CN102946855B - Topical ophthalmic section suspensoid containing tobramycin and dexamethasone - Google Patents
Topical ophthalmic section suspensoid containing tobramycin and dexamethasone Download PDFInfo
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Abstract
Describe the ophthalmic pharmaceutical compositions containing tobramycin, dexamethasone and deacetylated xanthan gum.The composition provide longer eye to be detained, to improve the eye bioavailability of tobramycin and dexamethasone.In preferred embodiments, said composition additionally provides the suspension of dexamethasone of improvement.Control the concentration of ionisable substance in said composition, to prevent xanthan gum from precipitating due to the ionic interaction between tobramycin and xanthan gum, allow compositions is being applied topically at the moment recover viscosity simultaneously.Disclose and use deacetylated xanthan gum to avoid at lay up period because pH change causes preparation unstable.
Description
Background of invention
The present invention relates to the field of the method for ophthalmology infection/anti-inflammatory composition and relevant treatment mammal, particularly people.More specifically, the present invention relates to the new eye infection/anti-inflammatory composition containing tobramycin and dexamethasone.
Tobramycin and Dexamethasone group are closed and are used for the treatment of ophthalmic infection and adjoint inflammation is known.Similarly, these compound combinations are used for the treatment of inflammation with prophylactic treatment (namely prevent or improve) infection, such as relevant to eye surgery infection is also known.The product of the type by AlconLaboratories, Inc. in the U.S. and other national conduct
(tobramycin 0.3%/dexamethasone 0.1%) eye suspensoid is sold.Since 1988, can obtain this product in the U.S..For many years, it is accepted by the ophthalmology infection/anti-inflammatory products widely as current level.U.S. Patent No. 5,149, provide in 694 about
the further details of the composition of board ophthalmology suspensoid.
The present invention relates to the tobramycin/dexamethasone compositions of the improvement being provided for topical ophthalmic application.Specifically, the present invention relates to and provide containing xanthan gum and there is the compositions of the pH of 5-6.Compositions in the preparation and before the use in a reservoir the viscosity of lay up period significantly lower than the viscosity usually desired according to xanthan gum concentration used.When using compositions to patient, this viscosity before use reduces for from drop bottle (such as DROPTAINER
tM, AlconLaboratories, Inc.) or other container in distribute compositions be favourable.The reduction of the viscosity of the lay up period of compositions in the preparation and before being applied to eye is attributable to the ionic interaction between the tobramycin that occurs under the pH of 5-6 scope and xanthan gum.If do not controlled, those interact and form tobramycin and the agglomerate of xanthan gum and/or the precipitation of xanthan gum by causing.The present invention is based in part on to have found to be proved to be and effectively can controls the interactional formulation components of tobramycin/xanthan gum and parameter.
As mentioned above, compositions of the present invention contains xanthan gum.Use xanthan gum as the component of ophthalmic composition in U.S. Patent No. 4,136,177; U.S. Patent No. 6,352,978; U.S. Patent No. 6,174,524; With U.S. Patent No. 6,261, on the books in 547.Described ' 978 patents describe the use that xanthan gum and tobramycin combine.It points out that xanthan gum and tobramycin are inconsistent under pH5.0-7.8, and instruction can avoid this inconsistent problem by preparing the tobramycin/xanthan gum compositions with the pH of 7.9-8.6 scope.Product based on the invention described in ' 978 patents is sold in Europe and some other countries by the branch of AlconLaboratories, Inc..
Described ' 524 describe the ophthalmic composition based on xanthan gum with ' 547 patents, and it is formulated into non-gelling liquid, is being applied topically at the moment gelation.' 524 and the compositions of ' 547 patents be formulated into and make their total ionic strength for about 120mM or following, preferred about 94mM or following.There is total ionic strength and contacting at the moment not gelation higher than ' 524 of about 120mM with the compositions of ' 547 patents.' 524 and the compositions of ' 547 patents normally sticky, when being applied topically at the moment gelation.On the contrary, compositions of the present invention has lower viscosity usually in bottle, but viscosity significantly increases after being applied to eye, because the interaction between tobramycin and xanthan gum is destroyed.
Tobramycin of the present invention/dexamethasone compositions is prepared under the pH of 5-6.In order to maintain the stability of dexamethasone, this pH scope is required.U.S. Patent No. 5,149,694 describe pH tobramycin/dexamethasone ophthalmic composition being used to this scope.
(tobramycin 0.3%/dexamethasone 0.1%) ophthalmology suspensoid also has the pH of this scope.
The present invention comes from such effort: by using xanthan gum as the carrier of tobramycin and dexamethasone, tobramycin/dexamethasone preparation that preparation improves, particularly when being applied topically at the moment provide the tobramycin of raising and/or the compositions of dexamethasone bioavailability.But, as mentioned above, find that the ionic interaction under pH5 to 6 of tobramycin and xanthan gum causes xanthan gum agglomerating and/or precipitate.In addition, find that xanthan gum carries out deacetylated at lay up period lentamente, thus cause stability problem.As being hereafter explained in more detail, the present invention is based on the discovery of the method addressed these problems.
