JP5728082B2 - Topical ophthalmic suspension containing tobramycin and dexamethasone - Google Patents

Description

The present invention relates to ophthalmic anti-infective / anti-inflammatory compositions and related treatment methods in mammals, particularly humans. More specifically, the present invention relates to a novel ophthalmic anti-infective / anti-inflammatory composition comprising tobramycin and dexamethasone.

  It is known to use tobramycin and dexamethasone in combination to treat ocular infections and associated inflammation. Similarly, it is also known to use these compounds in combination to treat inflammation and prevent infection (ie, prevent or ameliorate) infection, eg, in combination with ocular surgical procedures. . This type of product is available from Alcon Laboratories, Inc. In the United States and other countries as TOBRADEX® (tobramycin 0.3% / dexamethasone 0.1%) ophthalmic suspension (tobradex ophthalmic solution). This product has been available in the United States since 1988. For many years it has been widely accepted to be a state-of-the-art ophthalmic anti-infective / anti-inflammatory product. Further details regarding the composition of the TOBRADEX® brand ophthalmic suspension are provided in US Pat.

The present invention relates to the provision of improved tobramycin / dexamethasone compositions for topical administration to the eye. In particular, the present invention relates to providing a composition comprising xanthan gum and having a pH in the range of 5-6. The viscosity of the composition during manufacture and in the container before use is considerably lower than would normally be expected based on the concentration of xanthan gum used. This reduction in viscosity prior to use is advantageous when the composition is administered to a patient compared to dispensing the composition from an eye drop bottle (eg, DROPTAINER ^™ , Alcon Laboratories, Inc.) or other containers. The decrease in viscosity of the composition during manufacture and storage prior to administration to the eye is due to ionic interactions between tobramycin and xanthan gum that occur at a pH of 5-6. These interactions, if not controlled, cause tobramycin and xanthan gum agglomeration and / or xanthan gum precipitation. The present invention is based, in part, on the discovery of formulation ingredients and parameters that have been shown to be effective in controlling tobramycin / xanthan gum interactions.

  As indicated above, the composition of the present invention comprises xanthan gum. The use of xanthan gum as a component of an ophthalmic composition is described in Patent Document 2, Patent Document 3, Patent Document 4, and Patent Document 5. The patent of U.S. Patent No. 6,057,033 describes the use of xanthan gum in combination with tobramycin. It indicates that xanthan gum and tobramycin are incompatible at a pH of 5.0 to 7.8, and the tobramycin / xanthan gum composition is formulated to have a pH in the range of 7.9 to 8.6. Teaches that this incompatibility problem can be avoided. Products based on the invention described in the patent of US Pat. No. 6,057,049 are available in Europe and several other countries in Alcon Laboratories, Inc. It is marketed by an affiliated company.

  The patents in US Pat. Nos. 6,057,049 and 5,037,059 describe xanthan-based ophthalmic compositions formulated as non-gelling liquids that gel upon topical administration to the eye. The patented compositions of US Pat. Nos. 6,099,036 and 5,035,059 are formulated such that their total ionic strength is about 120 mM or lower, and preferably about 94 mM or lower. The patent compositions of Patent Document 4 and Patent Document 5 having a total ionic strength greater than about 120 mM do not gel upon contact with the eye. The patented compositions of US Pat. Nos. 5,099,086 and 5,028,5 are generally viscous and gel upon topical administration to the eye. In contrast, the compositions of the present invention generally have a lower viscosity in the bottle, but the viscosity increases significantly after administration to the eye because the interaction between tobramycin and xanthan gum is broken.

  The tobramycin / dexamethasone composition of the present invention is formulated at a pH of 5 to 6. This pH range is necessary to maintain the stability of dexamethasone. The use of this range of pH for ophthalmic tobramycin / dexamethasone compositions is described in US Pat. TOBRADEX® (tobramycin 0.3% / dexamethasone 0.1%) ophthalmic suspension also has a pH in this range.

  The present invention provides improved bioavailability of tobramycin and / or dexamethasone upon topical administration to the eye by using xanthan gum as an improved tobramycin / dexamethasone formulation, particularly tobramycin and dexamethasone vehicle. Out of efforts to produce the provided composition. However, as described above, it has been discovered that ionic interactions between tobramycin and xanthan gum at a pH of 5 to 6 cause agglomeration and / or precipitation of xanthan gum. In addition, it has been discovered that xanthan gum undergoes slow deacetylation during storage, thereby causing stability problems. As described in more detail below, the present invention is based on the discovery of solutions to these problems.

