CN107847496A - Perle containing Fexofenadine fourth - Google Patents
Perle containing Fexofenadine fourth Download PDFInfo
- Publication number
- CN107847496A CN107847496A CN201680011220.1A CN201680011220A CN107847496A CN 107847496 A CN107847496 A CN 107847496A CN 201680011220 A CN201680011220 A CN 201680011220A CN 107847496 A CN107847496 A CN 107847496A
- Authority
- CN
- China
- Prior art keywords
- weight
- fexofenadine
- composition
- pharmaceutically acceptable
- mixture
- 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.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
Abstract
The liquid softgel filled compositions of bioavailable are disclosed, it is included：A) Fexofenadine fourth or Fexofenadine fourth salt；B) pharmaceutically acceptable poly- (aklylene glycol) is contained, optionally pharmaceutically acceptable aklylene glycol, optionally pharmaceutically acceptable Polymer compatibilizers, and the matrix of optionally pharmaceutically acceptable surfactant；And c) pharmaceutically acceptable acidulant.Also disclose the soft gel capsule of the method for preparing such filled compositions and the Liquid fill compositions containing the bioavailable.
Description
The reference of related application
This application claims the U.S. Provisional Application No. 62/255,615 submitted on November 16th, 2015 and in 2015
The priority of year 2 months U.S. Patent Application No.s submitted for 20th 14/627,589.The content of the application is whole by quoting
Body is incorporated herein.
The field of disclosed theme
Theme disclosed in the present application is related to the filling group of the bioavailable containing Fexofenadine fourth or Fexofenadine fourth salt
Compound, the Perle filled with the Fexofenadine fourth filled compositions of bioavailable and the method for preparing them.
Background
Fexofenadine fourth is to be used to treat allergic symptom, such as the antihistamine of hay fever, nasal obstruction and nettle rash or measles
Thing.It is known as third generation antihistaminic, represents that its effect is limited to periphery (i.e. outside brain and spinal cord), this is most of antihistamine
Agent mediates the position of their sedation effect；Therefore, Fexofenadine fourth has the calm side effect of very little.Fexofenadine fourth by with
In the mitigation sign related to pollinosis, and be used to treat chronic urticaria.It can not cure rhinitis and nettle
Measles, but the exacerbation of rhinitis and nettle rash can be prevented, and the seriousness of the symptom related to those patient's condition is reduced, it is anti-so as to provide
Renaturation sneezing, rhinorrhea, eyes are itched and the mitigation of general physical fatigue.
Fexofenadine fourth is lipophilicity solid, is generally applied with hydrochloride form.
Fexofenadine fourth free alkali and Fexofenadine fourth salt dissolubility inequality, and preparing with enough in aqueous
Problem be present in effectively applying in bioavilability.Under minimum requirements, the preparation of excellent in design should can be with absorbable shape
The hydrophobic compound of therapeutically effective amount is delivered to its desired absorption site by formula.When hydrophobic therapeutic agent delivering need with it is water-based
When physiological environment (such as gastric juice and intestinal juice) interacts, even such minimal function is also difficult to.Further, since stomach and intestine
Function and the difference of food intake, the drug absorption in Different Individual may be dramatically different.Accordingly, it is determined that and control dosage very
It is difficult.Other challenges of Fexofenadine fourth preparation for orally administering are the low-solubilities of compound, particularly in acid stomach
Under the conditions of liquid (solubility of fexofenadine hydrochloride fourth is 0.2mg in the aqueous buffer per ml pH 1.2).
By Fexofenadine fourth be formulated as combination of oral medication another problem is that its is irritating strong and bitter
Taste and pleasant impression, which results in the treatment compliance of difference or be not obedient to even, thus have for treatment effect negative
Face rings.
When Fexofenadine fourth to be formulated as being used to orally administer, the combination of the physical characteristic needs conscientiously to select medicine system
Agent.There is still a need for stable and isolation Fexofenadine fourth, provide enough bio-absorbable degree and most at last active delivery to people
The elegant formulations of internal appropriate targets.
The general introduction of disclosed theme
Provided herein is provide desired protection and stabilized new formulation to Fexofenadine fourth active component.Said preparation is also
The bioavailability of enhancing is provided.
Considered with reference to more than, preparing the holistic approach of fexofenadine hydrochloride fourth includes：In Perle (soft gel)
Isolate active component (AI), and especially AI is dissolved in suitable filled compositions matrix, the matrix includes alkylidene
Polymer compatibilizers in glycol and poly- (aklylene glycol) medium, and optional combination has surfactant.With pharmaceutically acceptable
Acidulant the pH of filled compositions is maintained into acid range, its reclaimed water accounts for small percentage by weight.
Increase soluble base and include two parts.Part A is that pharmaceutically acceptable aklylene glycol (such as propane diols), pharmacy can connect
Poly- (aklylene glycol) (such as polyethylene glycol (PEG)) received and pharmaceutically acceptable solubilized polymer (such as polyvinylpyrrolidone
(PVP)) hydrophilic mixture.Part B is that water, pharmaceutically acceptable acidulant (such as citric acid) and optional pharmacy can
The mixture of the surfactant (such as lauryl sodium sulfate (SLS)) of receiving.Optional surfactant can be ionic
Or nonionic (such as polysorbate).By A and part B combination to form increasing soluble base, and to the solubilising base
Fexofenadine hydrochloride fourth is added in matter to form filled compositions.
The Fexofenadine fourth filled compositions of the present invention can be encapsulated into the Perle of the present invention.
In some embodiments of filled compositions, Fexofenadine fourth AI is the form of Fexofenadine fourth free alkali.
In some embodiments, Fexofenadine fourth AI is Fexofenadine fourth salt.In one embodiment, Fexofenadine fourth salt is hydrochloric acid
Fexofenadine fourth.In some embodiments, Fexofenadine fourth free alkali or Fexofenadine fourth salt are unique active components.