Summary of the invention
The present invention relates to and provide containing tobramycin and dexamethasone and be suitable for being applied topically to the pharmaceutical composition of the improvement of the eyes of human patients.The preparation parameter that compositions of the present invention is based in part on and has found to control ionic interaction between tobramycin and xanthan gum, maintain dexamethasone stability simultaneously.Those interactional controls make the present inventor can provide the compositions with very favorable physical property.More specifically, because the interaction between tobramycin and xanthan gum is controlled, compositions of the present invention has favourable rheological property, and those character improve the bioavailability of medicine, particularly tobramycin and the dexamethasone being locally applied to eye.In addition, said composition provides significant improvement relative to the suspensoid of the dexamethasone (i.e. dexamethasone alcohol (dexamethasonealcohol)) wherein with relatively insoluble form, even if make patient not contain the bottle of compositions once in a while in accordance with description jolting before being applied to eye, the utilization rate of the dexamethasone of suspendible in compositions also significantly can not be reduced.
The solution of the xanthan gum containing the present invention's concentration used or suspensoid normally glue very much.As being hereafter explained in more detail, the present invention is based in part on following discovery: create ionic interaction as the tobramycin of cationic molecule and electronegative xanthan molecules, thus reduce the viscosity of compositions.When being applied at the moment, because the ionic interaction between tobramycin and xanthan gum is destroyed, the viscosity of tobramycin/xanthan gum compositions of the present invention is restored (namely increasing), and causing eye to be detained thus increases and the raising of eye bioavailability.But, during the preparation of compositions and at compositions lay up period before use, ionic interaction between tobramycin and xanthan gum must be controlled to avoid the formation of precipitation and agglomerating and maintenance xanthan gum is dispersed in the composition.The present invention is based in part on and determines such preparation characteristic sum parameter: they control the ionic interaction between tobramycin and xanthan gum in preparation and storage period, maintain the stability of dexamethasone simultaneously.
Tobramycin is positively charged molecule, and xanthan gum is electronegative.When merging in the aqueous solution being in acid pH or suspensoid, tobramycin will make xanthan gum precipitate or form agglomerate.This precipitation or agglomerating be unacceptable in two.First, tobramycin and xanthan gum are no longer uniformly distributed in the composition.This is unacceptable, because often drip compositions must provide all even expected amount composition component, particularly active component when distributing from suitable bottle or other container.Secondly, tobramycin causes xanthan gum to lose the viscosifying action of compositions to the precipitation of xanthan gum or agglomerating effect, and the viscosity of compositions can be returned back to and the value of aqueous phase etc. (that is, about 1 centipoise).
U.S. Patent No. 6,352,978 are based in part on discovery can control these ionic interactions by utilizing alkaline pH (i.e. pH8.0 or higher).But, in tobramycin of the present invention/dexamethasone compositions, use alkaline pH to be impossible, because dexamethasone is unstable under this pH level.Dexamethasone is stable at pH5 to 6 time, but under this pH, electronegative xanthan gum and positively charged tobramycin interact, and form the precipitation of material and/or the agglomerate of cohesion.
The present inventor has been found that: controlling the ionic interaction between tobramycin and xanthan gum by utilizing ionization material (ionicspecies) to avoid the formation of precipitation or agglomerate and the viscosity of tobramycin/suspension of dexamethasone of the present invention or solution to be maintained within the acceptable range before being applied to eye, can overcome problem discussed above.By including the ionization material relevant to xanthan gum or tobramycin in, reducing direct interaction between these compounds thus, achieve this control.Ionization material for this object can be under the pH of 5-6 scope, be separated into anion and cationic any pharmaceutically acceptable material, but is preferably inorganic electrolyte or organic buffer agent, such as sodium chloride, potassium chloride or sodium sulfate.
When being applied at the moment, because the complex between xanthan gum and tobramycin is destroyed, the viscosity of compositions of the present invention is restored.That is, when being applied at the moment, the viscosity of compositions of the present invention raises, and thereby increases compositions and is retained in the persistent period on anterior corneal surface and improves a bioavailability.Such as, because eye bioavailability improves, the dexamethasone having determined only 0.05w/v% concentration in the present compositions just with
in ophthalmology suspensoid, the dexamethasone of 0.1w/v% concentration is bioequivalent.
The present invention is also based in part on following discovery: the compositions based on xanthan gum of the present invention has good suspendible character.More specifically, relative to prior art
preparation, Dexamethasone particles keeps the time of suspendible significantly longer in the present compositions.This improvement provides important advantage, particularly for the patient sometimes forgotten or ignore the explanation " before use shake well " being applicable to all ophthalmology suspension compositions.
The present invention is also based in part on following discovery: if by deacetylated at least in part, then xanthan gum will be more much effective as viscosifier in the present compositions.More specifically, xanthan gum is deacetylated lentamente in aqueous solution.Determine: the pH of this deacetylated further reduction compositions, increase the ionic interaction between tobramycin and dexamethasone thus.These interactions cause viscosity loss at first, finally cause xanthan gum and tobramycin is agglomerating and/or precipitation.The present inventor determines: by making xanthan gum deacetylated before including compositions of the present invention in, can overcome this problem.