US Pat. No. 5,149,694 US Pat. No. 4,136,177 US Pat. No. 6,352,978 US Pat. No. 6,174,524 US Pat. No. 6,261,547

  The present invention relates to the provision of an improved pharmaceutical composition comprising tobramycin and dexamethasone and suitable for topical administration to the eye of a human patient. The compositions of the present invention are based, in part, on the discovery of formulation parameters that control ionic interactions between tobramycin and xanthan gum while maintaining dexamethasone stability. Controlling their interaction has allowed us to provide compositions that have very advantageous physical properties. More specifically, the compositions of the present invention have advantageous hydrodynamic properties as a result of controlled interaction between tobramycin and xanthan gum, and these properties are locally applied to the eye. Enhance the bioavailability of administered drugs, especially tobramycin and dexamethasone. In addition, the composition provides significant improvements compared to suspensions in a form in which dexamethasone is relatively insoluble (ie, dexamethasone alcohol), and the composition is sometimes formulated by patients prior to administration to the eye. Failure to follow the instructions to shake the bottle containing the product does not significantly reduce the availability of dexamethasone suspended in the composition.

  The solution or suspension containing the concentration of xanthan gum used in the present invention is usually very viscous. As described in more detail below, the present invention, in part, allows the cationic molecule tobramycin to ionically interact with negatively charged xanthan gum molecules, thereby reducing the viscosity of the composition. Based on the discovery. Upon administration to the eye, as a result of disruption of the ionic interaction between tobramycin and xanthan gum, the viscosity of the tobramycin / xanthan gum composition of the present invention is restored (ie, increased), thereby increasing retention of the eye. Causes an increase and enhanced bioavailability in the eye. However, during the manufacture of the composition and during storage of the composition prior to use, to avoid the formation of precipitates and agglomerates and to maintain a uniform distribution of xanthan gum in the composition, tobramycin and xanthan gum The ionic interaction between the two must be controlled. The present invention is based, in part, on the identification of formulation features and parameters that control ionic interactions between tobramycin and xanthan gum during manufacturing and storage while maintaining dexamethasone stability.

  Tobramycin is a positively charged molecule, while xanthan gum is negatively charged. When combined in aqueous solutions or suspensions at acidic pH, tobramycin precipitates xanthan gum or forms agglomerates. Such precipitation or agglomeration is unacceptable in two ways. First, tobramycin and xanthan gum are no longer uniformly distributed in the composition. This is acceptable because each drop of the composition must provide a uniform and predictable amount of the components of the composition, particularly the active ingredient, when administered from an appropriate bottle or other container. Can not. Second, the precipitation or agglomeration effect of tobramycin on xanthan gum causes a loss of xanthan gum's viscosity enhancing effect on the composition, and the viscosity of the composition can revert to a value equivalent to water (ie about 1 centipoise).

  US Pat. No. 6,352,978 is based in part on the discovery that these ionic interactions can be controlled by utilizing alkaline pH (ie, 8.0 or higher pH). However, since dexamethasone is unstable at this pH level, it is not possible to use an alkaline pH in the tobramycin / dexamethasone composition of the present invention. Dexamethasone is stable at a pH of 5 to 6, but negatively charged xanthan gum and positively charged tobramycin interact at this pH to form a precipitate and / or agglomerate of material.

  We have discussed above to avoid the formation of precipitates or lumps and to maintain the viscosity of the tobramycin / dexamethasone suspension or solution within an acceptable range prior to administration to the eye. It has been discovered that the problem can be overcome by using ionic species to control ionic interactions between tobramycin and xanthan gum. This control is achieved by including ionic species that bind xanthan gum or tobramycin, thereby inhibiting direct interactions between these compounds. The ionic species used for this purpose can be any pharmaceutically acceptable agent that dissociates into anions and cations at a pH in the range of 5 to 6, but is preferably sodium chloride, potassium chloride, or An inorganic electrolyte or organic buffer, such as sodium sulfate.

  Upon administration to the eye, the viscosity of the composition of the present invention is restored due to the breakdown of the complex between xanthan gum and tobramycin. That is, upon administration to the eye, the viscosity of the composition of the present invention increases, thereby increasing the length of time that the composition is retained on the corneal surface and enhancing the bioavailability of the eye To do. For example, as a result of this enhanced ocular bioavailability, a concentration of only 0.05 w / v% dexamethasone in the compositions of the present invention results in a 0. 0% in TOBRADEX® ophthalmic suspension. Biologically equivalent to a dexamethasone concentration of 1 w / v%.

  The present invention is also based in part on the discovery that the xanthan gum-based compositions of the present invention have excellent suspending properties. More specifically, the dexamethasone particles remain in suspension significantly longer in the compositions of the present invention compared to previous TOBRADEX® formulations. This improvement provides important advantages, especially for patients who occasionally forget or overlook the “shake well before use” instructions that apply to all ophthalmic suspension compositions.