In some embodiments, one or more other active components are added into the filling preparation containing Fexofenadine fourth.
One aspect of the present invention is related to the liquid softgel filled compositions of bioavailable, the gross weight based on composition,
Composition includes：A) 4-40% Fexofenadine fourth or Fexofenadine fourth salt by weight；B) matrix, it contains：Bi) with weight
Count 40-80% pharmaceutically acceptable poly- (aklylene glycol)；Bii) optionally, 0-30%'s by weight is pharmaceutically acceptable
Aklylene glycol；Biii) 0-10% by weight, preferably 1-10% pharmaceutically acceptable Polymer compatibilizers by weight；
And biv) optionally, 0-6% (such as 0.001-6%) pharmaceutically acceptable surfactant by weight；And c) with weight
Gauge 0.001-2% pharmaceutically acceptable acidulant.In one embodiment, by weight, pharmaceutically acceptable surface
Activating agent exists with 0 to about 0.5%.Embodiment of the present invention includes the composition with least one following characteristics：(a) with
Weight meter, Fexofenadine fourth or Fexofenadine fourth salt are with matrix with about 1:1.5 to about 1:24 ratio is present；Or (b) with weight
Gauge, Fexofenadine fourth or Fexofenadine fourth salt are with pharmaceutically acceptable polymer with about 40:1 to about 2:5 ratio is present；Or
By weight, Fexofenadine fourth or Fexofenadine fourth salt and pharmaceutically acceptable surfactant (if present) are with about by person (c)
40000:1 to about 2:3 ratio is present.One embodiment of composition has feature (a), (b) and the whole in (c).Group
The another embodiment of compound has feature (a) and (b).In one embodiment, Fexofenadine fourth salt is hydrochloric acid Fei Suofei
That fourth.In preferred embodiments, Fexofenadine fourth or Fexofenadine fourth salt are unique active components.Other realities of composition
Scheme is applied also comprising one or more other active components.In one embodiment, pharmaceutically acceptable poly- (alkylidene two
Alcohol) it is selected from PEG (PEG)；It is preferably selected from following PEG：PEG 200,300,400,600, their mixture,
And their mixtures with PEG 800,1000,2000,3000,4000,5000,6000,7000 or 8000.In an implementation
In scheme, pharmaceutically acceptable aklylene glycol is propane diols.It is pharmaceutically acceptable in an embodiment of filled compositions
Polymer compatibilizers be polyvinylpyrrolidone (PVP).In one embodiment, PVP be selected from PVP K12, PVP K17,
PVP K30, PVP K60 and PVP K90；Preferably, polyvinylpyrrolidone is PVP K17.In one embodiment, pharmacy
Acceptable surfactant is selected from lauryl sodium sulfate, polysorbate and PEG-8 caprylic/capric glyceride.At one
In embodiment, composition is free of surfactant.In another embodiment, composition includes by weight 0 to about 0.5%
Pharmaceutically acceptable surfactant.In one embodiment, acidulant is selected from pharmaceutically acceptable organic acid and two
The mixture of the pharmaceutically acceptable organic acid of kind or more kind.In preferred embodiments, acidulant is selected from：Lactic acid, malic acid,
Citric acid, fumaric acid, ascorbic acid, the mixture of tartaric acid and two or more in them.In particularly preferred implementation
In scheme, acidulant includes citric acid.
Another aspect of the present invention is related to the method for the liquid softgel filled compositions for preparing above bioavailable, and it is wrapped
Include following step：(a) poly- (aklylene glycol) is combined in rustless steel container with aklylene glycol, and the mixture is added
The temperature of heat to 65 ± 5 DEG C, wherein stirring first time period to obtain the first mixture；(b) into the first suspension with a small amount of sides
Formula is slowly added Polymer compatibilizers and stirred, and after addition powder is completed, continues stirring the at that same temperature
Two periods are to obtain the second mixture；(c) by by surfactant (if present) and acidulant and water individually not
Combined in rust steel container to prepare the 3rd mixture, and the mixture is heated to 65 ± 5 DEG C of temperature, wherein stirring the 3rd
Period；(d) by described second and the 3rd mixture combine at that same temperature, wherein the 4th period of mixing is to provide the
Four mixtures；(e) Fexofenadine fourth or Fexofenadine fourth salt are added in a manner of a small amount of into the 4th mixture, wherein in phase
Stirred at same temperature, and after addition powder is completed, continue to stir for the 5th period to obtain the 5th mixture；And
(f) the 5th mixture is cooled down and deaerated to environment temperature, there is provided the liquid softgel filled compositions.
Another aspect of the present invention is related to soft gel capsule, and it includes soft solidifying with the liquid of bioavailable disclosed above
The Perle of glue filled compositions filling.In one embodiment, the gelatin bag of soft gelatin (soft gel) capsule
Containing the mixture based on ox, birds, pig, marine organisms or the gelatin of plant or two or more in them.In a reality
Apply in scheme, soft gel capsule also includes enteric coating.Enteric coating preferably comprises controlled release polymer.In one embodiment, control
It is resistance to acid polymer to release polymer.
Another aspect of the present invention is related to the liquid softgel filled compositions of bioavailable, the gross weight based on composition
Amount, composition are substantially consisting of the following：A) 4-40% fexofenadine hydrochloride fourth by weight；B) matrix, it contains：Bi) with
Weight meter 40-80% PEG 400；Bii) optionally, 0-30% propane diols by weight；Biii) 0-10% by weight,
It is preferred that 1-10% polyvinylpyrrolidone by weight；And biv) optionally, 0.001-6% dodecyl sulphur by weight
Sour sodium；C) 0.001-2% citric acid by weight；And d) 1-10% water.In one embodiment, by weight,
Pharmaceutically acceptable surfactant exists with 0 to about 0.5%.In one embodiment, the gross weight based on composition, it is raw
The available liquid softgel filled compositions of thing are substantially consisting of the following：A) about 13.9% fexofenadine hydrochloride by weight
Fourth；B) matrix, it contains：Bi) about 64.2% PEG 400 by weight；Bii) about 15.2% propane diols by weight；
Biii) about 3.4% polyvinylpyrrolidone by weight；And biv) by weight about 0.3% lauryl sodium sulfate；c)
About 0.5% citric acid by weight；And d) about 2.5% water.