Accompanying drawing is sketched
The figure of Fig. 1 shows the impact of sodium chloride concentration as described in Example 3 on the viscosity of representative formulation of the present invention;
The figure of Fig. 2 shows the impact of pH as described in Example 3 on the viscosity of representative formulation of the present invention;
The figure of Fig. 3 show there is pH7.4 as described in Example 3 phosphate buffered salt solution on the impact of the viscosity of representative formulation of the present invention;
The figure of Fig. 4 describes the relation between sodium chloride equipotent concentration as described in Example 4 and viscosity; With
The figure of Fig. 5 shows the eye bioavailability data of three kinds of representative formulation of the present invention compared with the preparation of prior art as described in Example 5.
The explanation of preferred embodiment
Compositions of the present invention is formulated into sterile aqueous suspension, and it comprises the tobramycin that concentration is 0.1 to 0.5 weight/volume percent (w/v%), preferably 0.3w/v%; Concentration is the dexamethasone of 0.03 to 0.1w/v%, preferably 0.05w/v%; It is the aqueous carrier of de-(second) acidylate xanthan gum of 0.3 to 0.9w/v%, preferably 0.6w/v% containing concentration; And ionization material, present in an amount at least sufficient to limit the interaction between tobramycin and xanthan gum, so that the viscosity of suspensoid 18 months periods after the preparation date maintain the scope of 10-700 centipoise (" cps "), preferably 10-300cps.The pH scope that this suspensoid has is 5-6.
Ionization material used in the present invention can be any pharmaceutically acceptable compound being separated into cation and anionic group under the pH of 5-6 scope.Described compound can be inorganic compound or organic compound, but is preferably inorganic electrolyte, organic buffer agent or its combination.The example of this kind of ionization material comprises sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium citrate, potassium citrate, sodium phosphate, potassium phosphate, sodium acetate, sodium borate, boric acid/dew alcohol complex, boric acid/sorbitol complex and their combination.
The viscosity of total amount on compositions of the ionisable substance existed in compositions of the present invention has impact.Compositions containing presenting in an amount at least sufficient to one or more ionizable compound reducing or stop the ionic interaction between tobramycin and xanthan gum, to avoid forming precipitation or agglomerating in compositions, and must be no more than the range of viscosities of afore mentioned rules.Therefore, compositions must containing presenting in an amount at least sufficient to the viscosity (being called " initial viscosity ") in the preparation providing at least 10cps to compositions, the ionization material preferably presenting in an amount at least sufficient to provide the initial viscosity of 15cps or higher, more preferably present in an amount at least sufficient to provide the initial viscosity of 25cps or higher herein.The initial viscosity of compositions is preferably the scope of 25 to 175cps.
Selected concrete ionization material is depended in the impact of ionization material on ionic strength and viscosity.Such as, sodium sulfate affects height about 5.3 times on the impact of ionic strength and viscosity than sodium chloride.Can normal experiment be utilized, in the pH scope specified herein, tobramycin concentrations, xanthan gum concentration and range of viscosities, determine the relative effect of different ionized salts.When relating to compositions of the present invention, the parameter of unique key is the precipitation or agglomerating that the amount of ionizable salt must be enough to avoid the formation of tobramycin and xanthan gum, and the viscosity not increasing compositions is to higher than 700cps or more preferably 300cps.
Because moisture loses from compositions, the viscosity of ophthalmology suspensoid of the present invention can be passed in time and increase a little.Therefore, suspensoid is formulated into the scope its viscosity being gone through maintain for 18 months 10-700cps, preferably 10-300cps.Compositions of the present invention from preparation time until the viscosity be applied at the moment is referred to herein as " the external viscosity " of compositions.
The viscosity number represented herein is based on about 6sec
-1shear rate and the temperature of 25 DEG C under use Bu Shi (Brookfield) viscometer.Adopt rotating shaft C P-52 can obtain about 6sec at 1.5rpm or rotating shaft C P-41 at 3rpm at 1.5rpm, rotating shaft C P-42 at 3 revs/min of (" rpm "), rotating shaft C P-51
-1shear rate.Rotating shaft C P-52 and CP-51 is typically for measuring the viscosity higher than 300 centipoises (" cps ").Rotating shaft C P-42 and CP-41 is usually typically for measuring the viscosity lower than 300cps.
As mentioned above, the viscosity of compositions of the present invention is at the moment recovered being applied to, thus the viscosity of compositions after topical ophthalmic is used is higher than the viscosity after the preparation and when storing in a reservoir before being applied to eye.This increase is because its pH and ionic strength change cause when a small amount of compositions (namely one or two) touches tear (i.e. the tear) of human eye.That is, the electrolyte in tear increases pH and the ionic strength of compositions, and this causes the viscosity of compositions to increase, and the eye which thereby enhancing compositions is detained and bioavailability.
Viscosity in the body measuring compositions of the present invention, be namely applied to eye after viscosity be very difficult.But, can use Viscosity Model in analogue body described below evaluate in vivo tear on the impact of the viscosity of compositions of the present invention.Viscosity (being namely applied topically to the viscosity after eye) in the body simulating compositions of the present invention by adding a small amount of following phosphate buffered salt solution in compositions.
for the phosphate buffered salt solution of viscosity measurement in analogue body
| Composition | Amount (w/v%) |
| Sodium hydrogen phosphate (anhydrous) | 0.57％ |
| Biphosphate sodium-hydrate | 0.08％ |
| Sodium chloride | 0.65％ |
| Pure water | Appropriate to 100% |
| pH | 7.4 |
In compositions of the present invention, add above-mentioned phosphate buffered salt solution (" PBS solution ") simulate the impact of tear on composition viscosity.By PBS solution with 1: 10 ratio add in compositions, that is, every 10 parts of tobramycin/dexamethasone/xanthan gum compositions of the present invention add 1 part of PBS solution.
