MXPA00005554A - Trovafloxacin oral suspensions - Google Patents
Trovafloxacin oral suspensionsInfo
- Publication number
- MXPA00005554A MXPA00005554A MXPA/A/2000/005554A MXPA00005554A MXPA00005554A MX PA00005554 A MXPA00005554 A MX PA00005554A MX PA00005554 A MXPA00005554 A MX PA00005554A MX PA00005554 A MXPA00005554 A MX PA00005554A
- Authority
- MX
- Mexico
- Prior art keywords
- amount
- trovafloxacin
- suspension
- weight
- crystal
- Prior art date
Links
- 239000000725 suspension Substances 0.000 title claims abstract description 105
- WVPSKSLAZQPAKQ-CDMJZVDBSA-N Trovafloxacin Chemical compound C([C@H]1[C@@H]([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F WVPSKSLAZQPAKQ-CDMJZVDBSA-N 0.000 title claims abstract description 63
- 229960000497 trovafloxacin Drugs 0.000 title claims abstract description 52
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- 238000007792 addition Methods 0.000 claims description 23
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- 239000003795 chemical substances by application Substances 0.000 claims description 17
- DYNZICQDCVYXFW-AHZSKCOESA-N trovafloxacin mesylate Chemical compound CS(O)(=O)=O.C([C@H]1[C@@H]([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F DYNZICQDCVYXFW-AHZSKCOESA-N 0.000 claims description 17
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Abstract
This invention relates to suspensions for oral administration comprising novel trovafloxacin zwitterionic crystals, and processes for preparing such crystals. This invention further relates to other pharmaceutical compositions comprising these novel crystals, and to methods of using these suspensions, and these novel crystals in such other dosage forms, for treating bacterial infections in mammals.
Description
ORAL SUSPENSIONS OF TROVAFLOXACINO
FIELD OF THE INVENTION
This invention provides oral suspensions comprising the antibiotic trovafloxacin. This invention also provides new zwitterionic crystals of trovafloxacin. In addition, this invention provides new methods for preparing such crystals. In addition, this invention provides methods for employing these suspensions, and these new crystals, in other dosage forms, for treating bacterial infections.
BACKGROUND OF THE INVENTION
Trovafloxacin is a well-known quinolonic antibacterial of Formula I
Trovafloxacin has the chemical name: acid (1a, 5a, 6a) -7- (6-amino-3-azabicyclo [3.1.0] ex-3-yl) -1 - (2,4-difluorophenyl) -6- fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridin-3-carboxylic acid.
Trovafloxacin, and related salts and derivatives thereof, and their antibacterial activities, are disclosed in U.S. Pat. Nos. 5,164,402; 5,229,396; 5,266,569; 5,391,763; and 5,763,454; and in international PCT applications number PCT / US95 / 07211, published as WO 96/39406 and number IB / 96/00756, published as WO 97/07800. Trovafloxacin is available as a trovafloxacin salt by particular acid addition, namely trovafloxacin mesylate (Tablet) for oral administration, and as alatrofloxacin mesylate (prodrug) for intravenous administration (Physicians' Desk Reference (PDR)). , 53rd edition, Medical Economics Co., Inc., Montvale, NJ, pages 2414-2421 (1999) Chemically, as discussed above, trovafloxacin mesylate, a fluoronaphthyridone related to fluoroquinolone antibacterials, is monomethanesulfonate from (1a, 5a, 6a) -7- (6-amino-3-aza-bicyclo [3.1.0] hex-3-yl) -1- (2,4-difluorophenyl) -6-fluoro-1, 4 --dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, of Formula III
(III).