Another aspect of the present invention is related to the liquid softgel filled compositions of bioavailable, the gross weight based on composition
Amount, composition are consisting of the following：A) 4-40% Fexofenadine fourth or Fexofenadine fourth salt by weight；B) matrix, it is under
State composition：I) 40-80% pharmaceutically acceptable poly- (aklylene glycol) by weight；Ii) 0-30% pharmacy by weight
Acceptable aklylene glycol；And iii) 0-10%, preferably 1-10% pharmaceutically acceptable polymerization by weight by weight
Thing solubilizer；C) 0.001-2% pharmaceutically acceptable acidulant by weight；And d) 1-10% water.In an implementation
In scheme, the gross weight based on composition, the liquid softgel filled compositions of bioavailable are consisting of the following：A) with weight
The fexofenadine hydrochloride fourth of meter about 13.9%；B) matrix, its is consisting of the following：I) about 64.5% PEG 400 by weight；
Ii) about 15.2% propane diols by weight；And iii) by weight about 3.4% polyvinylpyrrolidone；C) by weight
About 0.5% citric acid；And d) about 2.5% water.
One embodiment of combination of the above thing is related to soft gel capsule, and it includes soft with the liquid of above bioavailable
The Perle of gel-filled composition filling.Preferably, polyvinylpyrrolidone is PVP K17.
Accompanying drawing briefly describes
Fig. 1 show the filler solution without lauryl sodium sulfate store at ambient temperature 4 months after figure
Piece.
The detailed description of preferred embodiment
Fexofenadine fourth free alkali has formula (I) structure：
The active component being generally used as pharmaceutically acceptable salt (such as hydrochloride) rather than free alkali in pharmaceutical composition.
One aspect of the present invention is related to the liquid softgel filled compositions of bioavailable, the gross weight based on composition,
Composition includes：A) by weight 4-40% (such as 5-35%, 5-20%, 10-30%, 15-25%, about 13%, about 14%,
About 15% or Fexofenadine fourth about 20%) or Fexofenadine fourth salt；B) matrix, it contains：Bi) 40-80% by weight
The pharmaceutically acceptable of (such as 45-75%, 50-70%, 55-65%, about 60%, about 64%, 64-65% or about 65%) is gathered
(aklylene glycol)；Bii) optionally, 0-30% (such as 5-30%, 5-25%, 10-25%, 15-16%, 15- by weight
20%th, up to about 14%, up to about 15% or pharmaceutically acceptable aklylene glycol up to about 16%)；Biii) optionally
Ground, by weight 0-10% (such as 1-10%, 1-9%, 2-8%, 3-7%, 4-6%, 3-4%, up to about 1%, up to about
2%th, up to about 3%, up to about 4%, up to about 5%, up to about 6%, up to about 7%, up to about 8%, up to about 9% or
Up to about 10%) pharmaceutically acceptable Polymer compatibilizers；And biv) optionally, 0-6% (such as 0.001- by weight
6%th, 0.001-0.8%, 0.001-0.9%, 0.01-2%, 0.1-1%, 0.2-0.5%, up to about 0.1%, up to about
0.2%th, up to about 0.3%, up to about 0.4%, up to about 0.5%, up to about 0.6%, up to about 0.7%, up to about 0.8%
Or pharmaceutically acceptable surfactant up to about 0.9%)；Alternatively, by weight, pharmaceutically acceptable surface-active
Agent exists with 0 to about 0.5%；And c) by weight 0.001-2% (such as 0.01-1%, 0.1-0.8%, 0.4-0.6%,
About 0.4%, about 0.5% or pharmaceutically acceptable acidulant about 0.6%).Embodiment of the present invention includes having at least
A kind of composition of following characteristics：(a) by weight, Fexofenadine fourth or Fexofenadine fourth salt and matrix are with about 1:1.5 to about
1:24 (e.g., from about 1:20th, about 1:15th, about 1:10th, about 1:6th, about 1:5.7th, about 1:5 or about 1:4) ratio is present；Or (b)
By weight, Fexofenadine fourth or Fexofenadine fourth salt and pharmaceutically acceptable polymer are with about 40:1 to about 2:5 (e.g., from about
30:1st, about 20:1st, about 10:1st, about 5:1st, about 4.1:1st, about 4:1 or about 3:1) ratio is present；It is non-or (c) is by weight
Suo Feinading or Fexofenadine fourth salt and pharmaceutically acceptable surfactant (if present) are with about 40000:1 to about 2:3 (examples
Such as from about 10000:1st, about 5000:1st, about 2500:1st, about 1000:1st, about 500:1st, about 100:1st, about 50:1st, about 46:1st, about 40:1、
About 30:1st, about 20:1 or about 10:1) ratio is present.One embodiment of composition has feature (a), (b) and (c)
All.In one embodiment, composition has the whole of feature (a), (b) and (c), and by weight, surface-active
Agent exists with 0 to about 0.5%.Other embodiments of composition are free of surfactant, and therefore only have feature (a) and
(b).In one embodiment, Fexofenadine fourth salt is fexofenadine hydrochloride fourth.In preferred embodiments, Fexofenadine fourth
Or Fexofenadine fourth salt is unique active component.Other embodiments of composition also comprising one or more other activity into
Point.In one embodiment, pharmaceutically acceptable poly- (aklylene glycol) is selected from PEG (PEG)；Preferably, PEG
Selected from PEG 200,300,400,600, their mixture, and they are with PEG 800,1000,2000,3000,4000,
5000th, 6000,7000 or 8000 mixture.In one embodiment, pharmaceutically acceptable aklylene glycol is propane diols.