The invention is also based, in part, on the discovery that xanthan gum is much more effective as a viscosity enhancer in the compositions of the invention when it is at least partially deacetylated. More specifically, xanthan gum undergoes slow deacetylation in aqueous solution. Such deacetylation has been determined to further reduce the pH of the composition, thereby increasing the ionic interaction between tobramycin and dexamethasone. These interactions initially cause a loss of viscosity and ultimately agglomeration and / or precipitation of xanthan gum and tobramycin. The inventors have determined that this problem can be overcome by deacetylating xanthan gum prior to inclusion in the composition of the present invention.
For example, the present invention provides the following items.
(Item 1)
A topical ophthalmic composition comprising:
0.1 to 0.5 w / v% tobramycin;
0.03 to 0.1 w / v% dexamethasone;
An aqueous ophthalmically acceptable vehicle comprising deacetylated xanthan gum at a concentration of 0.3 to 0.9%; and
One or more ionizable species , wherein the tobramycin and the deacetylation are maintained such that the in vitro viscosity of the composition is maintained within the range of 10 to 700 cp at a shear rate of 6 sec ⁻¹ and a temperature of 25 ° C. One or more ionizable species in an amount sufficient to limit ionic interactions between the xanthane gum
Including
A composition having a pH of 5 to 6.
(Item 2)
2. The composition of item 1, wherein the one or more ionizable species is selected from the group consisting of an inorganic electrolyte, an organic buffer, and combinations thereof.
(Item 3)
The one or more ionizable species is sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium citrate, potassium citrate, sodium phosphate, potassium phosphate, sodium acetate, sodium borate, boron Item 3. The composition according to Item 2, selected from the group consisting of acid / mannitol complex, boric acid / sorbitol complex, and combinations thereof.
(Item 4)
4. The composition of item 3, wherein the ionizable species is selected from the group consisting of sodium chloride, sodium sulfate, and combinations thereof.
(Item 5)
The composition of item 1, wherein the in vitro viscosity of the composition is in the range of 10 to 300 cp.
(Item 6)
6. The composition of item 5, wherein the composition has an initial viscosity of 25 to 175 cp.
(Item 7)
7. A composition according to item 6, wherein the composition has an in vitro / in vivo viscosity ratio of 0.01 to 0.65.
(Item 8)
8. The composition of item 7, wherein the one or more ionizable species is selected from the group consisting of an inorganic electrolyte, an organic buffer, and combinations thereof.
(Item 9)
The one or more ionizable species is sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium citrate, potassium citrate, sodium phosphate, potassium phosphate, sodium acetate, sodium borate, boron 9. The composition of item 8, selected from the group consisting of acid / mannitol complex, boric acid / sorbitol complex, and combinations thereof.
(Item 10)
10. The composition of item 9, wherein the ionizable species is selected from the group consisting of sodium chloride, sodium sulfate, and combinations thereof.
(Item 11)
Items 1-10, wherein the composition comprises tobramycin at a concentration of 0.3 w / v%, xanthan gum at a concentration of 0.6 w / v%, and dexamethasone at a concentration of 0.05 w / v%. A composition according to 1.
(Item 12)
Item 12. The composition according to Item 11, wherein the pH of the composition is about 5.7.
(Item 13)
A method of treating an inflammatory condition of the eye, wherein either an infection or a risk of infection exists, comprising topically applying a therapeutically effective amount of the composition of item 1 to the affected eye. ,Method.
(Item 14)
A method of treating an inflammatory condition of the eye, wherein either an infection or a risk of infection exists, comprising applying a therapeutically effective amount of the composition of item 11 to the affected eye. Method.

FIG. 1 is a graph showing the effect of sodium chloride concentration on the viscosity of a representative formulation of the present invention, as described in Example 3. FIG. 2 is a graph showing the effect of pH on the viscosity of a representative formulation of the present invention, as described in Example 3. FIG. 3 is a graph showing the effect of phosphate buffered saline having a pH of 7.4 on the viscosity of a representative formulation of the present invention, as described in Example 3. FIG. 4 is a graph showing the relationship between sodium chloride equivalent concentration and viscosity as described in Example 4. FIG. 5 is a graph showing ocular bioavailability for three representative formulations of the present invention compared to a prior art formulation as described in Example 5.

  The composition of the present invention comprises tobramycin at a concentration of 0.1 to 0.5 weight / volume percent (w / v%), preferably 0.3 w / v%; 0.03 to 0.1 w / v%, preferably Dexamethasone at a concentration of 0.05 w / v%; an aqueous medium comprising a deacylated xanthan gum at a concentration of 0.3 to 0.9 w / v%, preferably 0.6 w / v%; and from the date of manufacture Sufficient to limit the interaction between tobramycin and xanthan gum so that the viscosity of the suspension is maintained within the range of 10 to 700 centipoise (“cp”), preferably 10 to 300 cp, for 18 months Formulated as a sterile aqueous suspension containing a significant amount of ionic species. The suspension has a pH in the range of 5-6.

  The ionic species used in the present invention can be any pharmaceutically acceptable compound that dissociates into cationic and anionic components at a pH in the range of 5 to 6. The compound can be an inorganic compound or an organic compound, but is preferably an inorganic electrolyte, an organic buffer, or a combination thereof. Examples of such ionic species are sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium citrate, potassium citrate, sodium phosphate, potassium phosphate, sodium acetate, sodium borate, boric acid / Includes mannitol complex, boric acid / sorbitol complex, and combinations thereof.