For the object of this description, in the actual body estimating compositions of the present invention, viscosity is identical with viscosity in the analogue body of said composition.Therefore, be interchangeable to all appellations of " in body viscosity " with " in analogue body viscosity " herein.Herein to all appellations of " in analogue body viscosity " and " in vitro/in vivo ratio of viscosities " all based on Viscosity Model in the above-mentioned Viscosity Measurement Methods of use and analogue body.
The ratio of the viscosity of compositions of the present invention before being applied to eye and the viscosity of this same combination after application one drops to eye is referred to herein as " in vitro/in vivo ratio of viscosities ".Compositions of the present invention preferably has
extremely
or 0.01 to 0.65 in vitro/in vivo ratio of viscosities of scope.
Aforementioned ratio also can be expressed as a percentage, and namely external viscosity is multiplied by 100 again divided by viscosity in analogue body.Therefore, the external viscosity that in external viscosity and analogue body, the aforementioned range of the ratio of viscosity is equivalent to wherein compositions of the present invention be described compositions analogue body in viscosity 1% to 65% scope.
Relative viscosity value also can be expressed as the ratio of viscosity and external viscosity in body.Compositions of the present invention preferably has
extremely
body in/external ratio of viscosities, in its body being equivalent to wherein compositions, viscosity is the scope of the external viscosity about 1.5 to 100 times of described compositions.
Tobramycin, dexamethasone and xanthan gum used in Sterile ophthalmic suspensoid of the present invention are known compounds, and can easily obtain from various source.Salt-independent shape such as the dexamethasone alcohol of dexamethasone is preferred.But, the salt form of dexamethasone also can be used as dexamethasone sodium phosphate.When selecting dexamethasone salt, the ionic strength must considered to dissociate dexamethasone salt when determining the concentration of the ionisable substance controlled needed for the ionic interaction between tobramycin and xanthan gum the ion that formed contributes.
The xanthan gum of pharmaceutical grade should be used.Xanthan gum preferably should carry out secondary filter (polish-filtered) before use.Those skilled in the art easily can determine the selection of suitable filtering technique.As discussed above, xanthan gum must be deacetylated, to improve the stability of suspensoid of the present invention at lay up period.The acetic acid content of xanthan gum is based on the acetic acid be combined with xanthan gum.Acetic acid content is typically expressed as the percentage by weight of xanthan gum.Xanthan gum raw material by usually have maximum 6% in conjunction with acetic acid.Deacetylated xanthan gum used in the present invention contain be less than 2% in conjunction with acetic acid, be preferably less than 1% in conjunction with acetic acid.Further illustrate in Examples below 1 and 2 and make the importance of deacetylated xanthan gum and can deacetylated method be carried out.
As mentioned above, compositions of the present invention has the pH of 5-6.Compositions also will have the acceptable osmotic pressure of ophthalmology, it typically is 200 to 400 m osmoles/kg water (mOsm/kg).When the buffer agent selecting to be suitable for the pH of compositions to maintain in the particular range of 5-6 and/or selected area update strategy pressure regulator, the impact of this kind of material on the ionisable substance content of compositions must be considered.Such as, if in order to the sodium chloride regulating osmotic pressure to add ionization material concentration is increased above acceptable level (namely, for target viscosities value), then may be necessary with nonionic osmotic pressure regulator as all or part of sodium chloride replaced by propylene glycol.
Compositions of the present invention can such as, containing normally used other composition various, anti-microbial preservative (such as benzalkonium chloride) and wetting agent in ophthalmic pharmaceutical compositions.Compositions is preferably formulated and is packaged into multiple dose product, but also can prepare when not using conventional anti-microbial preservative and be packaged in the unit dose vial of sealing.
Compositions of the present invention can be used for treating the Ocular inflammatory disease that wherein there is infection or infection risk.Term as used herein " treatment " is contained the active treatment of existing disease and is in the prophylactic treatment of the patient developing into disease (such as infecting).Compositions of the present invention can be used in particular for treating the eye inflammation relevant with the ocular injury that wound causes and injecting (such as retrobulbar injection, rear nearly sclera injects and front nearly sclera is injected) relevant inflammation with eye surgery (such as cataract operation, operation on retina, lasik surgery) and eye.
This treatment can be carried out by the trouble eye that a small amount of (such as one drops to two) compositions of the present invention is applied to patient every day for 2 to 4 times.But dosage and administration frequency can be adjusted by clinicist.