In an embodiment of filled compositions, pharmaceutically acceptable Polymer compatibilizers are polyvinylpyrrolidone (PVP).
In one embodiment, PVP is selected from PVP K12, PVP K17, PVP K30, PVP K60 and PVP K90, covers about 2000 to about
1500000 molecular weight ranges；Preferably, polyvinylpyrrolidone is PVP K17.In one embodiment, pharmacy can connect
The surfactant received be selected from lauryl sodium sulfate, polysorbate (such as20th, 40,60,80 etc.) and
PEG-8 caprylic/caprics glyceride (such as, also referred to as caprylic capric PEG-8 glyceride).
In one embodiment, acidulant is selected from pharmaceutically acceptable organic acid and two or more pharmaceutically acceptable organic acids
Mixture.In preferred embodiments, acidulant is selected from lactic acid, malic acid, citric acid, fumaric acid, ascorbic acid, tartaric acid
And the mixture of two or more in them.In particularly preferred embodiments, acidulant includes citric acid.
Another aspect of the present invention is related to the method for the liquid softgel filled compositions for preparing above bioavailable, and it is wrapped
Include following step：(a) poly- (aklylene glycol) is combined in rustless steel container with aklylene glycol, and the mixture is added
Heat to 65 ± 5 DEG C of temperature, wherein stirring (preferably with high shear mixing) first time period (preferably 25-35 minutes, or until
Homogenize) to obtain the first mixture；(b) Polymer compatibilizers are slowly added in a manner of a small amount of into the first suspension and stirred,
And after addition powder is completed, continue to stir second time period (preferably 25-35 minutes) at that same temperature to obtain
Second mixture；(c) by the way that optional surfactant and acidulant are combined to make in single rustless steel container with water
Standby 3rd mixture, and the mixture is heated to 65 ± 5 DEG C of temperature, wherein (preferably 12-18 points of the 3rd period of stirring
Clock, or until homogenize)；(d) by described second and the 3rd mixture combine at that same temperature, wherein mixing the 4th when
Between section (preferably 13-17 minutes) to provide the 4th mixture；(e) Fei Suofei is added in a manner of a small amount of into the 4th mixture
That fourth or Fexofenadine fourth salt simultaneously stir at that same temperature, and after addition powder is completed, continue to stir for the 5th time
Section (preferably 40-50 minutes) is to obtain the 5th mixture；And the 5th mixture is cooled down and deaerated to environment temperature by (f)
Degree, there is provided the liquid softgel filled compositions.
Another aspect of the present invention is related to soft gel capsule, and it includes the liquid softgel with bioavailable disclosed above
The Perle of filled compositions filling.In one embodiment, the gelatin of soft gelatin (soft gel) capsule includes
Mixture based on ox, birds, pig, marine organisms or the gelatin of plant or two or more in them.In an implementation
In scheme, soft gel capsule also includes enteric coating.Enteric coating preferably comprises controlled release polymer.In one embodiment, controlled release
Polymer is resistance to acid polymer.
Another aspect of the present invention is related to the liquid softgel filled compositions of bioavailable, the gross weight based on composition
Amount, composition are substantially consisting of the following：A) 4-40% (such as 5-35%, 5-20%, 10-30%, 15-25%, about by weight
13%th, about 14%, about 15% or fexofenadine hydrochloride fourth about 20%)；B) matrix, it contains：Bi) 40- by weight
The PEG 400 of 80% (such as 45-75%, 50-70%, 55-65%, about 60%, about 64%, 64-65% or about 65%)；
Bii) optionally, 0-30% (such as 5-30%, 5-25%, 10-25%, 15-16%, 15-20%, up to about by weight
14%th, up to about 15% or propane diols up to about 16%)；Biii) optionally, by weight 0-10% (such as 1-10%,
1-9%, 2-8%, 3-7%, 4-6%, 3-4%, up to about 3%, up to about 4% or polyvinylpyrrolidine up to about 5%)
Ketone；And biv) optionally, 0-6% (such as 0.001-6%, 0-0.5%, 0.01-2%, 0.1-1%, 0.2- by weight
0.5%th, up to about 0.2%, up to about 0.3% or lauryl sodium sulfate up to about 0.4%)；C) by weight
0.001-2% (such as 0.01-1%, 0.1-0.8%, 0.4-0.6%, about 0.4%, about 0.5% or about 0.6%) lemon
Acid；And d) 1-10% (such as 1-8%, 2-5%, 2-3%, about 2%, about 2.5% or about 3%) water.In optional implementation
In scheme, composition contains 0 to about 0.5wt% surfactant.In an embodiment of filled compositions, surface is lived
Property agent concentration is 0%, there is provided the composition without surfactant.
One embodiment is related to the liquid softgel filled compositions of bioavailable, the gross weight based on composition,
Composition is substantially consisting of the following：A) about 13.9% fexofenadine hydrochloride fourth by weight；B) matrix, it contains：Bi) with weight
The PEG 400 of gauge about 64.2%；Bii) about 15.2% propane diols by weight；Biii) about 3.4% poly- second by weight
Alkene pyrrolidone；And biv) by weight about 0.3% lauryl sodium sulfate；C) about 0.5% citric acid by weight；With
And d) about 2.5% water.
