CN105848643A - Racecadotril compositions - Google Patents

Racecadotril compositions Download PDF

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Publication number
CN105848643A
CN105848643A CN201480070543.9A CN201480070543A CN105848643A CN 105848643 A CN105848643 A CN 105848643A CN 201480070543 A CN201480070543 A CN 201480070543A CN 105848643 A CN105848643 A CN 105848643A
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weight
compositions
racecadotril
dosage form
surfactant
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D-Y·李
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Johnson and Johnson Consumer Inc
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Johnson and Johnson Consumer Companies LLC
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Priority claimed from US14/138,309 external-priority patent/US9801819B2/en
Application filed by Johnson and Johnson Consumer Companies LLC filed Critical Johnson and Johnson Consumer Companies LLC
Publication of CN105848643A publication Critical patent/CN105848643A/en
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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

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  • Chemical & Material Sciences (AREA)
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  • Dispersion Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

A lipid composition comprising racecadotril, at least one surfactant and a lipid.

Description

Racecadotril compositions
Technical field
The present invention relates to microemulsion composition based on lipoid.More particularly it relates to comprise medicine The microemulsion composition based on lipoid of thing active component and the method preparing described compositions.
Background technology
Diarrhoea is a kind of intestinal tract disease, it is characterised in that the frequency of water sample stool increases.Diarrhoea may be by Many reasons causes, the diarrhoea caused including antibacterial or virus.The food intolerance caused by anaphylaxis Or edible food such as fat or maror may cause diarrhoea.Alimentary toxicosis is likely to cause abdomen Rush down.In some cases, diarrhoea is probably the symptom of other diseases and disease.
Diarrhoea is intestinal or the symptom of other body function diseases.Multiple prescription can be taken and OTC (over-the-counter) is produced Product carry out relieving the pain caused by diseases.But, the many products in these products have secondary work while relieving the pain caused by diseases With.
Racecadotril is also used for treatment diarrhoea.Which reduce (i) water and electrolyte is too much secreted into enteric cavity In, the symptom that the incidence rate of (ii) acute diarrhea is relevant with persistent period and (iii) diarrhoea.
It addition, racecadotril is a kind of to show poor dissolubility and poor oral bioavailability rate Active constituents of medicine.At present, racecadotril has solid oral dosage forms.
Summary of the invention
The present invention relates to comprise the microemulsion group of racecadotril, at least one surfactant and lipoid Compound.
In one embodiment, the microemulsion composition of the present invention comprises about 0.01 weight % to about The racecadotril of 24.0 weight %, a total of about 1 weight % to about 95 weight % surfactant with And about 0.01 weight % to the lipoid of about 60 weight %, wherein each weight % is based on the group of 100mL Compound meter.
Present invention additionally comprises a kind of method for person under inspection diarrhoea occur is treated, including being subject to Inspection person is administered orally the step of the compositions comprising racecadotril, at least one surfactant and lipoid.
Detailed description of the invention
As used herein, " microemulsion " refers to the liquid of lipoid, water and at least one surfactant Mixture.Microemulsion is characterised by its clarification, Thermodynamically stable and isotropic outward appearance.
As used herein, " stablizing " refers to that compositions to naked eyes clarification and is substantially free of racemization card Many bent chemical degradations, the change of basic color, turbidity or oiliness globule.At 40 DEG C at least about 3 In individual month, aqueous components and/or non-aqueous composition do not have separated.It is highly preferred that at 40 DEG C Under at least about 6 months, aqueous components and/or non-aqueous composition do not have separated.At one In embodiment, when storing three months at 40 DEG C, gross weight % based on racecadotril is counted, and disappears Total chemical degradation products of rotation cadotril should be less than 0.5 weight %, such as less than 0.2 weight %.Separately In one embodiment, after storing six months at 40 DEG C, gross weight % based on racecadotril Meter, total chemical degradation products of racecadotril should be less than 0.5 weight %, such as less than 0.2 weight Amount %.By calculating the catabolite peak area in HPLC chromatogram relative to racecadotril peak The peak area % of peak area determines the percentage ratio of catabolite.In one embodiment, at 40 DEG C During lower preservation 3 months, total % based on racecadotril counts, total chemical degradation products of racecadotril Should be less than the 0.5% of racecadotril, such as less than disappearing 0.2%.