  The total amount of ionizable species present in the composition of the present invention affects the viscosity of the composition. The composition is used to inhibit or eliminate ionic interactions between tobramycin and xanthan gum so as to avoid the formation of precipitates or clumps in the composition without exceeding the viscosity range specified above. A sufficient amount must contain one or more ionizable compounds. Thus, the composition is preferably in an amount sufficient to provide a composition having a viscosity at the time of manufacture of at least 10 cp (referred to herein as “initial viscosity”), preferably 15 cp or higher. The ionic species should be included in an amount sufficient to provide the most, and most preferably in an amount sufficient to provide an initial viscosity of 25 cp or higher. The initial viscosity of the composition is preferably in the range of 25 to 175 cp.

  The effect of ionic species on ionic strength and viscosity depends on the particular ionic species selected. For example, the effect of sodium sulfate on ionic strength and viscosity is about 5.3 times stronger than that of sodium chloride. The relative effects of different ionized salts can be determined by routine experimentation within the pH range, tobramycin concentration, xanthan gum concentration, and viscosity range specified herein. As far as the composition of the present invention is concerned, the only critical parameter is that the amount of ionizable salt does not increase the viscosity of the composition above 700 cp, or more preferably above 300 cp, or tobramycin and xanthan gum precipitation or That is enough to avoid the formation of agglomerates.

  The viscosity of the ophthalmic suspensions of the present invention may increase somewhat over time due to the loss of moisture from the composition. The suspension is therefore formulated to maintain its viscosity within the range of 10 to 700 cp, preferably 10 to 300 cp, for 18 months. The viscosity of the composition of the present invention from the time of manufacture to administration to the eye is referred to herein as the “in vitro viscosity” of the composition.

The viscosity values represented herein are based on the use of a Brookfield viscometer at a shear rate of about 6 sec ⁻¹ and a temperature of 25 ° C. A shear rate of about 6 sec ⁻¹ is spindle CP-52 at 3 revolutions per minute (“rpm”), spindle CP-51 at 1.5 rpm, spindle CP-42 at 1.5 rpm, or 3 rpm. This can be achieved by using spindle CP-41. Spindles CP-52 and CP-51 are typically used to measure viscosities greater than 300 centipoise (“cp”). Spindles CP-42 and CP-41 are generally used to measure viscosities typically less than 300 cp.

  As indicated above, the viscosity of the composition of the present invention is restored upon administration to the eye, and the viscosity of the composition after topical ocular administration is maintained during storage in a container, after manufacture, and to the eye. Higher than the viscosity before administration. This increase is caused by a shift in the pH and ionic strength of the composition when a small amount (ie 1 or 2 drops) comes into contact with the tears of the human eye (ie tears). That is, the electrolyte in tear fluid increases the pH and ionic strength of the composition, which increases the viscosity of the composition, thereby enhancing the retention and bioavailability of the composition in the eye.

  It is not readily possible to measure the viscosity of the composition of the invention in vivo, ie after administration to the eye. However, the simulated in vivo viscosity model described below can be utilized to assess the effect of tears on the viscosity of the compositions of the invention in vivo. The viscosity of the composition of the invention in vivo (ie after topical administration to the eye) is simulated by adding a small amount of the following phosphate buffered saline to the composition:

上記で記載したリン酸緩衝化食塩水（「ＰＢＳ溶液」）の、本発明の組成物への追加は、組成物の粘度に対する涙液の影響をシミュレートする。１対１０の比で、すなわち１０部の本発明のトブラマイシン／デキサメタゾン／キサンタンガム組成物あたり、１部のＰＢＳ溶液の比で、そのＰＢＳ溶液をその組成物に加える。

The addition of the phosphate buffered saline described above (“PBS solution”) to the composition of the present invention simulates the effect of tears on the viscosity of the composition. The PBS solution is added to the composition in a ratio of 1 to 10, ie, a ratio of 1 part PBS solution per 10 parts of the tobramycin / dexamethasone / xanthan gum composition of the invention.

  For the purposes of this specification, it is assumed that the actual in vivo viscosity of the composition of the present invention is the same as the simulated in vivo viscosity of such composition. Thus, all references herein to “in vivo viscosity” are interchangeable with “simulated in vivo viscosity”. All references to “simulated in vivo viscosity” and “in vitro / in vivo viscosity ratio” herein are based on the use of the viscosity measurement procedure described above and a simulated in vivo viscosity model.

  The ratio of the viscosity of the composition of the present invention before administration to the eye to the viscosity of the same composition after administration of the drop to the eye is referred to herein as the “in vitro / in vivo viscosity ratio”. The compositions of the present invention preferably have an in vitro / in vivo viscosity ratio in the range of 1/100 to 65/100 or 0.01 to 0.65.

  The foregoing ratio can also be expressed in terms of percentage, i.e., in vitro viscosity divided by simulated in vivo viscosity multiplied by 100. Thus, the aforementioned range for the ratio of in vitro viscosity to simulated in vivo viscosity is equivalent to the range where the in vitro viscosity of the composition of the present invention is 1% to 65% of the simulated in vivo viscosity of the composition. is there.