Another aspect of the present invention is related to the liquid softgel filled compositions of bioavailable, the gross weight based on composition
Amount, composition are consisting of the following：A) 4-40% Fexofenadine fourth or Fexofenadine fourth salt by weight；B) matrix, it is under
State composition：I) 40-80% pharmaceutically acceptable poly- (aklylene glycol) by weight；Ii) 0-30% pharmacy by weight
Acceptable aklylene glycol；And iii) 0-10%, preferably 1-10% pharmaceutically acceptable polymerization by weight by weight
Thing solubilizer；C) 0.001-2% pharmaceutically acceptable acidulant by weight；And d) 1-10% water.In an implementation
In scheme, the gross weight based on composition, the liquid softgel filled compositions of bioavailable are consisting of the following：A) with weight
The fexofenadine hydrochloride fourth of meter about 13.9%；B) matrix, its is consisting of the following：I) about 64.5% PEG 400 by weight；
Ii) about 15.2% propane diols by weight；And iii) by weight about 3.4% polyvinylpyrrolidone；C) by weight
About 0.5% citric acid；And d) about 2.5% water.
One embodiment of combination of the above thing is related to soft gel capsule, and it includes soft with the liquid of above bioavailable
The Perle of gel-filled composition filling.Preferably, polyvinylpyrrolidone is PVP K17.
It can utilize conventional revolving die method that liquid softgel filling preparation is encapsulated into soft gelatin shell to form soft gel
Capsule.Suitable soft gelatin shell can include：(i) 35-60% gelatin by weight；(ii) 10-15%'s by weight is sweet
Oil；(iii) 11-20% sorbierite by weight；(iv) 20-40% pure water by weight；And (v) is by weight
0.0001-0.002% artificial color.
The soft gel capsule of the present invention can also be prepared by other methods well-known in the art.See, e.g.
P.K.Wilkinson et al., " Softgels:Manufacturing Considerations,”Drugs and the
Pharmaceutical Sciences,41(Specialized Drug Delivery Systems)；P.Tyle,Ed.
(Marcel Dekker,Inc.,New York,1990)409-449；F.S.Hom et al., " Capsules, Soft "
Encyclopedia of Pharmaceutical Technology,vol.2；J.Swarbrick and J.C.Boylan,
eds.(Marcel Dekker,Inc.,New York,1990)pp.269-284；M.S.Patel et al., " Advances in
Softgel Formulation Technology,”Manufacturing Chemist,vol.60,no.7,pp.26-28
(in July, 1989)；M.S.Patel et al., " Softgel Technology, " Manufacturing Chemist, vol.60,
No.8, pp.47-49 (in August, 1989)；R.F.Emerson,“Softgel(Soft Gelatin Capsule)Update,”
Drug Development and Industrial Pharmacy(Interphex '86 Conference),vol.12,
no.8&9,pp.1133-1144(1986)；And W.R.Ebert, " Soft Elastic Gelatin Capsules:A
Unique Dosage Form,”Pharmaceutical Technology,vol.1,no.5,pp.44-50(1977)。
In being disclosed herein, there is provided multiple number ranges.It should be appreciated that this also specifically discloses the upper limit of the scope
Each intermediate value between lower limit, intermediate value reach 1/10th of lower limit unit, unless context clearly refers in addition
It is bright.The present invention covers any defined numerical value or the intermediate value in prescribed limit and any other stated number in prescribed limit
Each smaller range between value or intermediate value.These small range of upper and lower bounds independently can be contained in or arrange
Except in the scope, and the present invention is also covered by wherein including one in bound or not comprising bound or bag
Small range of each scope containing both bounds, while meet the requirement of any end value clearly excluded in prescribed limit.
Defined scope include bound in one or two in the case of, present invention additionally comprises by comprising bound in one
Individual or two excluded scopes.Term " about " be often referred to plus or minus shown numerical value 10%.For example, " about 10% " can
With the scope of instruction 9% to 11%, and " about 20 " can represent 18-22." about " based on context other implications will be aobvious
And be clear to, such as round up, such as " about 1 " can also mean 0.5 to 1.4.
Embodiment
Embodiment 1. contains the filled compositions of the bioavailable of the fexofenadine hydrochloride fourth as active component
All the components are mixed according to the flow of embodiment 2.
The method that embodiment 2. prepares the filled compositions of embodiment 1 and 3
A) in suitable rustless steel container, to PEG 400, PEG 600, either other liquid PEG or liquid PEG are mixed
Propane diols is added in compound.Solution is heated to 65 DEG C ± 5 DEG C.Using stainless steel propellor/high-shear mixer by it is all into
Divide mixing 30 ± 5 minutes or until homogenize.
B) be slowly added into solution a) in a manner of a small amount of PVP K17 (or PVP K12 or PVP K30 or PVP K60,
Or PVP K90 or mixture), while persistently mixed at 65 DEG C ± 5 DEG C.Other 30 are sufficiently mixed after addition powder is completed
± 5 minutes.
C) water, lauryl sodium sulfate and citric acid are added in other suitable rustless steel container.At 65 DEG C ± 5
Mix 15 ± 3 minutes or until homogenize at DEG C.
D) the addition solution c) into solution b).Continue to mix other 15 ± 2 minutes at 65 DEG C ± 5 DEG C.
E) fexofenadine hydrochloride fourth is added in a manner of a small amount of into solution d), while continues to mix under 65 DEG C ± 5 °.
After adding powder completion, mix other 45 ± 5 minutes.
F) solution is cooled to room temperature and deaerated.
Above suspension is encapsulated into Perle (soft gel).Optionally, then in a manner of usual to soft gel
Capsule provides the enteric coating by being formed as the hydroxypropyl methyl cellulose stearic acid and castor oil of plasticiser.
Embodiment 3. contains the filled compositions of the bioavailable of the fexofenadine hydrochloride fourth as active component
All the components are mixed according to the flow of embodiment 2.
Then, the soft gel capsule sample prepared in above-described manner is subjected to Detection of Stability.More specifically,
By sample capsules under 75%, 65% or 60% relative humidity (RH), it is incubated at 40 DEG C, 30 DEG C or 25 DEG C 1 month, 2
The moon, 3 months or 9 months.It was found that within the period, sample capsules keep transparent, and filled compositions remain on and are
Bright and tasteless solution.