Can assert, some therapeutic agents chosen except tobramycin can interact with substantially identical with tobramycin mode and xanthan gum, and can be used for the present invention.Not bound by theory, it is believed that in molecule that the therapeutic agent molecules with two or more positive charge or cationic charge can interact with the mode identical with tobramycin and xanthan gum.Further, not bound by theory, it is believed that most fluoroquinolone therapeutic agent can interact with the mode and xanthan gum that are similar to tobramycin.As an example, the present inventor has been found that: ionization material can be used for controlling the interaction between Moxifloxacin and xanthan gum, with provide substantially with those similar in vitro/in vivo ratios of viscosities as discussed above.
embodiment 1
Described below is the also not deacetylated xanthan gum of utilization and prepare tobramycin/dexamethasone/xanthan gum preparation.Also been evaluated the stability of gained preparation, as explained below.
the preparation of xanthan gum stock solution
Hot water is added in container.To weigh xanthan gum, slowly add under mixing in container.Temperature is adjusted to 60 DEG C, xanthan gum and water are mixed to evenly.Add pure water and reach final goal weight to make compositions, be mixed to evenly.Elevate the temperature to 70 DEG C, afterwards by suitable accurate filter as 1.2 μm of filters filter.
xanthan gum stock solution is used to prepare tobramycin/dexamethasone preparation
The tobramycin of specified amount in following table 1A, sodium chloride, boric acid and disodium edetate to be joined in a part of pure water and to dissolve.Add hydrochloric acid or sulphuric acid to reduce pH.Add in serosity or pulverous tyloxapol and dexamethasone.Add the xanthan gum stock solution of batch and fully mix.Add 1N hydrochloric acid or 1N sulphuric acid to reach target pH.Add pure water and reach final volume, fully mix.The viscosity of gained preparation is measured with the shear rate of 6sec-1.Each viscosity number is presented in following table 1A.
table 1A
| Preparation is numbered | 107201 | 107209 |
| Composition | W/V％ | W/V％ |
| Tobramycin | 0.3 | 0.3 |
| Dexamethasone | 0.1 | 0.1 |
| Xanthan gum | 0.9 | 0.9 |
| Sodium chloride | 0.42 | 0.08 |
| Tyloxapol | 0.05 | 0.05 |
| Boric acid | 0.5 | 1 |
| Disodium edetate | 0.01 | 0.01 |
| Sodium hydroxide | Regulate pH to 5.5 | Regulate pH to 5.7 |
| Hydrochloric acid | Regulate pH to 5.5 | Nothing |
| Sulphuric acid | Nothing | Regulate pH to 5.7 |
| Pure water | Appropriate to 100% | Appropriate to 100% |
| Result | ||
| At shear rate 6sec -1(cps) viscosity under | 418 | 642 |
The preparation described in table 1A is made to carry out accelerated stability test.As shown in following table 1B, pH and the viscosity of the preparation using also not deacetylated xanthan gum to prepare decline when storing.This finally makes preparation not use.Especially, the even loss of properties of suspensoid.
table 1B
The pH of tobramycin/dexamethasone preparation using not deacetylated xanthan gum to prepare and the stability of viscosity
embodiment 2
Described below is according to principle of the present invention, comprise use deacetylated xanthan gum prepare tobramycin/dexamethasone preparation.
the preparation of xanthan gum stock solution and carry out pretreatment with alkali
Hot water is added in container.To weigh xanthan gum, slowly add under mixing in container.Add 1NNaOH or the equivalent of 2.5ml relative to every 1 gram of xanthan gum, then mix 20 minutes.1NHCI or the equivalent of 1.66ml is added subsequently relative to every 1 gram of xanthan gum.Add pure water and regulate target weight, then mix 15 minutes.Subsequently by deacetylated xanthan gum by suitable filter as 1.2um filter filters.
pretreated xanthan gum stock solution is used to prepare tobramycin/dexamethasone preparation
The tobramycin of specified amount, sodium chloride, sodium sulfate, disodium edetate and propylene glycol are joined in a part of pure water, then add in serosity or pulverous tyloxapol and dexamethasone.Use 1N salt acid for adjusting pH to the pH a little more than target pH.Then add above-mentioned deacetylated xanthan gum stock solution, gained suspension is fully mixed.Adopt HCI and/or NaOH solution to regulate pH to target level, measure the viscosity of preparation.
table 2A
| Preparation is numbered | 108536 |
| Composition | W/V％ |
| Tobramycin | 0.3 |
| Dexamethasone | 0.1 |
| Xanthan gum | 0.6 |
| Sodium chloride | 0.24 |
| Propylene glycol | 0.6 |
| Tyloxapol | 0.05 |
| Sodium sulfate (anhydrous) | 0.25 |
| Disodium edetate | 0.01 |
| Benzalkonium chloride | 0.01 |
| Sodium hydroxide | Regulate pH to 5.75 |
| Hydrochloric acid | Regulate pH to 5.75 |
| Pure water | Appropriate to 100% |
| Result | W/V％ |
| At shear rate 6sec -1(cps) viscosity under | 116 |
| At shear rate 6sec -1(cps) viscosity in the analogue body under | 1059 |
| With the formulation viscosity that the % of viscosity in analogue body represents | 11％ |
As shown in following table 2B, different from the preparation 107201 and 107209 in embodiment 1, the pH value of the preparation 108536 containing deacetylated xanthan gum is quite stable when storing.Therefore, the viscosity of preparation 108536 keeps stable at lay up period or improves, instead of reduces as in Example 1.