The Tablets are available as blue, film-coated, 100 mg and 200 mg tablets (trovafloxacin equivalent), and also contain microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and magnesium stearate. The coating of the tablet is a mixture of hydroxypropylcellulose, hydroxypropylmethylcellulose, titanium dioxide (TiO2), polyethylene glycol, and aluminum lacquer FD &C blue No. 2. Oral dosage forms of pharmaceutical agents are generally preferred because they allow for easy administration and Low cost, which generally encourages acceptance by the patient. However, some pharmaceutical agents, for example penicillin, ampicillin and erythromycin, exhibit the undesirable characteristic of bitter taste, either during or immediately after oral administration, which generally decreases patient acceptance, in particular in pediatric patients. Generally, sweetening agents such as sucrose as well as flavoring agents are added to said orally administered pharmaceutical compositions to mask said bitter taste and aftertaste. Other taste masking agents are known, such as those described in U.S. Pat. No. 5,633,006, which describes the use of an alkaline earth oxide in a pharmaceutical composition in liquid suspension, to mask the bitter taste and / or aftertaste of the bitter taste of a bitter pharmaceutical agent. Alternatively, it is also known in the art to mask such bitterness by microencapsulating the unpleasant taste agent within a coating of ethyl cellulose, or other cellulose derivatives, to provide chewable, masked taste dosage forms. As discussed above for some pharmaceutical agents, trovafloxacin solutions have also been identified as having the undesirable characteristic of bitter taste either during or immediately after oral administration. The Tablets contain a salt of trovafloxacin, not a zwitterion of trovafloxacin, and are suitably buffered to overcome these taste problems.; however, tablets are not always the preferred dosage form, for example for pediatric patients, and for patients who are unable to swallow the tablets. This invention overcomes the taste problems associated with such trovafloxacin solutions by providing liquid suspensions comprising novel zwitterionic trovafloxacin crystals which, in part due to their unexpected physical and chemical stability, allow the preparation of substantially homogeneous suspensions. Providing such substantially homogeneous suspensions allows accurate dosing. In addition, providing homogeneous suspensions that can be easily poured also facilitates oral administration, since, for example, it is not necessary to simultaneously consume any other fluid, as is typically done with a tablet dosage form. In addition, a certain population of patients, specifically pediatric patients, are generally more receptive to a fluid that they can see and swallow, or mix with food (when appropriate), than a tablet or a needle. Moreover, the caregiver, for example the father or a doctor, who administers the medicine to a pediatric patient in the form of a liquid reduces both the fears of a choking (in the case of the tablet) and the dangers of handling a needle and a syringe (in the case of an injection). It is also easier to administer to a large number of patients at one time, for example no fluid is needed to pass the tablet, and generates less waste, for example the container of a suspension versus sterile syringes and individual needles for each patient . This invention is also not intended to deny the usefulness of dissolving a tablet in a pharmaceutically acceptable buffer, and administering it orally; however, the liquid suspension pharmaceutical compositions of this invention provide the advantage that they are ready for immediate administration as they are marketed. Moreover, because of the aforementioned physical and chemical properties of the new zwitterionic trovafloxacin crystals that are included in the suspensions of this invention, these suspensions, unlike suspensions in general, are resuspended very quickly when agitated, and return to sediment very slowly, both properties that together allow a desirable homogeneity over a period of time suitable for oral administration. In U.S. Pat. No. 5,763,454 mentioned above describes a new crystalline form of a salt of trovafloxacin, ie trovafloxacin mesylate, methods for employing the compound for the treatment of bacterial infections in mammals, especially humans, and pharmaceutical compositions comprising the compound. In contrast, in the aforementioned WO 97/07800 new zwitterionic crystalline forms of trovafloxacin (instead of salts) of Formula II are described.