As used herein, " self-emulsifying microemulsion drug delivery system " (SMEDDS) is oil, surface activity The mixture of agent and sometimes cosolvent.SMEDDS can be used for preparation system, to improve highly lipophilicization The oral absorption of compound.When being incorporated in aqueous phase, SMEDDS spontaneously uses gentle agitation emulsifying To produce tiny O/w emulsion.Medicine in SMEDDS occurs with small drop sizes and shows Go out the dissolubility and permeability increased.SMEDDS can be prepared make for liquid form or solid form With.When using in solid form, solid is encapsulated in capsule or tablet.Sense due to speed Know, the visual appearance of pharmaceutical composition and be easy to swallow, that liquid is filled or the semi-solid capsule filled Agent is the preferred dosage form of some consumer.
The present invention is the microemulsion combination comprising racecadotril, at least one surfactant and lipoid Thing.
Various researchs have shown that racecadotril can effectively reduce the symptom of diarrhoea.Racecadotril is excellent It has an advantage that racecadotril is proved to have less side effect in of other drug, such as control Constipation after treatment.
Racecadotril has a dissolubility in relatively low water, and the most about 10 micrograms/in the least Rise.In the present compositions, during racecadotril may be dissolved in microemulsion.
Racecadotril with emulsion compositions about 0.01 weight % of every 100ml to about 24.0 weight % Amount is comprised in microemulsion composition.Preferably, racecadotril is the Emulsion combination of every 100ml Thing about 0.01 weight % is to about 18.0 weight %, and the most about 0.01 weight % is to about 12.0 weights Amount %, and emulsion compositions about 0.01 weight % of even more preferably still every 100ml is to about 10.0 weights Amount %.In one embodiment, racecadotril is emulsion compositions about 4.0 weight of every 100ml Amount % to about 24.0 weight %.In another embodiment, racecadotril is the breast of every 100ml Liquid compositions about 4.0 weight % is to about 18.0 weight %.In still another embodiment, racecadotril For emulsion compositions about 4.0 weight % of every 100ml to about 12.0 weight %.In further embodiment In, racecadotril is that emulsion compositions about 4.0 weight % of every 100ml is to about 10.0 weight %.
The microemulsion composition of the present invention comprises at least one surfactant.Surfactant can as a example by Such as nonionic surfactant, cationic surfactant, anion surfactant or theirs is mixed Compound.
Suitably surfactant includes such as having hydrophilic lipophile balance (HLB) value less than 12 Water-insoluble surfactant and the water dissolvable surfactant with the HLB value more than 12.Tool High HLB and hydrophilic surfactant is had to contribute to the formation of oil-water drop.Surfactant essence Upper for amphipathic and can dissolve or the hydrophobic pharmaceutical compounds of solubilising high relative contents.