  Relative viscosity values can also be expressed as the ratio of in vivo viscosity to in vitro viscosity. The composition of the present invention preferably has an in vivo / in vitro viscosity ratio of 100/1 to 100/65, which is a range where the in vivo viscosity of the composition is about 1.5 to 100 times higher than the in vitro viscosity of the composition. Is equivalent to

  Tobramycin, dexamethasone, and xanthan gum utilized in the sterile ophthalmic suspension of the present invention are known compounds and are readily available from a variety of sources. Non-salt forms of dexamethasone are preferred, such as dexamethasone alcohol. However, salt forms of dexamethasone, such as dexamethasone sodium phosphate, can also be used. When choosing a dexamethasone salt, it is contributed by the ions formed during the dissociation of the dexamethasone salt in determining the concentration of ionizable species required to control the ionic interaction between tobramycin and xanthan gum. Ionic strength must be considered.

  Pharmaceutical grade xanthan gum should be used. The xanthan gum should preferably be polished and filtered before use. The selection of an appropriate filtration technique can be readily determined by one skilled in the art. As discussed above, the xanthan gum must be deacetylated to enhance the stability of the suspension of the present invention during storage. The acetate content of xanthan gum is based on acetate bound to xanthan gum. The acetate content is typically expressed as a percent of xanthan gum based on weight. Xanthan gum raw materials typically have up to 6% bound acetate. The deacetylated xanthan gum used in the present invention comprises less than 2% bound acetate, and preferably less than 1% bound acetate. The importance of deacetylating xanthan gum and the process by which deacetylation can be performed are further illustrated in Examples 1 and 2 below.

  As indicated above, the composition of the present invention has a pH of 5 to 6. The composition also has an ophthalmologically acceptable osmotic pressure, which is typically in the range of 200 to 400 milliosmoles per kilogram of water (mOsm / kg). When selecting an appropriate buffer to maintain the pH of the composition in the specified range of 5 to 6, and / or when selecting an osmotic pressure regulator, such agents can be ionized by the composition. The effect on the content of the species must be considered. For example, if sodium chloride added for the purpose of adjusting osmotic pressure increases the ionic species concentration beyond an acceptable level (ie compared to the target viscosity value), all or part of the sodium chloride is It may be necessary to replace a nonionic osmotic pressure regulator such as propylene glycol.

  The compositions of the present invention may include a variety of other ingredients typically used in ophthalmic pharmaceutical compositions, such as antimicrobial preservatives (eg, benzalkonium chloride) and wetting agents. The composition is preferably formulated and packaged as a multi-dose product, but may be formulated without conventional antimicrobial preservatives and packaged in sealed unit dose vials.

  The compositions of the present invention are useful for the treatment of inflammatory conditions in the eye where either infection or risk of infection exists. As used herein, the term “treatment” includes both active treatment of an existing condition and prophylactic treatment of patients at risk of developing a condition (eg, infection). The compositions of the present invention may cause ocular inflammation associated with eye damage resulting from trauma, and ocular surgical procedures (eg, cataract surgery, retinal surgery, LASIK surgery) and intraocular injections (eg, post-ocular injection, posterior strength) It is particularly useful for the treatment of inflammation associated with superior juxtacular injection and anterior near scleral injection.

  Such treatment can be performed by applying a small amount (eg, 1 to 2 drops) of the composition of the invention to the affected eye or both of the patient 2 to 4 times per day. However, both dose and frequency of administration can be varied by the clinician.

  It is contemplated that a small number of selected therapeutic agents other than tobramycin can interact with xanthan gum in substantially the same manner as tobramycin and can be used in the present invention. Without being bound by theory, it is believed that therapeutic molecules that have more than one positive or cationic charge in the molecule can interact with xanthan gum in the same manner as tobramycin. Further, without being bound by theory, it is believed that a significant portion of fluoroquinolone therapeutics can interact with xanthan gum in a manner similar to tobramycin. As one example, the inventors use ionic species to control the interaction between moxifloxacin and xanthan gum, resulting in an in vitro / in vivo viscosity ratio substantially similar to that discussed above. I found it to get.

Example 1
The preparation of a tobramycin / dexamethasone / xanthan gum formulation using non-deacetylated xanthan gum is described below. The stability of the resulting formulation was also evaluated as described below.

Preparation of xanthan gum stock solution Hot water was added to the container. Xanthan gum was weighed and slowly added to the container with mixing. The temperature was adjusted to 60 ° C. and xanthan gum and water were mixed until uniform. Purified water was added to bring the composition to the final target weight and mixed until uniform. The temperature was raised to 70 ° C. before filtering through a suitable polishing filter, eg a 1.2 μm filter.

Preparation of Tobramycin / Dexamethasone Formulation Using Xanthan Gum Stock Solution The amounts of tobramycin, sodium chloride, boric acid and disodium edetate specified in Table 1A below were added to a portion of purified water and dissolved. Hydrochloric acid or sulfuric acid was added to lower the pH. Tyloxapol and dexamethasone were added as a slurry or powder. A batch amount of xanthan gum stock solution was added and mixed well. 1N hydrochloric acid or 1N sulfuric acid was added to reach the target pH. Purified water was added to final volume and mixed well. The viscosity of the resulting formulation was measured at a shear rate of 6 sec- ¹ . The respective viscosity values are shown in Table 1A below.