table 2B
The pH of tobramycin/dexamethasone preparation using deacetylated (pretreated) xanthan gum to prepare and the stability of viscosity
ND=undetermined
embodiment 3
Further illustrate tobramycin herein on the impact of the initial viscosity of compositions of the present invention with when recovery compositions being applied at the moment viscosity.Adopt deacetylated xanthan gum to prepare the preparation shown in following table 3A, it is the preparation numbering 108536 of upper table described in 2A of different batches, and is the representative of compositions of the present invention.At shear rate 6sec
-1under measure the initial viscosity of preparation, be defined as 42cps.
table 3A
| Component | ％w/v | Function |
| Tobramycin | 0.3 | Activating agent |
| Dexamethasone (micronization) | 0.1 | Activating agent |
| Benzalkonium chloride | 0.01 | Antiseptic |
| Tyloxapol | 0.05 | Wetting agent |
| Disodium edetate | 0.01 | Anti-corrosive aids |
| Sodium chloride | 0.23±0.04 | Tonicity agent |
| Sodium sulfate | 0.25 | Tonicity agent |
| Xanthan gum | 0.6％ | Viscosity modifier |
| Propylene glycol | 0.6 | Tonicity agent |
| Hydrochloric acid and/or sodium hydroxide | Regulate pH to 5.7 | PH adjusting agent |
| Pure water | Appropriate to 100 | Solvent |
Also prepared the second preparation, it is identical with the preparation shown in table 3A except not containing tobramycin.Recording the initial viscosity that the second preparation has is 836cps.
PH slightly increases or adds a small amount of ion (such as sodium chloride, phosphate buffer) and reduces ionic interaction between tobramycin and xanthan gum, has recovered formulation viscosity thus.Fig. 1-3 illustrates this phenomenon.Fig. 1 shows: when adding 0.2g sodium chloride in 100mL preparation, and the viscosity of the preparation of table described in 3A increaseds to over 1,000cps from 42cps.Fig. 2 show: when pH is heightened to 6.2 time, formulation viscosity increaseds to over 1,100cps by the 42cps under pH5.7, and when pH is 6.4, formulation viscosity is increased to 1,300cps.Fig. 3 shows: when adding the above-mentioned PBS solution of 10mL in 100mL suspensoid, formulation viscosity is increased to 1,059cps by 42cps.
When removing tobramycin from the formula shown in table 3A, formulation viscosity does not increase after mixing with PBS solution.Specifically, when being joined in 100ml preparation by 10ml phosphate buffered salt solution, the preparation recording the revision not containing tobramycin has the viscosity of 667cps.In other words, after adding phosphate buffered salt solution, viscosity in fact the viscosity of the preparation of amendment be reduced to 667cps analogue body from the initial viscosity of 836cps.
embodiment 4
As discussed below with set forth such, the viscosity of compositions of the present invention is subject to the impact of the ionic strength of compositions and the amount of pH and tobramycin selected in the specified scope of 0.1-0.5w/v% and 0.3-0.9w/v% respectively and xanthan gum.To provide in table 4A-4E the preparation listed and related data to set forth and to explain the interaction of these factors further.
The comparison of preparation A-D and these compositionss viscosity number has separately set forth tobramycin to the impact of viscosity of compositions of xanthan gum containing concentration being 0.6w/v%.Specifically, be the initial viscosity that the preparation A of the tobramycin of 0.3w/v% has 15 centipoises (" cps ") containing concentration, and except not having the initial viscosity of 919cps containing the formulation C identical with preparation A except tobramycin.Therefore, in preparation A, having of tobramycin helps reduce the viscosity of compositions.This impact of tobramycin is more also clearly based on preparation B and D.(preparation A and B not containing dexamethasone, but is the representative example of tobramycin of the present invention/dexamethasone compositions.There is provided formulation C and D for comparing object, they are not the representative example of compositions of the present invention.)
Stabilize the viscosity of preparation A by including 23.9mM (0.34%) sodium sulfate in, sodium sulfate is preferred ionisable substance.Preparation A also comprises about 10mM sodium chloride, because deacetylated xanthan gum stock solution contains during deacetylation step owing to adding sodium hydroxide and hydrochloric acid and the sodium chloride formed.Ionic contributions from EDTA (disodium edetate) and benzalkonium chloride is unessential, because their concentration is very low.
Stabilize the viscosity of preparation B by including 138.2mM sodium chloride in, sodium chloride is also preferred ionisable substance.
Sodium chloride or sodium sulfate can be used to stablize the viscosity of compositions of the present invention.But required sodium sulfate concentration is much smaller than sodium chloride concentration.About 1mM sodium sulfate is equivalent to 5.3mM sodium chloride.This is confirmed by embodiment A, B and E to L.
The viscosity of preparation A, B and E to L is in contrast to the drafting of sodium chloride equivalence ion concentration in the diagram.The sodium chloride equivalence ion concentration of these preparations is defined as " sodium chloride concentration (mM)+5.3 sodium sulfate concentration (mM) ".The viscosity of the preparation containing 0.3% tobramycin and 0.6% xanthan gum increases along with the increase of sodium chloride equivalence ion concentration.For the sodium chloride equivalence ion concentration of 134 to 150mM scope, viscosity is the preferable range of 10 to 300cps.