Non-limiting example includes: Tween, dimethyl acetylamide (DMA), dimethyl sulfoxide (DMSO), ethanol, glycerol, METHYLPYRROLIDONE (NMP), PEG 300, PEG 400, Poloxamer188, propylene glycol, phospholipid, HSPC (HSPC), distearyl phosphorus Phosphatidyl glycerol ester (DSPG), L-α-dimyristoyl phosphatidyl choline (DMPC), L-α-two myristoyl Phosphatidyl glycerol ester (DMPG), Polyethylene Glycol 35 Oleum Ricini (CREMOPHOR EL, CREMOPHOR ELP), Polyethylene Glycol 40 castor oil hydrogenated (Cremophor RH 40), poly-second two Alcohol 60 castor oil hydrogenated (CREMOPHOR RH 60), polysorbate20 (TWEEN 20), poly- PS80 (TWEEN 80), d-alpha-tocopherol cetomacrogol 1000 succinate (TPGS), Solutol HS-15, the sorbitan oleate that anhydrates (SPAN 20), PEG 300 caprylic/capric glyceride (SOFTIGEN 767), PEG 400 caprylic/capric glyceride (LABRASOL), PEG 300 oleic acid Glyceride (LABRAFIL M-1944CS), Polyethylene Glycol 35 Oleum Ricini (ETOCAS 35), octanoic acid are sweet Grease (monoglyceride and diglyceride) (IMWITOR), PEG 300 glyceryl linoleate (LABRAFIL M-2125CS), Polyethylene Glycol 8 stearate (PEG 400 monostearate), Polyethylene Glycol 40 stearate (PEG 1750 monostearate), Oleum menthae and combinations thereof.
It addition, suitably surfactant includes the Polyethylene Glycol of such as sorbitan monolaurate The glyceride of derivant such as polysorbate, Labraso, Pegylation Deng.
In one embodiment, surfactant is Polyethylene Glycol 35 Oleum Ricini and glycerol caprylate The combination of (monoglyceride and diglyceride) NF.
In the present compositions, the total weight percent of surfactant is the microemulsion of every 100ml Liquid compositions about 1 weight % is to about 95 weight %.Preferably, surfactant is the micro-of every 100ml Emulsion compositions about 25 weight % is to about 95 weight %, and the most about 30 weight % are to about 90 Weight %.In one embodiment, surfactant is the microemulsion composition about 45 of every 100ml Weight % is to about 95 weight %.
Lipoid is the another kind of solvent of the present composition.It is many that lipoid contributes to solubilising racemization card Song, and also promote self emulsifying process.Suitably lipoid includes such as vegetable oil (modified and/or water Solve), there is long chain triglyceride and the medium chain triglyceride of different saturation, and can be used it Combination.
It addition, lipophilic and water-fast monoglyceride, diglyceride and/or triglyceride emulsifying agent (fat and oil) is (purchased from Abitec company, with trade nameSell) can be used as lipoid. Such as, Cera Flava, oleic acid, soya bean fatty acid, d-alpha-tocopherol (vitamin E), Semen Maydis oil list-two-three Diglyceride, middle chain (C8/C10) monoglyceride and diglyceride, long chain triglyceride, Oleum Ricini, jade Miyou, Oleum Gossypii semen, olive oil, Oleum Arachidis hypogaeae semen, Oleum menthae, safflower oil, sesame oil, soybean oil, hydrogen Change soybean oil, hydrogenated vegetable oil, medium chain triglyceride, derive from the caprylic/capric glycerol three of Oleum Cocois Ester, palm seed oil and combinations thereof.
Lipoid is comprised with the amount of emulsion compositions about 0.01 weight % of every 100ml to about 60 weight % In the composition.Preferably, lipoid is about 0.01 weight % to about 50 weight %.Implement at another In scheme, lipoid be emulsion compositions about 1 weight % of every 100ml to about 20 weight %, more preferably Emulsion compositions about 1 weight % of the every 100ml in ground is to about 15 weight % and the most every The emulsion compositions of 100ml about 1 weight % is to about 10 weight %.In a specific embodiment, Lipoid is that emulsion compositions about 1 weight % of every 100ml is to about 2 weight %.
Wish to make the water content in compositions minimize.Water content in compositions will be mainly by being wrapped Moisture content containing every kind of component in the composition.In one embodiment, based on compositions Gross weight % meter, the water content of compositions is less than about 3.5 weight %.In another embodiment, Gross weight % based on compositions is counted, and the water content of compositions is less than about 2.5 weight %.Real at another Executing in scheme, gross weight % based on compositions is counted, and the water content of compositions is less than about 0.5 weight %. In still another embodiment, gross weight % based on compositions is counted, and the water content of compositions is less than about 0.2 weight %.