selected from the group consisting of its non-hygroscopic crystalline polymorph (polymorph Pl) and its hygroscopic polymorph (polymorph Pll), and a pentahydrate, methods for its preparation, for example from a metastable form of zwitterion of trovafloxacin (an acicular form), and methods for treating bacterial infections in mammals by administering said compounds, for example in the form of a suspension. A tablet, dissolved in a suitable aqueous buffer, for example sodium bicarbonate, contains crystals of the acicular form. This invention provides additional new zwitterionic crystals of trovafloxacin, specifically a sheet form and a rod shape, both four sided and six sided, the six sided shape being preferable. In an aqueous medium, the acicular shape known above, as well as the new forms of sheet and four-sided rod, are all transformed, over the course of various periods of time, into the new six-sided rods. This invention also provides novel methods for preparing the sheet and rod crystals of this invention from the above-mentioned known acicular form. This invention also provides new methods for the interconversion between the sheet and rod forms. In addition, the crystals of the acicular form, prepared by dissolving a Tablet in a suitable aqueous buffer, will eventually become the six-sided rod form. The oral administration of suspensions comprising these new zwitterionic trovafloxacin crystals does not produce appreciable bitter taste or aftertaste. In addition, once resuspended, these crystals tend to remain in suspension, rather than to sediment, which allows a more accurate dosage. Moreover, the suspensions of this invention provide a more desirable dosage form for certain patients, for example children and the elderly. This invention also provides methods for treating bacterial infections by administering such crystals or suspensions comprising such crystals.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is based on the discovery that a liquid pharmaceutical composition or suspension comprising a new zwitterion crystalline form of trovafloxacin of a sheet form, or of a four-sided rod shape, or of a rod form of six sides, and preferably of a six-sided rod shape, can be administered orally without any taste or appreciable bitter aftertaste. These suspensions provide the patient with an alternative dosage form, in addition to the tablet or the alatrofloxacin mesylate injection (prodrug). In a first aspect, this invention provides a new crystalline zwitterion of trovafloxacin of a six-sided rod shape, characterized in that it has the following X-ray wet cake diffraction pattern:
As described above, when a Tablet is dissolved in a suitable aqueous buffer (an aqueous buffer that adjusts the pH to a value from about pH 4 to about pH 11, for example sodium bicarbonate), which results in zwitterion of trovafloxacin in an acicular form, these needles will be converted over time, for example weeks, into the new six-sided rods. However, since a dissolved tablet will generally be prepared as such for immediate oral administration, and while the tablet lacks preservatives, sufficient time may probably not elapse to allow the conversion of such needles to the six-sided rods. , before oral administration. In a second aspect, this invention provides a novel zwitterion / crystalline hydrate of trovafloxacin of a four-sided rod shape, characterized by the following crystalline parameters derived from the standard crystallographic analysis of single-crystal by X-rays: formula -C2oH15N4? 3F3 (zwitterion) , C2oHi N4? 3F3"Na + • 4.75 H2O (512.9); cell dimensions - a = 11, 202 (2) A, b = 15.2630 (1) A, c = 15.8910 (1) A, a = 103.24 (1) °, ß = 110.02 (1, ? = 108.71 (1) °, V = 2235.8 (4) A3; and space group - P1 bar. In a third aspect, this invention provides a new crystalline zwitterion of trovafloxacin of a sheet form, characterized by having the following X-ray powder diffraction pattern.
In a fourth aspect, this invention provides new methods for preparing the rods and sheets mentioned above. The rods and sheets can be prepared from the aforementioned needles. The rods can be prepared from the needles directly, or the needles can first be converted into sheets. The sheets can also be prepared from the rods. This invention provides new methods for preparing the six-sided rods from the needles, which, in sequence, comprise the steps of: preparing an aqueous solution of a trovafloxacin salt by the addition of acids; precipitating the zwitterion from said salt by adjusting the pH of said aqueous solution to a pH of about pH 4 at about pH 10; and maintaining said solution at room temperature for a period of time. A preferred pH is from about pH 4 to about pH 7. A preferred amount of trovafloxacin salt by acid addition is from about 10 mg / ml to about 200 mg / ml. A particularly preferred amount of trovafloxacin salt by acid addition is from about 35 mg / ml to about 120 mg / ml. An especially preferred amount of trovafloxacin salt by addition of acids is about 100 mg / ml. The salt of trovafloxacin is added by the addition of acids to water, at a preferred temperature of about 5 ° C to about 40 ° C; at a particularly preferred temperature of about 15 ° C to about 30 ° C; and at an especially preferred temperature of about 25 ° C to about 30 ° C. This invention provides other methods for preparing the six-sided rods from the needles, passing through the sheets, adding heating and cooling operations to the processes described immediately above. More specifically, the methods comprise, in sequence, the steps of: preparing an aqueous solution of a trovafloxacin salt by the addition of acids; precipitating the zwitterion from said salt by adjusting the pH of said aqueous solution to a pH of about pH 4 at about pH 10, at a first temperature of at least about 70 ° C; and cooling said solution to a second temperature below