Other ionisable substance can be used to replace sodium chloride or sodium sulfate.Preferred ionized salts has sodium chloride, sodium sulfate, sodium citrate, sodium phosphate, sodium borate, sodium acetate, potassium chloride, calcium chloride and magnesium chloride.Different ionization materials determines sodium chloride equipotent concentration by needing the different factor (be 5.3 for sodium sulfate).This factor can be determined containing the sodium chloride of different proportion and the sample of other salt by preparation.Then, the viscosity results of those samples can be analyzed to determine determining the factor of sodium chloride equipotent concentration.For the salt with multivalent ion, this factor will be greater than 1.
For given active part and concentration thereof, provide the sodium chloride equivalence ion concentration range of relatively low viscosity will depend on pH and xanthan gum concentration.For 0.3% tobramycin solution, preparation M with N shows: need higher sodium chloride equivalence ion concentration to provide viscosity similar compared with under pH5.75 5.5 times at lower pH value.
Preparation O, P and Q show: under Stationary pH (5.5), when xanthan gum concentration is increased to 0.9% by 0.6%, need lower sodium chloride equivalence ion concentration.
table 4A
table 4B
table 4C
table 4D
table 4E
embodiment 5
rabbit bioavailability study result
Relative to
(tobramycin 0.3%/dexamethasone 0.1%) ophthalmology suspensoid have rated the eye bioavailability of Three Represents compositions of the present invention.The formula of compositions of the present invention is presented in following table 5A.
the formula of ophthalmology suspensoid is presented at U.S. Patent No. 5,149, in the embodiment 1 of 694.
table 5A
Eyes to Male New Zealand rabbits use each compositions.After administered formulation, collect Aqueous humor samples at 0.5,0.75,1,2 and 3 hour from eyes, adopt LC-MS/MS method as described below to measure the concentration of dexamethasone.
Adopt the dexamethasone concentration in certified HPLC tandem mass spectrum (HPLC/SM/MS) method measurement rabbit aqueous humor.In the method, puncture extraction 25.0 microlitre aqueous humor aliquot, using beclometasone as interior mark, extracts with methyl tertiary butyl ether(MTBE).Be evaporated to by organic layer dry, the 10mM ammonium formate 20: 80: reconstruct in methanol, sample introduction in reversed-phase HPLC post, adopt isocratic condition, mobility has and reconstructs identical composition used with sample.Make effluent carry out cation electrospray ionization, it is cracked that the protonated molecular ion of dexamethasone and beclometasone carries out collision.The multiple-reaction monitoring of m/z393.1 → 373.4 and 409.3 → 391.4 transition for dexamethasone and beclometasone allows concrete detection respectively.The working range of the method is 1.00 to 200ng/mL.
The mean aqueous humor concentration of dexamethasone in contrast to time drafting in Figure 5.Following table 5B provides the Cmax (C of dexamethasone in aqueous humor
max) and area under curve (AUC) value:
table 5B
Aforementioned result shows: for the preparation based on xanthan gum of the present invention of the dexamethasone respectively containing 0.05% and 0.1% concentration, and aqueous humor concentration is than containing 0.1% dexamethasone
the aqueous humor concentration of suspensoid is much higher.These results confirm that the bioavailability of compositions of the present invention is higher.
Claims (12)
1. topical ophthalmic section compositions, comprises:
The tobramycin of 0.1 to 0.5w/v%;
The dexamethasone of 0.03 to 0.1w/v%;
It is the acceptable aqueous carrier of ophthalmology of the deacetylated xanthan gum of 0.3 to 0.9% containing concentration; With one or more ionisable substance, present in an amount at least sufficient to limit the ionic interaction between tobramycin and deacetylated xanthan gum, so that the external viscosity of compositions is at shear rate 6sec
-1with the scope maintaining 25-175cps at temperature 25 DEG C; Described compositions has the pH of 5-6.
2. compositions according to claim 1, one or more ionisable substance wherein said are selected from inorganic electrolyte, organic buffer agent and combination thereof.
3. compositions according to claim 2, one or more ionisable substance wherein said are selected from sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium citrate, potassium citrate, sodium phosphate, potassium phosphate, sodium acetate, sodium borate, boric acid/mannitol complex, boric acid/sorbitol complex and combination thereof.
4. compositions according to claim 3, wherein said ionisable substance is selected from sodium chloride, sodium sulfate and combination thereof.
5. compositions according to claim 1, wherein said compositions has the in vitro/in vivo ratio of viscosities of 0.01-0.65.
6. compositions according to claim 5, one or more ionisable substance wherein said are selected from inorganic electrolyte, organic buffer agent and combination thereof.
7. compositions according to claim 6, one or more ionisable substance wherein said are selected from sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium citrate, potassium citrate, sodium phosphate, potassium phosphate, sodium acetate, sodium borate, boric acid/mannitol complex, boric acid/sorbitol complex and combination thereof.
8. compositions according to claim 7, wherein said ionisable substance is selected from sodium chloride, sodium sulfate and combination thereof.
9., according to the compositions of any one of claim 1-8, the deacetylated xanthan gum that wherein said compositions contains tobramycin that concentration is 0.3w/v%, concentration is 0.6w/v% and concentration are the dexamethasone of 0.05w/v%.
10. compositions according to claim 9, the pH of wherein said compositions is about 5.7.