Alternatively, the emulsion compositions of the present invention can comprise Multiple components.
Any coloring agent being applicable to food or pharmaceutical product all can use in the present invention.Typical Toner includes such as azo dye, quinophthalone dyestuff, kiton colors, ton class dyestuff, indigo-blue Class dyestuff, ferrum oxide, hydrated ferric oxide., titanium dioxide, natural dye and their mixture.More Specifically, suitable coloring agent includes but not limited to patent blue V, acid viride nitens BS, red 2G, azo Rubine, carmine 4R, amaranth, D&C are red 33, D&C is red 22, D&C is red 26, D&C is red 28, D&C Huang 10, FD&C Huang 5, FD&C Huang 6, FD&C be red 3, FD&C is red 40, FD&C indigo plant 1, FD&C indigo plant 2, FD&C are green 3, brilliant black BN, white carbon black, iron oxide black, ferrum oxide Red, iron oxide yellow, titanium dioxide, riboflavin, carotene, anthocyanidin, Rhizoma Curcumae Longae, cochineal carry Take thing, chlorophyll, canthaxanthin, caramel, betanin and their mixture.
Similarly, flavoring agent can be comprised in emulsion compositions.Add the flavoring agent in compositions to Amount depend on desired taste characteristics.
Said composition can comprise other compositions or component, such as: aromatic；Sweeting agent, such as trichlorine Sucrose, Sorbitol, high-fructose corn syrup, sugar etc.；Viscosity modifier, such as xanthan gum；Anti- Rotten agent such as sodium benzoate NF, buffer agent (such as citric acid and/or sodium chloride)；Or their mixing Thing.
The emulsion compositions of the present invention can be prepared by any method known to those skilled in the art, As long as desired composition can be obtained.
Suitably method includes such as merging in blending tank every kind of composition, and wherein this composition can be continuously Or add by any way, as long as reaching expected results.Additionally, married operation should be enough to by Every kind of composition mixes in compositions.
Evaluate the main method of emulsion intercalation method based on the degradation analysis analyzed.Can be by measuring emulsifying Speed, droplets size distribution and turbidimetry estimate the efficiency of self emulsifying.
It addition, stability can be assessed by measuring the turbidity of emulsion.This assessment aids in determining whether emulsion The most rapidly and reach balance within the reproducible time.
Also by checking that stability is assessed in supersaturation (precipitation).By the preparation of 1ml is placed in tool Have in the beaker of 250ml 0.1N HCL and test.If the precipitation of being formed, then system is supersaturation 's.
In one embodiment of the invention, microemulsion composition is as direct oral consumption Encapsulate emulsion and be applied.In another embodiment, microemulsion composition is to comprise microemulsion group The form of the oral soft gelatin capsule of compound and be applied.In still another embodiment, microemulsion group Compound is applied with the form of multiple microgel pearls of comprising microemulsion composition.Implement at another In scheme, microemulsion composition is executed with the form of the hard gelatin capsule that comprises microemulsion composition With.When microemulsion composition is comprised in hard gelatin capsule, hard gelatin capsule can be banding. In still another embodiment, microemulsion composition is to comprise suppository or the enema of microemulsion composition Form and be applied.
Alternatively, the microemulsion composition of the present invention comprises the second active component.An embodiment In, the second active component is digestive system health active component.Non-limiting example includes such as hypocatharsis Agent, antacid, proton pump inhibitor, gas-tight agent, Bendectin, H2 blocker, the second diarrhea.
In one embodiment, during the second active component is incorporated into microemulsion substrate.Real at another Executing in scheme, the second active component is present in another of dosage form composition separate with microemulsion composition In part.In still another embodiment, the second active component is loaded into microcapsule.
Suitable anti-gas agent includes but not limited to dimethicone.
The most other antidiarrheal includes but not limited to loperamide.