about 70 ° C. A preferred pH is from about pH 4 to about pH 7. This invention still provides other methods for preparing the six-sided rods from the needles, through the four-sided sheets and rods, which comprise preparing an aqueous solution. of a trovafloxacin salt by the addition of acids; precipitating the zwitterion from said salt by adjusting the pH of said aqueous solution to a pH of about pH 9 to about pH 12, at a first temperature of at least about 70 ° C; and cooling said solution to a second temperature below about 70 ° C. After said cooling, and before said period of time elapses to generate the six-sided rods mentioned above (for example from about 2 days to about 5 days), the crystals are converted from sheets into the new four-sided rods ( for example from about 12 hours to about 36 hours). A preferred pH is about pH 9.5. This invention also provides for sheet conversion of any of the six-sided rod preparations provided herein, by heating the solutions comprising the sheets to a temperature of at least about 70 ° C. An even less bitter taste or aftertaste has been described for crystal preparations of this invention adjusted to a final pH of from about pH 6 to about pH 8, and preferably about pH 7. Therefore, it is preferred that the resulting crystal preparations comprise the additional operation of, when necessary, adjusting the pH to a value from about pH 6 to about pH 8, and preferably about pH 7. In a fifth aspect, this invention provides pharmaceutical compositions comprising a new zwitterionic trovafloxacin crystal of the rod forms four-sided or six-sided, either of sheet form, and a pharmaceutically acceptable carrier, vehicle or diluent. In a particularly preferred embodiment, this invention provides pharmaceutical compositions for oral administration. In an especially preferred embodiment, this invention provides liquid pharmaceutical compositions for oral administration. In another especially preferred embodiment of this fifth aspect, this invention provides suspensions for oral administration comprising an antibacterial effective amount of a new zwitterionic trovafloxacin crystal of the sheet form, or of the four-sided rod form or of the six-sided rod form, and a pharmaceutically acceptable carrier, vehicle or diluent, wherein pharmaceutically acceptable means that the carrier, diluent, carrier, excipients, and / or salt must be compatible with the other ingredients of the formulation, and they must not be harmful to the receiver thereof, provided that, when said suspension comprises said four-sided rod form or said six-sided rod form, said suspension comprises an amount of water sufficient to maintain said rod form. The suspensions additionally include, optionally, one or more suspending agents, one or more anti-caking agents, one or more preservatives, one or more buffering agents, one or more sweetening agents, and one or more flavoring agents. A preferred suspension comprises zwitterion of trovafloxacin of the six-sided rod form, a suspending agent, an anti-caking agent, a combination of preservatives, and a combination of buffering agents, and has a pH of about pH 6 at about pH 8. Another preferred suspension comprises zwitterion of trovafloxacin of the six-sided rod form, a suspending agent, an anti-caking agent, a combination of preservatives, a combination of buffering agents, a sweetening agent, and a flavoring agent, and has a pH from about pH 6 to about pH 8. A particularly preferred suspension comprises from about 1 mg / ml to about 40 mg / ml zwitterion of trovafloxacin of the six-sided rod form, from about 0.05 wt% to about 1.0% by weight of xanthan gum, from about 0.01% by weight to about 2.0% by weight of silicon dioxide oidal, from about 0.05 mg / ml to about 3.0 mg / ml of methylparaben, from about 0.05 mg / ml to about 0.3 mg / ml of propylparaben, from about 0.05 mg / ml to about 0.2 mg / ml butylparaben, from about 5 mM to about 100 mM of a combination of anhydrous dibasic sodium phosphate and monobasic sodium phosphate monohydrate, from about 10 wt% to about 60 wt% sucrose, and about 0 , 01% by weight to about 1.0% by weight of strawberry flavor, and has a pH of from about pH 6.7 to about pH 7.3. An especially preferred suspension comprises from about 10 mg / ml to about 20 mg / ml zwitterion of trovafloxacin of the six-sided rod form, from about 0.20 wt% to about 0.30 wt% of xanthan gum , from about 0.05% by weight to about 0.20% by weight of colloidal silicon dioxide, from about 0.5 mg / ml to about 3.0 mg / ml of methylparaben, of about 0.05 mg / ml at about 0.3 mg / ml propylparaben, from about 0.05 mg / ml to about 0.2 mg / ml butylparaben, from about 5 mM to about 100 mM of a combination of anhydrous dibasic sodium phosphate and monobasic sodium phosphate monohydrate, from about 10% by weight to about 30% by weight of sucrose, and from about 0.03% by weight to about 0 , 6% by weight of strawberry flavor, and has a pH of about 7. Aqueous suspensions comprising a crystal as defined in said first aspect and an amount of water sufficient to maintain said six-rod form are also provided. sides of said glass, and those aqueous suspensions comprising a crystal as defined in said second aspect and an amount of water sufficient to maintain said four-sided rod shape of said crystal. In a sixth aspect, this invention provides methods for treating a bacterial infection in a mammal, comprising administering to said mammal an antibacterial effective amount of a new crystalline zwitterion of trovafloxacin of a sheet form, or of a rod form of four. sides, or of a six-sided rod shape, wherein the treatment includes, among others, preventive treatment (eg prophylactic),