At the beginning and end of each period, the stability of high performance liquid chromatography (HPLC) determination sample capsule is utilized.Will
Active component in each sample capsule is measured as sample capsules being dissolved in 0.01N HCl after 45 minutes, is opened relative to test
The percentage of the active component during beginning.It was found that at the end of the period, at least 97% active component is still complete
, and related to active component or from active component compound (produces during the impurity and processing in such as raw material
Catabolite) be less than 0.36%.
Result above indicates, after long period, said preparation is dissolved in soft gel capsule and stable Fexofenadine fourth
Aspect is excellent.
Embodiment 4. contains the bioavailable without surfactant of the fexofenadine hydrochloride fourth as active component
Filled compositions
The method that embodiment 5. prepares the filled compositions without surfactant of embodiment 4
A) in suitable rustless steel container, to PEG 400, PEG 600, either other liquid PEG or liquid PEG are mixed
Propane diols is added in compound.Solution is heated to 65 DEG C ± 5 DEG C.Using stainless steel propellor/high-shear mixer by it is all into
Divide mixing 30 ± 5 minutes or until homogenize.
B) be slowly added into solution a) in a manner of a small amount of PVP K17 (or PVP K12 or PVP K30 or PVP K60,
Or PVP K90 or mixture), while persistently mixed at 65 DEG C ± 5 DEG C.Other 30 are sufficiently mixed after addition powder is completed
± 5 minutes.
C) water and citric acid are added in other suitable rustless steel container.15 ± 3 points are mixed at 65 DEG C ± 5 DEG C
Clock until homogenizes.
D) the addition solution c) into solution b).Continue to mix other 15 ± 2 minutes at 65 DEG C ± 5 DEG C.
E) fexofenadine hydrochloride fourth is added in a manner of a small amount of into solution d), while continues to mix under 65 DEG C ± 5 °.
After adding powder completion, mix other 45 ± 5 minutes.
F) solution is cooled to room temperature and deaerated.
The stability test of embodiment 6.
By filled compositions sample 40 DEG C and 75% relative humidity (RH) under be incubated period for specifying.Using efficient
The stability of liquid chromatogram (HPLC) determination sample.Standard items and sample solution are prepared, and are stored in room temperature lucifuge, and are being made
By its sample introduction to HPLC in standby 72 hours.Stability result is presented in the following table：
1Related compound is compound related to active component or from active component, such as the impurity in raw material
With caused catabolite during processing.
The bioavilability of embodiment 7. is tested
In this embodiment, it is soft solidifying containing 180mg fexofenadine hydrochloride fourths to what is prepared in above-described manner
The absorption rate of Fexofenadine fourth and degree are detected in glue capsule, and with reference product (i.e.Allergy
(fexofenadine hydrochloride fourth) 180mg tablets) it is compared.On the feed with speed and degree are determined under the conditions of both on an empty stomach.
In short, the research is made up of two stages of 3 days by a definite date, the removing phase of at least 14 days is separated by between processing.
The 0th hour the 1st day during each research, 14 normal, each in health, the masculinity and femininity individual do not smoked receives 1
The Fexofenadine fourth tablet or capsule of unit.21 PK blood samples were gathered altogether during 36 hours to be used to analyze Fexofenadine
Fourth.
It was found that compared with the individual for taking tablet, taken non-in the individual of soft gel capsule with the conditions of empty stomach on the feed
Suo Feinading mean plasma concentration quickly reaches peak value.In addition, compared with the individual for taking tablet, soft gel glue is taken
Mean peak plasma in the individual of capsule is considerably higher.As a result indicate, it is disclosed herein soft solidifying containing Fexofenadine fourth
Glue capsule provides the bioavilability improved.
Particular embodiments disclosed above be only interpreted as it is illustrative, and not in any way to other disclosures
Cause to limit.In the case where not being further elaborated on, it is believed that those skilled in the art are based on description herein energy maximum journey
Degree ground utilizes the present invention.
Other embodiments
All features disclosed in this specification can be combined in any combination.Disclosed in this specification
Each feature being serviced substituted in the optional feature of identical, equivalent or similar purpose.Therefore, unless expressly stated otherwise, institute is public
Each feature opened only is a series of equivalent or similar characteristics examples.
As described above, those skilled in the art can readily determine that the substantive property of the present invention, and not take off
In the case of the spirit and scope of the present invention, it can make various changes to the present invention and improve different to adapt it to
Purposes and situation.Therefore, other embodiments are also in the scope of protection of present invention.
Herein cited all publications are integrally incorporated by quoting herein.
Claims (26)
1. the liquid softgel filled compositions of bioavailable, based on the gross weight of the composition, the composition includes：
A) 4-40% Fexofenadine fourth or Fexofenadine fourth salt by weight；
B) matrix, it is included：
I) 40-80% pharmaceutically acceptable poly- (aklylene glycol) by weight；
Ii) optionally, 0-30% pharmaceutically acceptable aklylene glycol by weight；
Iii) optionally, 0-10% pharmaceutically acceptable Polymer compatibilizers by weight；With
Iv) optionally, 0-6% pharmaceutically acceptable surfactant by weight；And
C) 0.001-2% pharmaceutically acceptable acidulant by weight.
2. composition as claimed in claim 1, it has at least one following characteristics：
(a) by weight, the Fexofenadine fourth or Fexofenadine fourth salt and the matrix are with about 1:1.5 to about 1:24 ratio
In the presence of；Or
(b) by weight, the Fexofenadine fourth or Fexofenadine fourth salt and the pharmaceutically acceptable polymer are with about 40:1
To about 2:5 ratio is present；Or
(c) by weight, the Fexofenadine fourth or Fexofenadine fourth salt and the pharmaceutically acceptable surfactant are with about
40000:1 to about 2:3 ratio is present.