In one embodiment, the microemulsion composition of the present invention comprises about 8.0 weight % to about 10.0 The racecadotril of weight %, a total of about 88 weight % are to the surfactant and about of about 91 weight % The lipoid of 1 weight % to about 2 weight %, wherein each weight % is based on the compositions meter of 100mL.
In another embodiment, the microemulsion composition of the present invention comprises about 0.01 weight % to about The racecadotril of 24.0 weight %, a total of about 1 weight % to about 95 weight % surfactant with And about 0.01 weight % to the lipoid of about 60 weight %, wherein each weight % is based on the group of 100mL Compound meter.
In still another embodiment, the microemulsion composition of the present invention comprises about 3.0 weight % to about The racecadotril of 7.0 weight %, a total of about 40 weight % to about 53 weight % surfactant with And about 40 weight % to the lipoid of about 53 weight %, wherein each weight % is based on the combination of 100mL Thing meter.
The microemulsion composition of the present invention can deliver in any suitable delivery system.Such as, one In individual embodiment, microemulsion composition oral administration delivers.In another embodiment, microemulsion Compositions delivers with bladder dosage form.In still another embodiment, microemulsion composition is with hard coat Dosage form delivers.In still another embodiment, Tabules is used for delivering microemulsion composition.
Additionally, use Horiba SZ-100 nano-particle size analysis instrument by moving under 90 degree of angle of scatterings The drop size of the compositions of the present invention is measured in state light scattering (DLS).During measuring, sample is placed in In the temperature-controlled chamber of 25 DEG C.Before measurement will start, in 10mM NaCl solution, utilize nominal 100nm polystyrene latex (PSL) dimensional standard carrys out inspection apparatus performance.These counting rates measured Scope is 100 ten thousand to 300 ten thousand countings per second.Measure every time and continue one minute.The data acquisition of gained It is analyzed by cumulant technology.
Equally, by the dynamic light scattering (DLS) with 90 degree of angle of scatterings at Particle Size Analyzer (PSS) place To measure drop size on Nicomp 380 nano-particle size analysis instrument.All measurements are all entered at 23 DEG C OK.After instrument preheats, utilize NIST can trace to the source reference material (i.e. polystyrene latex) somascope The degree of accuracy of device is challenging to.During the sample continuing 15 minutes is measured, scattering strength determines At 150kHz-500kHz.The data obtained uses cumulant technology to be analyzed.
Present invention additionally comprises a kind of method that person under inspection to there is diarrhoea treats, it includes being examined Person is administered orally the step of the compositions comprising racecadotril, at least one surfactant and lipoid.
Examples provided below further illustrates the compositions and methods of the invention.Should be appreciated that this Invention is not limited to described embodiment.
Embodiment 1
The racecadotril lipid composition concentrated: in the gelatine capsule that liquid is filled
Table 1: compositions based on racecadotril lipoid accounts for the percentage ratio of compositions: triglyceride type 1
1: permissible35USP/NF, EP, JP are commercially available from CRODA Healthcare
2: permissible988USP/NF, EP, JP are commercially available from CREMER
3: permissible810N (caprylic/capric triglyceride；70:30/C8:C10) USP/NF, EP, JP from CRHMER is commercially available
Table 2: compositions based on racecadotril lipoid accounts for the percentage ratio of compositions: triglyceride type 2
1: permissible35USP/NF, EP, JP are commercially available from CRODA Healthcare
2: permissible988USP/NF, EP, JP are commercially available from CREMER
3: permissible812N (caprylic/capric triglyceride；60:40/C8:C10) USP/NF, EP, JP from CRHMER is commercially available
Utilize the material in Tables 1 and 2, take following blend step to form microemulsion.Preparation altogether Including 6 mixture of 3 ratios, the most each mixture utilizes MIGLYOL 810N (table 1) prepare with MIGLYOL 812N (table 2).
Step 1: in suitable container, by Polyethylene Glycol 35 Oleum Ricini (35), octanoic acid Glyceride (988) and medium chain triglyceride (810N&812N) with following Weight ratio be prepared as three single mixture: 88:10:2 (ratio 1), 58:40:2 (ratio 2) and 30:68:2 (ratio 3).