11. treatment effective doses claim 1 compositions for the preparation for the treatment of wherein exist infect or infection risk ophthalmic inflammatory disorders topical application medicine in purposes.
The purposes of compositions in the medicine of ophthalmic inflammatory disorders that wherein there is infection or infection risk for the preparation for the treatment of of the claim 9 of 12. treatment effective doses.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2010/039618 WO2011162752A1 (en) | 2010-06-23 | 2010-06-23 | Topical ophthalmic suspensions containing tobramycin and dexamethasone |
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| CN102946855A CN102946855A (en) | 2013-02-27 |
| CN102946855B true CN102946855B (en) | 2016-01-06 |
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| EP (1) | EP2585037A1 (en) |
| JP (1) | JP5728082B2 (en) |
| KR (1) | KR20130094280A (en) |
| CN (1) | CN102946855B (en) |
| AU (1) | AU2010356098B2 (en) |
| BR (1) | BR112012033052A2 (en) |
| CA (1) | CA2801731A1 (en) |
| MX (1) | MX2012015051A (en) |
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| GB201208080D0 (en) * | 2012-05-09 | 2012-06-20 | Norton Healthcare Ltd | Tobramycin formulation |
| JP6527315B2 (en) * | 2014-08-08 | 2019-06-05 | Ｄｓｐ五協フード＆ケミカル株式会社 | Fast-dissolving thickener, thickener for people with dysphagia and dysphagia, food and drink for patients with dysphagia and dysphagia |
| CN109260219B (en) * | 2018-11-30 | 2021-03-09 | 山东省药学科学院 | Articular cavity injection preparation and application thereof |
| IT202000002296A1 (en) * | 2020-02-06 | 2021-08-06 | Sifi Spa | Topical ophthalmic formulations based on xanthan with reduced dosage |
| IT202200000821A1 (en) * | 2022-01-19 | 2023-07-19 | Sifi Spa | TOPICAL OPHTHALMIC FORMULATIONS BASED ON XANTHANE WITH REDUCED DOSAGE |
| CN115006412B (en) * | 2022-05-20 | 2023-11-10 | 北京诺康达医药科技股份有限公司 | Compound tobramycin eye drops and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999006023A1 (en) * | 1997-07-29 | 1999-02-11 | Alcon Laboratories, Inc. | Ophthalmic compositions containing galactomannan polymers and borate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4136177A (en) | 1977-01-31 | 1979-01-23 | American Home Products Corp. | Xanthan gum therapeutic compositions |
| US5149694A (en) | 1988-03-09 | 1992-09-22 | Alcon Laboratories, Inc. | Combination of tobramycin and dexamethasone for topical ophthalmic use |
| EP1069913B1 (en) * | 1998-04-07 | 2003-07-23 | Alcon Laboratories, Inc. | Gelling ophthalmic compositions containing xanthan gum |
| US6174524B1 (en) | 1999-03-26 | 2001-01-16 | Alcon Laboratories, Inc. | Gelling ophthalmic compositions containing xanthan gum |
| US6261547B1 (en) | 1998-04-07 | 2001-07-17 | Alcon Manufacturing, Ltd. | Gelling ophthalmic compositions containing xanthan gum |
| DK1305033T3 (en) * | 2000-07-28 | 2005-01-31 | Alcon Inc | Pharmaceutical supplements containing tobramycin and xanthan gum |
-
2010
- 2010-06-23 WO PCT/US2010/039618 patent/WO2011162752A1/en active Application Filing
- 2010-06-23 KR KR1020137000258A patent/KR20130094280A/en active IP Right Grant
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- 2010-06-23 MX MX2012015051A patent/MX2012015051A/en active IP Right Grant
- 2010-06-23 EP EP10726406.1A patent/EP2585037A1/en not_active Withdrawn
- 2010-06-23 CA CA2801731A patent/CA2801731A1/en not_active Abandoned
- 2010-06-23 CN CN201080067666.9A patent/CN102946855B/en not_active Expired - Fee Related
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999006023A1 (en) * | 1997-07-29 | 1999-02-11 | Alcon Laboratories, Inc. | Ophthalmic compositions containing galactomannan polymers and borate |
Non-Patent Citations (1)
| Title |
|---|
| Effectiveness of a new tobramycin (0.3%) and dexamethasone (0.05%) formulation in the treatment of experimental Pseudomonas keratitis;MCCORMICK C ET AL;《CURRENT MEDICAL RESEARCH AND OPINION》;20080601;第24卷(第6期);第1569-1575页 * |
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| ZA201209240B (en) | 2014-02-26 |
| JP5728082B2 (en) | 2015-06-03 |
| AU2010356098A1 (en) | 2013-01-10 |
| CN102946855A (en) | 2013-02-27 |
| KR20130094280A (en) | 2013-08-23 |
| WO2011162752A1 (en) | 2011-12-29 |
| JP2013529632A (en) | 2013-07-22 |
| MX2012015051A (en) | 2013-02-15 |
| EP2585037A1 (en) | 2013-05-01 |
| CA2801731A1 (en) | 2011-12-29 |
| BR112012033052A2 (en) | 2019-09-24 |
| AU2010356098B2 (en) | 2014-08-14 |
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