3. composition as claimed in claim 2, it has the feature (a), (b) and two or more in (c).
4. composition as claimed in claim 1, wherein the Fexofenadine fourth salt is fexofenadine hydrochloride fourth.
5. composition as claimed in claim 1, wherein the Fexofenadine fourth or Fexofenadine fourth salt be unique activity into
Point.
6. composition as claimed in claim 1, it is also comprising one or more other active components.
7. composition as claimed in claim 1, wherein pharmaceutically acceptable poly- (aklylene glycol) be selected from PEG 200 to
PEG 8000 and its mixture.
8. composition as claimed in claim 1, wherein the pharmaceutically acceptable aklylene glycol is propane diols.
9. composition as claimed in claim 1, wherein the pharmaceutically acceptable Polymer compatibilizers are polyvinylpyrrolidines
Ketone (PVP).
10. composition as claimed in claim 9, wherein the polyvinylpyrrolidone is selected from PVP K12, PVP K17, PVP
K30, PVP K60 and PVP K90.
11. composition as claimed in claim 10, wherein the polyvinylpyrrolidone is PVP K17.
12. composition as claimed in claim 1, wherein the acidulant be selected from pharmaceutically acceptable organic acid and two kinds or
The mixture of more kinds of pharmaceutically acceptable organic acids.
13. composition as claimed in claim 12, wherein the acidulant be selected from lactic acid, malic acid, citric acid, fumaric acid,
The mixture of ascorbic acid, tartaric acid and two or more in them.
14. composition as claimed in claim 12, wherein the acidulant includes citric acid.
15. preparing the method for the liquid softgel filled compositions of the bioavailable described in claim 1, it includes：
(a) poly- (aklylene glycol) is combined with the aklylene glycol in rustless steel container, and by the mixture
65 ± 5 DEG C of temperature is heated to, wherein stirring first time period to obtain the first mixture；
(b) Polymer compatibilizers are slowly added in a manner of a small amount of into first suspension, wherein in identical temperature
It is lower to stir second time period to obtain the second mixture；
(c) by by the surfactant or acidulant or both combined with water to make in single rustless steel container
Standby 3rd mixture, and the mixture is heated to 65 ± 5 DEG C of temperature, wherein the 3rd period of stirring；
(d) by described second and the 3rd mixture combine at that same temperature, wherein the 4th period of mixing is to provide the 4th
Mixture；
(e) the Fexofenadine fourth or Fexofenadine fourth salt are added in a manner of a small amount of into the 4th mixture, wherein in phase
Stirred for the 5th period at same temperature to obtain the 5th mixture；And
(f) the 5th mixture is cooled down and deaerated to environment temperature, there is provided the liquid softgel filled compositions.
16. soft gel capsule, it is included is filled with the liquid softgel filled compositions of the bioavailable described in claim 1
Perle.
17. soft gel capsule as claimed in claim 16, wherein the gelatin of the Perle include based on ox, birds,
Pig, the marine organisms either gelatin of plant or the mixture of two or more in them.
18. soft gel capsule as claimed in claim 16, it also includes enteric coating.
19. soft gel capsule as claimed in claim 18, wherein the enteric coating includes controlled release polymer.
20. soft gel capsule as claimed in claim 19, wherein the controlled release polymer is resistance to acid polymer.
21. the liquid softgel filled compositions of bioavailable, based on the gross weight of the composition, the composition is basic
It is consisting of the following：
A) 4-40% Fexofenadine fourth or fexofenadine hydrochloride fourth by weight；
B) matrix, it is included
I) 40-80% PEG 400 by weight；
Ii) optionally, 0-30% propane diols by weight；
Iii) optionally, 0-10% polyvinylpyrrolidone by weight；With
Iv) optionally, 0-6% lauryl sodium sulfate by weight；
C) 0.001-2% citric acid by weight；And
D) 1-10% water.
22. the liquid softgel filled compositions of bioavailable, based on the gross weight of the composition, the composition is under
State composition：
A) about 13.9% fexofenadine hydrochloride fourth by weight；
B) matrix, it is included：
I) about 64.5% PEG 400 by weight；
Ii) about 15.2% propane diols by weight；With
Iii) about 3.4% polyvinylpyrrolidone by weight；
C) about 0.5% citric acid by weight；And
D) about 2.5% water.
23. soft gel capsule, it includes and filled out with the liquid softgel filled compositions of the bioavailable described in claim 22
The Perle filled.
24. filled compositions as claimed in claim 22, wherein the polyvinylpyrrolidone is PVP K17.
25. the liquid softgel filled compositions of bioavailable, based on the gross weight of the composition, the composition is under
State composition：
A) 4-40% Fexofenadine fourth or Fexofenadine fourth salt by weight；
B) matrix, its is consisting of the following：
I) 40-80% pharmaceutically acceptable poly- (aklylene glycol) by weight；
Ii) 0-30% pharmaceutically acceptable aklylene glycol by weight；With
Iii) 0-10% pharmaceutically acceptable Polymer compatibilizers by weight；
C) 0.001-2% pharmaceutically acceptable acidulant by weight；And
D) 1-10% water.