Step 2: utilize vortex agitator to mix the mixture from step 1.
Step 3: utilize vortex agitator to be slowly added into racecadotril from step 2 In mixture and mix 5 minutes.
Step 4: the mixture from step 3 is placed in laboratory shaker and to mix 36 little Shi Zhizhi forms settled solution.
The stability of racecadotril lipid formulations
When the bottle at 40 DEG C of lower seals preserves 40.1 weeks, detect reality for racecadotril degraded Execute the chemical stability of the preparation of preparation in scheme 1, and be shown in Table 3.
Table 3: the stability data of preparation based on lipoid:
Preparation 1, preparation 3, preparation 5
Preparation 2, preparation 4, preparation 6
A, Sai Aofen free from foreign meter or impurity E in preparation 1, preparation 2, preparation 3, preparation 4, preparation 5, preparation 6
ND: do not detect
Preparation:
1.88% superfinishing Etocas 35,10%Imwitor 988,2%Miglyol 810N (ratio 1)
2.88% superfinishing Etocas 35,10%Imwitor 988,2%Miglyol 812N (ratio 1)
3.58% superfinishing Etocas 35,40%Imwitor 988,2%Miglyol 810N (ratio 2)
4.58% superfinishing Etocas 35,40%Imwitor 988,2%Miglyol 812N (ratio 2)
5.30% superfinishing Etocas 35,68%Imwitor 988,2%Miglyol 810N (ratio 3)
6.30% superfinishing Etocas 35,68%Imwitor 988,2%Miglyol 812N (ratio 3)
ND does not detects
Composition:
A. superfinishing Etocas 35 (NF, EP, JP):
Manufactured by CRODA Health Care
Polyethylene Glycol 35 Oleum Ricini
HLB value 14
B.Imwitor 988: middle chain partial glyceride
Manufactured by CREMER
Glycerol caprylate (monoglyceride and diglyceride)
Fusing point about 25 DEG C
HLB value 4
C.Imwitor 742: middle chain partial glyceride
Manufactured by CREMER
Caprylic/capric glyceride
Fusing point about 25 DEG C
HLB value 3-4
D.Miglyol: medium chain triglyceride (miglyol 812, fractionated coconut oil)
Manufactured by CREMER
Octanoic acid (C8)/capric acid (ClO) triglyceride
810N-70:30C8/C10 blend
812N-60:40C8/C10 blend
The conversion ratio of density based on various preparations:
Preparation 1/ preparation 2:1.042g/ml
Preparation 3/ preparation 4:1.028g/ml
Preparation 5/ preparation 6:1.016g/ml
Water content (% w/w):
Preparation Water content (% w/w)
1 0.02
2 0.02
3 0.08
4 0.08
5 0.13
6 0.13
7 0.09
8 0.09
9 0.10
10 0.10
Embodiment 2
The racecadotril lipid composition concentrated: in the gelatine capsule that liquid is filled
Table 4:
1: permissibleUSP/NF, EP, JP are commercially available from CREMER
2: permissible810N (caprylic/capric triglyceride；70:30/C8:C10) USP/NF, EP, JP from CRHMER is commercially available
3: permissible812N (caprylic/capric triglyceride；60:40/C8:C10) USP/NF, EP, JP from CRHMER is commercially available
Table 5:
1: can be with IMWITORUSP/NF, EP, JP are commercially available from CREMER
2: permissible810N (caprylic/capric triglyceride；70:30/C8:C10) USP/NF, EP, JP from CRHMER is commercially available
3: permissible812N (caprylic/capric triglyceride；60:40/C8:C10) USP/NF, EP, JP from CRHMER is commercially available
Method of testing:
Prepared by sample: (in acetonitrile)
1. pipette 1ml racecadotril lipid solution in 100ml volumetric flask (V.F.)
