wavelength of 252 nm.
- the following table shows the mean of the results obtained from three determinations, expressed as a percentage of proximate principle dissolved at different time ranges:
- a 5% solution (5g/100ml) of the polyacrylic acid is prepared to which the stoichiometric amount of the alkaline hydroxide is added.
- the sodium or potassium salt of the neutralized methacrylic copolymer is obtained by nebulizing the aqueous solution obtained in the previous stage (i) in a spray- dryer (SD04, Lab-Plant LTD, West Yorkshire, UK) using the following conditions. Spray-dryer conditions:
- METHOD mucin tablets of approx. 150 mg are prepared, with a diameter of
- the polymer tablets are prepared using the same method.
- the mucin tablet is fixed to a steel plate and hydrated for 5 min. with 2 drops of water.
- the polymer tablet is attached on the upper punch (12 mm diameter) and brought into contact with the mucin tablet for 5 min; the force needed to separate the two tablets is recorded.
- a tablet is applied to the gum, of six healthy volunteers, and its staying time is assessed.
- Each tablet weighs 25 mg.
- microspheres loaded with 30% of morphine were obtained by nebulizing through a standard nozzle (1mm internal diameter) of a spray-dryer (SD04, Lab- Plant LTD, West Yorkshire, UK) a solution of H 2 0: EtOH (80:20) containing a methacrylic polymer neutralized with NaOH or KOH and the proximate principle.
- the formulations for nebulization are shown in the following table.
- the results represent the mean of three determinations.
- microspheres loaded with 50% of piroxicam were obtained by nebulizing through a standard nozzle (1mm internal diameter) of a spray-dryer (SD04, Lab- Plant LTD, West Yorkshire, UK) a solution of H 0: acetone (50:50) containing a methacrylic polymer neutralized with KOH and the proximate principle.
- the composition of the fluid used for the nebulization is shown in the following table
- Drying conditions Flow speed: 10 ml/min. Incoming air temperature: 130°C
- microspheres A sample of microspheres was analyzed with the technique of scanning calorimetry (DSC 2010, TA Instruments, USA).
- the piroxicam contained in all the microspheres proved completely amorphized or moleculariy dispersed in the matrix.
- the dissolution speed of the piroxicam is greater for all the prepared microspheres compared with the pure substance. All the microspheres showed good bioadhesion properties.
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI001548 | 2000-07-10 | ||
IT2000MI001548A IT1318618B1 (it) | 2000-07-10 | 2000-07-10 | Microsfere bioadesive a rilascio rapido per la somministrazionesublinguale di principi attivi. |
PCT/IB2001/001243 WO2002003955A1 (en) | 2000-07-10 | 2001-07-09 | Fast release bioadhesive microspheres for the sublingual administration of proximate principles |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1301174A1 true EP1301174A1 (de) | 2003-04-16 |
Family
ID=11445441
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01945570A Withdrawn EP1301174A1 (de) | 2000-07-10 | 2001-07-09 | Bioadhäsive mikrokugeln mit schneller freisetzung für die sublinguale arnzeimittelverabreichung |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1301174A1 (de) |
AU (1) | AU2001267782A1 (de) |
IT (1) | IT1318618B1 (de) |
WO (1) | WO2002003955A1 (de) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10026698A1 (de) | 2000-05-30 | 2001-12-06 | Basf Ag | Selbstemulgierende Wirkstoffformulierung und Verwendung dieser Formulierung |
US6887493B2 (en) * | 2000-10-25 | 2005-05-03 | Adi Shefer | Multi component controlled release system for oral care, food products, nutraceutical, and beverages |
DE10244504A1 (de) * | 2002-09-25 | 2004-04-08 | Capsulution Nanoscience Ag | Schnellfreisetzende Darreichungsform mit schwerlöslichem Wirkstoff |
DE10332160A1 (de) | 2003-07-15 | 2005-02-03 | Röhm GmbH & Co. KG | Multipartikuläre Arzneiform, enthaltend mucoadhaesiv formulierte Peptid- oder Protein-Wirkstoffe, sowie ein Verfahren zur Herstellung der Arzneiform |
WO2005018600A2 (en) * | 2003-08-22 | 2005-03-03 | Cube Medical A/S | Method of treating a patient suffering from a solid tumour |
US8377952B2 (en) | 2003-08-28 | 2013-02-19 | Abbott Laboratories | Solid pharmaceutical dosage formulation |
US8025899B2 (en) | 2003-08-28 | 2011-09-27 | Abbott Laboratories | Solid pharmaceutical dosage form |
WO2005102287A2 (en) * | 2004-04-22 | 2005-11-03 | Duocort Ab | Pharmaceutical compositions for acute glucocorticoid therapy |
GB0613925D0 (en) | 2006-07-13 | 2006-08-23 | Unilever Plc | Improvements relating to nanodispersions |
CZ308594B6 (cs) * | 2014-09-29 | 2020-12-23 | VÝZKUMNÝ ÚSTAV VETERINÁRNÍHO LÉKAŘSTVÍ, v.v.i. | Mukoadhezivní nosiče částic, způsob přípravy a použití |
ITUB20153446A1 (it) * | 2015-09-07 | 2017-03-07 | Pharmafilm Srl | Film orodispersibili a rapida disgregazione per uso terapeutico o alimentare |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR1366002A (fr) * | 1965-05-14 | 1964-07-10 | Lansing Bagnall Ltd | Perfectionnements concernant des chariots industriels |
FR2621483B1 (fr) * | 1987-10-08 | 1991-09-20 | Medibrevex | Nouvelles formes galeniques de corticoides pour administration par voie per- et sublinguale et leur procede de preparation |
US5077051A (en) * | 1990-04-10 | 1991-12-31 | Warner-Lambert Company | Sustained release of active agents from bioadhesive microcapsules |
GB9009390D0 (en) * | 1990-04-26 | 1990-06-20 | Smith Kline French Lab | Pharmaceutical compositions |
JPH04230625A (ja) * | 1990-12-27 | 1992-08-19 | Standard Chem & Pharmaceut Corp Ltd | 噴霧乾燥したジクロフェナクナトリウムを含み腸溶性の被覆を有するマイクロカプセルからなる微分散した錠剤組成物の製造方法 |
DE19617716A1 (de) * | 1996-05-03 | 1997-11-06 | Basf Ag | In wäßriger Lösung redispergierbare Polymerpulver |
GB9700624D0 (en) * | 1997-01-14 | 1997-03-05 | Danbiosyst Uk | Drug delivery composition |
DE19704293A1 (de) * | 1997-02-05 | 1998-08-06 | Basf Ag | Zahnprothesenhaftmittel |
SE9803239D0 (sv) * | 1998-09-24 | 1998-09-24 | Diabact Ab | Composition for the treatment of acute pain |
-
2000
- 2000-07-10 IT IT2000MI001548A patent/IT1318618B1/it active
-
2001
- 2001-07-09 AU AU2001267782A patent/AU2001267782A1/en not_active Abandoned
- 2001-07-09 EP EP01945570A patent/EP1301174A1/de not_active Withdrawn
- 2001-07-09 WO PCT/IB2001/001243 patent/WO2002003955A1/en active Application Filing
Non-Patent Citations (1)
Title |
---|
See references of WO0203955A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU2001267782A1 (en) | 2002-01-21 |
ITMI20001548A0 (it) | 2000-07-10 |
IT1318618B1 (it) | 2003-08-27 |
ITMI20001548A1 (it) | 2002-01-10 |
WO2002003955A1 (en) | 2002-01-17 |
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