表１Ａに記載した処方物に、加速安定性試験を行った。下記の表１Ｂに示すように、脱アセチル化されていないキサンタンガムを用いて調製した処方物のｐＨおよび粘度は、保存のときに低下する。これは最終的にその処方物を使用不可能にする。具体的には、その懸濁液の均一な性質が失われた。

The formulations described in Table 1A were subjected to accelerated stability testing. As shown in Table 1B below, the pH and viscosity of formulations prepared with non-deacetylated xanthan gum decrease upon storage. This ultimately renders the formulation unusable. Specifically, the uniform properties of the suspension were lost.

実施例２
脱アセチル化キサンタンガムの使用を含む、本発明の原理によるトブラマイシン／デキサメタゾン処方物の調製を、下記で説明する。

Example 2
The preparation of a tobramycin / dexamethasone formulation according to the principles of the present invention, including the use of deacetylated xanthan gum, is described below.

Preparation of xanthan gum stock solution and pretreatment with base Hot water was added to the container. Xanthan gum was weighed and slowly added to the container with mixing. 2.5 ml of 1N NaOH or equivalent per gram of xanthan gum was added and then mixed for 20 minutes. Then 1.66 ml of 1N HCl or equivalent per gram of xanthan gum was added. Purified water was added to adjust to the target weight, followed by mixing for 15 minutes. The deacetylated xanthan gum was then filtered through a suitable filter, such as a 1.2 μm filter.

Preparation of Tobramycin / Dexamethasone Formulation Using Pretreated Xanthan Gum Stock Solution The specified amounts of tobramycin, sodium chloride, sodium sulfate, disodium edetate, and propylene glycol are added to a batch of purified water followed by tyloxapol and Dexamethasone was added as a slurry or powder. The pH was adjusted to slightly higher than the target pH using 1N hydrochloric acid. The deacetylated xanthan gum stock solution described above was then added and the resulting suspension was mixed well. The pH was adjusted to the target level with HCl and / or NaOH solution, and the viscosity of the formulation was measured.

下記の表２Ｂに示すように、脱アセチル化キサンタンガムを含む処方物１０８５３６のｐＨの値は、実施例１の処方物１０７２０１および１０７２０９と異なり、保存のときにかなり安定であった。結果として、処方物１０８５３６の粘度は、実施例１のように減少するのではなく、安定なままであるか、または増加した。

As shown in Table 2B below, the pH value of formulation 108536 containing deacetylated xanthan gum was different from formulations 107201 and 107209 of Example 1 and was fairly stable upon storage. As a result, the viscosity of formulation 108536 remained stable or increased rather than decreased as in Example 1.

実施例３
本発明の組成物の初期粘度に対するトブラマイシンの影響、およびその組成物を眼に投与したときの粘度の回復を、本明細書中でさらに説明する。上記の表２Ａで記載した処方物番号１０８５３６の異なるロットであり、そして本発明の組成物の代表的なものである、下記の表３Ａに示す処方物を、脱アセチル化キサンタンガムを用いて調製した。その処方物の初期粘度を、６ｓｅｃ^−１のせん断速度で測定し、そして４２ｃｐであると決定した。

Example 3
The effect of tobramycin on the initial viscosity of the compositions of the present invention and the restoration of viscosity when the composition is administered to the eye are further described herein. The formulations shown in Table 3A below, which are different lots of formulation number 108536 described in Table 2A above and are representative of the compositions of the present invention, were prepared using deacetylated xanthan gum. . The initial viscosity of the formulation was measured at a shear rate of 6 sec ⁻¹ and determined to be 42 cp.

トブラマイシンの省略以外は表３Ａに示した処方物と同一である２番目の処方物も調製した。その２番目の処方物は、８３６ｃｐの初期粘度を有すると決定した。

A second formulation was also prepared that was identical to the formulation shown in Table 3A except for omission of tobramycin. The second formulation was determined to have an initial viscosity of 836 cp.

  A slight increase in pH or the addition of a small amount of ions (eg sodium chloride, phosphate buffer) suppresses ionic interactions between tobramycin and xanthan gum, thereby restoring the viscosity of the formulation. This phenomenon is shown graphically in FIGS. FIG. 1 shows that the viscosity of the formulation described in Table 3A increases from 42 cp to over 1,000 cp when 0.2 g of sodium chloride is added to 100 mL of the formulation. FIG. 2 shows that the viscosity of the formulation increases from 42 cp at pH 5.7 to over 1,100 cp when the pH is adjusted upward to 6.2 and to 1,300 cp when the pH is 6.4. It shows that. FIG. 3 shows that the viscosity of the formulation increases from 42 cp to 1,059 cp when 10 mL of the PBS solution described above is added to 100 mL of the suspension.

  When tobramycin was removed from the formulation shown in Table 3A, the viscosity of the formulation did not increase after mixing with PBS solution. Specifically, a modified version of the formulation without tobramycin was determined to have a viscosity of 667 cp when 10 ml of phosphate buffered saline was added to 100 ml of the formulation. In other words, the viscosity of the modified formulation actually decreased from an initial viscosity of 836 cp to a simulated in vivo viscosity of 667 cp after addition of phosphate buffered saline.