2. utilize dilution in acetonitrile to certain volume.If it is necessary, add about 20ml dimethyl acetylamide.
3. if it is necessary, utilize acetonitrile that sample solution is diluted to about 0.1mg/mL further.
Sample analysis
Under conditions of being similar to hereafter advise, by the reference standard specimen (second of 0.1mg/mL racecadotril Nitrile solution) and sample be injected on suitable HPLC system.Modifiable parameter is to optimize chromatograph.
Use the peak area of the racecadotril of sample solution and the face, peak of the racecadotril of standard solution Long-pending comparison determines the mensuration to racecadotril.By the % relative to racecadotril chromatographic peak Peak area determines content of degradation products.
Chromatographic separation condition (European Pharmacopoeia racecadotril method):
Gradient table:
Time (min) Flow velocity %A %B
Initially 1.0 60 40
5 1.0 60 40
25 1.0 20 80
35 1.0 20 80
36 1.0 60 40
45 1.0 60 40
Mobile phase A: phosphate buffer, pH2.5(prepared by buffer agent: by molten for 1g potassium dihydrogen phosphate In Xie Yushui, utilizing phosphoric acid by pH regulator to 2.5, profit is diluted with water to 1000ml)
Mobile phase B: 100% acetonitrile
Embodiment 3
Racecadotril lipid composition: drop size
Step
Come at Horiba SZ-100 nano particle size by the dynamic light scattering (DLS) under 90 degree of angle of scatterings Drop size is measured on analyser.When measuring, sample is placed in the temperature-controlled chamber of 25 DEG C.Measure Before will starting, 10mM NaCl solution utilizes nominal 100nm polystyrene latex (PSL) Dimensional standard carrys out inspection apparatus performance.These counting rates measured are in the range of per second 100 ten thousand to 300 Ten thousand countings.Measure every time and continue one minute.The data obtained uses cumulant technology to be analyzed.
The dissolubility of preparation based on lipoid and drop size
* preparation 1, preparation 3, preparation 5
* preparation 2, preparation 4, preparation 6
* utilizing Horiba SZ-100 nano-particle size analysis instrument measured by dynamic light scattering (DLS), that measures for three times is average Value (n=3)
1 general step: every kind of preparation of 0.08g and the 0.1N HCl of 15mL are merged, and vortex mixed
2 density based on 1.042g/mL are calculated
3 density based on 1.028g/mL are calculated
4 density based on 1.016g/mL are calculated
The concentration of 5 racecadotrils is about 0.53mg/mL
The concentration of 6 racecadotrils is about 0.55mg/mL
The concentration of 7 racecadotrils is about 0.44mg/mL
The concentration of 8 racecadotrils is about 0.60mg/mL
The concentration of 9 racecadotrils is about 0.43mg/mL
The concentration of 10 racecadotrils is about 0.46mg/mL
* preparation sees embodiment 1
Equally, by the dynamic light scattering (DLS) with 90 degree of angle of scatterings at Particle Size Analyzer (PSS) place To measure drop size on Nicomp 380 nano-particle size analysis instrument.All measurements are all entered at 23 DEG C OK.After instrument preheats, utilize NIST can trace to the source reference material (i.e. polystyrene latex) somascope The degree of accuracy of device is challenging to.During the sample continuing 15 minutes is measured, scattering strength determines At 150kHz-500kHz.The data obtained uses cumulant technology to be analyzed.
* preparation 1, preparation 3, preparation 5
* preparation 2, preparation 4, preparation 6
* utilize Nicomp 380 nano-particle size analysis instrument measured by dynamic light scattering (DLS).
1 general step: for preparation 1 and 3, merge preparation and the 0.1N HCl of 4.8mL of 0.2mL, and mix；Right In preparation 2 and 4, merge preparation and the 0.1N HCl of 4.9mL of 0.1mL, and mix；For preparation 5 He 6, merge preparation and the 0.1N HCl of 4.9mL of 0.1mL, mixing, then the diluent of 2.5mL is joined In the 0.1N HCl of 2.5mL.