26. such as the filled compositions any one of claim 1,21 or 25, wherein by weight, it is described pharmaceutically acceptable
Polymer compatibilizers exist with 1-10%.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US14/627,589 US20160243044A1 (en) | 2015-02-20 | 2015-02-20 | Soft gelatin capsules containing fexofenadine |
| US14/627,589 | 2015-02-20 | ||
| US201562255615P | 2015-11-16 | 2015-11-16 | |
| US62/255,615 | 2015-11-16 | ||
| PCT/US2016/018574 WO2016134200A1 (en) | 2015-02-20 | 2016-02-19 | Soft gelatin capsules containing fexofenadine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107847496A true CN107847496A (en) | 2018-03-27 |
Family
ID=56692326
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201680011220.1A Pending CN107847496A (en) | 2015-02-20 | 2016-02-19 | Perle containing Fexofenadine fourth |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP3258934A4 (en) |
| CN (1) | CN107847496A (en) |
| HK (1) | HK1253053A1 (en) |
| WO (1) | WO2016134200A1 (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995023595A1 (en) * | 1994-03-02 | 1995-09-08 | The Procter & Gamble Company | Concentrated acetaminophen solution compositions |
| US20050266032A1 (en) * | 2003-12-17 | 2005-12-01 | Sovereign Pharmaceuticals, Ltd. | Dosage form containing multiple drugs |
| CN103313704A (en) * | 2011-01-14 | 2013-09-18 | 英仕柏集团有限责任公司 | Highly concentrated liquid acetaminophen solutions |
| CN103687592A (en) * | 2011-05-20 | 2014-03-26 | 安万特药物公司 | Pharmaceutical composition comprising fexofenadine |
| US20140357586A1 (en) * | 1999-11-23 | 2014-12-04 | Lipocine Inc. | Solid Carriers for Improved Delivery of Active Ingredients in Pharmaceutical Compositions |
| WO2015003109A1 (en) * | 2013-07-03 | 2015-01-08 | R.P. Scherer Technologies, Llc | Capsule formulation comprising fexofenadine |
| US20150108033A1 (en) * | 2013-10-21 | 2015-04-23 | Banner Life Sciences, LLC | Pharmaceutical compositions for poorly soluble active ingredients |
-
2016
- 2016-02-19 WO PCT/US2016/018574 patent/WO2016134200A1/en active Application Filing
- 2016-02-19 EP EP16753099.7A patent/EP3258934A4/en not_active Withdrawn
- 2016-02-19 CN CN201680011220.1A patent/CN107847496A/en active Pending
-
2018
- 2018-09-27 HK HK18112433.0A patent/HK1253053A1/en unknown
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995023595A1 (en) * | 1994-03-02 | 1995-09-08 | The Procter & Gamble Company | Concentrated acetaminophen solution compositions |
| US20140357586A1 (en) * | 1999-11-23 | 2014-12-04 | Lipocine Inc. | Solid Carriers for Improved Delivery of Active Ingredients in Pharmaceutical Compositions |
| US20050266032A1 (en) * | 2003-12-17 | 2005-12-01 | Sovereign Pharmaceuticals, Ltd. | Dosage form containing multiple drugs |
| CN103313704A (en) * | 2011-01-14 | 2013-09-18 | 英仕柏集团有限责任公司 | Highly concentrated liquid acetaminophen solutions |
| CN103687592A (en) * | 2011-05-20 | 2014-03-26 | 安万特药物公司 | Pharmaceutical composition comprising fexofenadine |
| WO2015003109A1 (en) * | 2013-07-03 | 2015-01-08 | R.P. Scherer Technologies, Llc | Capsule formulation comprising fexofenadine |
| US20150108033A1 (en) * | 2013-10-21 | 2015-04-23 | Banner Life Sciences, LLC | Pharmaceutical compositions for poorly soluble active ingredients |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3258934A1 (en) | 2017-12-27 |
| HK1253053A1 (en) | 2019-06-06 |
| EP3258934A4 (en) | 2018-09-05 |
| WO2016134200A1 (en) | 2016-08-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AP566A (en) | Oral dosage forms of azithromycin avoiding drug food interaction. | |
| TWI285118B (en) | Timed dual release dosage forms comprising a short acting hypnotic or a salt thereof | |
| US10617660B2 (en) | Compositions containing benzoate compound and tannic acid for treating central nervous system disorders | |
| US10342797B2 (en) | Solubility of therapeutic agents | |
| US20160287679A1 (en) | Pharmaceutical preparation | |
| TW200918078A (en) | Pharmaceutical composition comprising a pyrazole-O-glucoside derivative | |
| US20220323429A1 (en) | Pimavanserin for treating neurodegenerative diseases | |
| CN104812378B (en) | Solid dosage forms | |
| AU2016398029B2 (en) | Palatable compositions including sodium phenylbutyrate and uses thereof | |
| EP2651414A1 (en) | Combination therapy comprising vemurafenib and an interferon for use in the treatment of cancer | |
| CN104394691A (en) | Compositions and methods for treatment of irritable bowel syndrome with 5-aminosalicylate | |
| CN102481287A (en) | Pharmaceutical composition of temozolomide comprising vitamin c or vitamin c derivative and preparation method thereof | |
| HU229569B1 (en) | Multiparticulate controlled release selective serotonin reuptake inhibitor formulations | |
| CN109922801A (en) | The suspension and diluent of metronidazole and Baclofen | |
| CN107847496A (en) | Perle containing Fexofenadine fourth | |
| GB2614741A (en) | A liquid pharmaceutical formulation of clonidine hydrochloride | |
| ES2618930T5 (en) | Composition comprising diamine oxidase for the prevention of hangover symptoms | |
| WO2021127722A1 (en) | Pharmaceutical compositions | |
| JP2021536446A (en) | Compounds and methods for treating fungal infections | |
| US20180042857A1 (en) | Soft gelatin capsules containing fexofenadine | |
| CN107595799A (en) | A kind of compound enteric-coated oral disintegrating tablet and preparation method thereof | |
| JP6732351B1 (en) | Isoquercitrin composition | |
| EP4316471A1 (en) | Oral nanoparticles for bioactive compound, and method of preparing same | |
| CN106474095A (en) | A kind of for treating oral mucosa alite paste of oral mykoses and preparation method thereof | |
| US20050175686A1 (en) | Drug delivery system using a solubilized gelatin shell composition and unit dose drug delivery using a special shape soft gelatin capsule |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1253053 Country of ref document: HK |
|
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180327 |