Example 4
As discussed and explained below, the viscosity of the composition of the present invention is the ionic strength and pH of the composition, and 0.1 to 0.5 w / v% and 0.3 to 0.9 w / v% respectively Affected by the amount of tobramycin and xanthan gum selected within the stated range. The formulations and associated data shown in Tables 4A-4E are provided to further illustrate and explain the interaction of these factors.

Comparison of the viscosity values of formulations A to D and their respective compositions shows the effect of tobramycin on the viscosity of compositions containing xanthan gum at a concentration of 0.6 w / v%. Specifically, Formulation A containing tobramycin at a concentration of 0.3 w / v% has an initial viscosity of 15 centipoise (“cp”), while it is identical to Formulation A except for the lack of tobramycin Product C has an initial viscosity of 919 cp. Thus, the presence of tobramycin in Formulation A contributes to a decrease in the viscosity of the composition. This effect of tobramycin is also evident based on a comparison of formulations B and D. (Formulations A and B do not contain dexamethasone, but others are examples of representative tobramycin / dexamethasone compositions of the present invention. Formulations C and D are provided for comparative purposes and the present invention. It is not a representative example of the composition.)
The viscosity of Formulation A is stabilized by including 23.9 mM (0.34%) sodium sulfate, a preferred ionizable species. Formulation A also contains about 10 mM sodium chloride because the deacetylated xanthan gum stock solution contains sodium chloride formed by the addition of sodium hydroxide and hydrochloric acid during the deacetylation process. The ionic contributions from EDTA (disodium edetate) and benzalkonium chloride are small because their concentrations are very low.

  The viscosity of Formulation B is stabilized by including 138.2 mM sodium chloride, which is also a preferred ionizable species.

  The viscosity of the composition of the present invention can be stabilized using sodium chloride or sodium sulfate. However, the concentration of sodium sulfate required is much lower than that of sodium chloride. About 1 mM sodium sulfate is equivalent to 5.3 mM sodium chloride. This is illustrated by Examples A, B, and E through L.

  Formulations A, B and E to L viscosities versus sodium chloride equivalent ion concentration are plotted in FIG. The sodium chloride equivalent ion concentration for these formulations is defined as “sodium chloride concentration (mM) +5.3 sodium sulfate concentration (mM)”. The viscosity of a formulation containing 0.3% tobramycin and 0.6% xanthan gum increases as the sodium chloride equivalent ion concentration increases. Its viscosity is in the preferred range of 10 to 300 cp for a sodium chloride equivalent ion concentration range of 134 to 150 mM.

  Other ionizable species may be used in place of sodium chloride or sodium sulfate. Preferred ionized salts are sodium chloride, sodium sulfate, sodium citrate, sodium phosphate, sodium borate, sodium acetate, potassium chloride, calcium chloride, and magnesium chloride. Different ionized species require different coefficients (5.3 for sodium sulfate) to determine the sodium chloride equivalent concentration. This factor can be determined by making samples with different ratios of sodium chloride and other salts. The viscosity results of those samples can then be analyzed to determine a factor for determining the sodium chloride equivalent concentration. This coefficient is higher than that of salts with multivalent ions.

  For a given active moiety and its concentration, the sodium chloride equivalent ion concentration range that produces a relatively low viscosity depends on the pH and xanthan gum concentration. For a 0.3% tobramycin solution, formulations M and N have higher sodium chloride equivalents to produce a similar viscosity at a lower pH of 5.5 compared to at a pH of 5.75. Indicates that ion concentration is required.

  Formulations O, P and Q show that lower sodium chloride equivalent ion concentrations are required as xanthan gum concentration increases from 0.6% to 0.9% at a fixed pH (5.5) .

実施例５
ウサギ生物学的利用能試験結果
本発明の３つの代表的な組成物の眼の生物学的利用能を、ＴＯＢＲＡＤＥＸ（登録商標）（トブラマイシン０．３％／デキサメタゾン０．１％）眼用懸濁液と比較して評価した。本発明の組成物の処方物を、下記の表５Ａに示す。ＴＯＢＲＡＤＥＸ（登録商標）眼用懸濁液の処方物は、米国特許第５，１４９，６９４号の実施例１に示される。

Example 5
Rabbit Bioavailability Test Results Ocular bioavailability of three representative compositions of the present invention was determined by TOBRADEX® (tobramycin 0.3% / dexamethasone 0.1%) ocular suspension. Evaluation was made in comparison with the liquid. The formulation of the composition of the present invention is shown in Table 5A below. A formulation of TOBRADEX® ophthalmic suspension is shown in Example 1 of US Pat. No. 5,149,694.

それぞれの組成物を、雄Ｎｅｗ Ｚｅａｌａｎｄウサギの両眼に投与した。処方物の投与後、０．５、０．７５、１、２、および３時間において、水性体液サンプルを両目から採取し、そしてデキサメタゾンの濃度を、下記で記載するＬＣ−ＭＳ／ＭＳ手順を用いて決定した。

Each composition was administered to both eyes of a male New Zealand rabbit. At 0.5, 0.75, 1, 2, and 3 hours after administration of the formulation, aqueous bodily fluid samples were taken from both eyes, and dexamethasone concentrations were determined using the LC-MS / MS procedure described below. Decided.