2 density based on 1.042g/mL are calculated
3 density based on 1.028g/mL are calculated
4 density based on 1.016g/mL are calculated
The concentration of 5 racecadotrils is about 3.84mg/mL
The concentration of 6 racecadotrils is about 3.72mg/mL
The concentration of 7 racecadotrils is about 0.83mg/mL
The concentration of 8 racecadotrils is about 1.89mg/mL
The concentration of 9 racecadotrils is about 1.80mg/mL
The concentration of 10 racecadotrils is about 0.83mg/mL
* preparation sees embodiment 1
Although the most having combined specific embodiments of the present invention to describe the present invention, it will be obvious that Under conditions of conceiving without departing from invention disclosed herein, multiple change can be made, revise and become Type.Therefore, it is intended to contain belong in the essence of appended claims and broad scope all This type of change, amendment and modification.The disclosures of all patents application, patent and other publication All it is incorporated by reference in its entirety.

Claims (16)

1. a compositions, comprises:
Racecadotril；At least one surfactant, wherein said surfactant is selected from poly- Ethylene glycol 35 Oleum Ricini, glycerol caprylate (monoglyceride and diglyceride) and their group Close；And lipoid, wherein said lipoid is medium chain triglyceride.
Compositions the most according to claim 1, wherein said compositions is self-emulsifying systems.
Compositions the most according to claim 1, wherein said compositions stablizes about 40 at 40 DEG C Week.
Compositions the most according to claim 1, at least one surfactant wherein said is with often A total of about 1 weight % of the described emulsion compositions of 100mL exists to the amount of about 95 weight %.
Compositions the most according to claim 1, wherein said lipoid is with the described emulsion of every 100mL About 0.01 weight % of compositions exists to the amount of about 60 weight %.
Compositions the most according to claim 1, also comprises group optional selecting free the following to form Composition: preservative, sweeting agent, viscosity modifier, coloring agent, aromatic, flavoring agent and Their mixture.
Compositions the most according to claim 1, also comprises group optional selecting free the following to form Composition: citric acid, sodium benzoate, sucralose, flavoring agent and their mixture.
8. comprising a dosage form for compositions according to claim 1, wherein said dosage form is soft shell agent Type, duricrust dosage form or Tabules.
Compositions the most according to claim 1, wherein said compositions has based on described compositions The total moisture content of less than about 3.5 weight % of gross weight meter.
Compositions the most according to claim 1, is also included as the second of digestive health active component and lives Property composition.
11. 1 kinds of compositionss, including:
The racecadotril of about 0.01 weight % to about 24.0 weight %；
A total of about 1 weight % is to the surfactant of about 95 weight %；With
The lipoid of about 0.01 weight % to about 60 weight %；
Wherein each weight % compositions based on 100mL meter.
12. 1 kinds of dosage forms comprising compositions according to claim 15, wherein said dosage form is soft shell Dosage form, duricrust dosage form or Tabules.
13. compositionss according to claim 15, wherein said compositions stablizes about 40 at 40 DEG C Week.
14. 1 kinds of compositionss, including:
The racecadotril of about 3.0 weight % to about 7.0 weight %；
A total of about 40 weight % are to the surfactant of about 53 weight %；With
The lipoid of about 40 weight % to about 53 weight %；
Wherein each weight % compositions based on 100mL meter.
15. 1 kinds of dosage forms comprising compositions according to claim 18, wherein said dosage form is soft shell Dosage form, duricrust dosage form or Tabules.
16. 1 kinds, for the method treating person under inspection diarrhoea occur, are administered orally including described person under inspection The step of compositions according to claim 1.
CN201480070543.9A 2013-12-23 2014-12-22 Racecadotril compositions Pending CN105848643A (en)

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PCT/US2014/071887 WO2015100234A1 (en) 2013-03-15 2014-12-22 Racecadotril compositions

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