  Dexamethasone concentration in rabbit aqueous body fluids was measured using an approved HPLC tandem mass spectrometry (HPLC / SM / MS) method. In this procedure, to a 25.0 microliter aliquot of aqueous body fluid was added beclomethasone as an internal standard and extracted with methyl-t-butyl ether. The organic layer was evaporated to dryness and reconstituted with 20:80 10 mM ammonium formate: methanol and a reverse phase HPLC column under gradient-free conditions with a mobile phase of the same composition used to reconstitute the sample. Inject. Cation electrospray ionization is performed on the column effluent and collisional fragmentation is performed on the protonated molecular ions of dexamethasone and beclomethasone. Multiple reaction monitoring of the dexamethasone and beclomethasone transitions at m / z 393.1 → 373.4 and 409.3 → 391.4, respectively, allows specific detection. The operating range of the procedure is 1.00 to 200 ng / mL.

The average aqueous fluid concentration versus time for dexamethasone is plotted in FIG. The maximum concentration (C _max ) and area under the curve (AUC) value of dexamethasone in aqueous body fluid are shown in Table 5B below:

前述の結果は、デキサメタゾンをそれぞれ０．０５％および０．１％の濃度で含む、本発明のキサンタンベースの処方物の水性体液濃度は、０．１％のデキサメタゾンを含むＴＯＢＲＡＤＥＸ（登録商標）懸濁液のものよりはるかに高いことを示す。これらの結果は、本発明の組成物の優れた生物学的利用能を示す。

The above results show that the aqueous fluid concentration of the xanthan-based formulations of the present invention containing dexamethasone at concentrations of 0.05% and 0.1%, respectively, is a TOBRADEX® suspension containing 0.1% dexamethasone. It is much higher than that of the suspension. These results indicate the excellent bioavailability of the composition of the present invention.

Claims (15)

A topical ophthalmic composition comprising:
0.1 to 0.5 w / v% tobramycin;
0.03 to 0.1 w / v% dexamethasone;
An aqueous ophthalmically acceptable vehicle comprising deacetylated xanthan gum at a concentration of 0.3 to 0.9%; and one or more ionizable species, wherein the composition has an in vitro viscosity of 6 sec. An amount of 1 sufficient to limit the ionic interaction between the tobramycin and the deacetylated xanthan gum such that it is maintained in the range of 10 to 700 cp at a shear rate of ⁻¹ and a temperature of 25 ° C. Including one or more ionizable species,
5 have a pH of 6, dehydration acetylated xanthan gum containing bound acetate of less than 2%, the composition.   The composition of claim 1, wherein the one or more ionizable species is selected from the group consisting of an inorganic electrolyte, an organic buffer, and combinations thereof.   The one or more ionizable species is sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium citrate, potassium citrate, sodium phosphate, potassium phosphate, sodium acetate, sodium borate, boron 3. The composition of claim 2, wherein the composition is selected from the group consisting of an acid / mannitol complex, a boric acid / sorbitol complex, and combinations thereof.   4. The composition of claim 3, wherein the ionizable species is selected from the group consisting of sodium chloride, sodium sulfate, and combinations thereof.   The composition of claim 1, wherein the in vitro viscosity of the composition is in the range of 10 to 300 cp.   6. The composition of claim 5, wherein the composition has an initial viscosity of 25 to 175 cp.   The composition of claim 6, wherein the composition has an in vitro / in vivo viscosity ratio of 0.01 to 0.65.   8. The composition of claim 7, wherein the one or more ionizable species is selected from the group consisting of an inorganic electrolyte, an organic buffer, and combinations thereof.   The one or more ionizable species is sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium sulfate, sodium citrate, potassium citrate, sodium phosphate, potassium phosphate, sodium acetate, sodium borate, boron 9. The composition of claim 8, wherein the composition is selected from the group consisting of an acid / mannitol complex, a boric acid / sorbitol complex, and combinations thereof.   10. The composition of claim 9, wherein the ionizable species is selected from the group consisting of sodium chloride, sodium sulfate, and combinations thereof.   11. The composition of any one of the preceding claims, wherein the composition comprises tobramycin at a concentration of 0.3 w / v%, xanthan gum at a concentration of 0.6 w / v%, and dexamethasone at a concentration of 0.05 w / v%. The composition according to item.   The composition of claim 11, wherein the pH of the composition is about 5.7.   2. The composition of claim 1, for treating an inflammatory condition of the eye, wherein either an infection or a risk of infection exists, wherein the therapeutically effective amount of the composition is local to the affected eye. A composition, characterized in that it is applied.   12. The composition of claim 11 for treating an inflammatory condition of the eye in which either infection or risk of infection exists.   15. A composition according to any one of the preceding claims, wherein the deacetylated xanthan gum comprises less than 1% bound acetate.

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