palliative treatment, and curative treatment. All documents cited herein, including the foregoing, are hereby incorporated by reference, in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise indicated, throughout this document:% is percent, ° C is degrees Celsius, d is day or days, g is gram or grams, h is hour or hours, kg is kilogram or kilograms , I is liter or liters, mg is milligram or milligrams, min is minute or minutes, ml is milliliter or milliliters, mM is millimolar (concentration), N is normal (concentration), NaHCO3 is sodium bicarbonate, NaOH is sodium hydroxide, ta is room temperature, and r.p.m. it's revolutions per minute. As discussed above, this specification provides several new methods for preparing the new zwitterionic trovafloxacin crystals, and the use thereof in pharmaceutical compositions in liquid suspension for the treatment of bacterial infections. Most of these procedures begin with the operation of adding a trovafloxacin salt by adding acids to water, with agitation, if necessary, to maintain homogeneity. In the processes of this invention, any suitable acid addition salt may be employed. Suitable alcohols of such salts by the addition of acids include, for example, mineral acids such as hydrobromic, hydrochloric, hydroiodic, sulfuric, nitric and phosphoric acids; organic acids such as sulfamic acid, sulfonic acid, for example benzenesulfonic (besylate), p-toluenesulfonic (tosylate), methanesulfonic (mesylate) and trifluoromethanesulfonic (trifluoromesylate); and carboxylic acids such as acetic, ascorbic, benzoic, cinnamic, citric, fumaric, gluconic, maleic, malic, propionic, succinic, and tartaric acids. A preferred anion is mesylate. Next, the pH of the aqueous solution comprising the zwitterion of trovafloxacin of the acicular form is measured and adjusted to a pH depending on the particular procedure being used. For example, when the six-sided rods are prepared directly from the needles, the pH is adjusted to a value of at least about pH 4 at about pH 10, preferably about pH 6 to about pH 8, and most preferably at about pH 7. However, adjusting the pH to a value between pH 4 and pH 5, and preferably pH 4.3, accelerates, for example in days versus weeks, the conversion of the needles into the rods. When a similar low pH is employed for this acceleration, the resulting solution is then adjusted, once the conversion is complete, to a pH value from about pH 6 to about pH 8, and preferably about pH 7. In addition, when the six-sided rods are prepared from the needles, passing through the sheets and the four-sided rods, in this order, the pH is adjusted to a value of about pH 9 to about pH 12, and preferably about pH 9.5 Those skilled in the art will understand, from this specification, how to adjust the pH of the aqueous solution comprising the zwitterion of trovafloxacin to form the desired crystalline forms in any given situation. When the method employed is the process for preparing the six-sided rods from the needles, passing through the sheets and the four-sided rods, the preferred base for adjusting the pH to a value of about pH 9 to about pH 12, It is NaOH. A preferred concentration of such NaOH is from about 1% to about 20%. A particularly preferred concentration of such NaOH is about 10%. As will be appreciated by those skilled in the art, in the methods of the present invention, or to adjust the pH of any suspension of this invention, any suitable material capable of effecting a pH change may be employed., for example, any suitable acid or base can be used to adjust the pH of the zwitterion aqueous solution of trovafloxacin, as well as for any other operation within any of the new methods of this invention that requires a pH adjustment, also including neutralization, for example with NaHCO3, of a Tablet, to create zwitterion of trovafloxacin. Suitable bases include inorganic bases such as alkali metal or alkaline earth metal hydroxides, carbonates and bicarbonates, phosphates, and organic bases such as citrate, tri-alkyl (C?) Amines, pyridine and morpholine. For example, sodium citrate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, calcium phosphate or magnesium sulfate can be used to raise the pH, while hydrochloric acid or sulfuric acid can be used to lower the pH. In addition, any suitable way of determining the pH can be employed in the methods of the present invention, including, for example, immersing pH test strips in the solutions of the processes, or using an appropriate pH meter. In addition to the process of this invention for preparing the six-sided rods directly from the needles, this invention also provides methods for preparing the six-sided rods from the needles, but going through a sheet conversion, prior to on the six-sided rods. The sheets are prepared from the needles by heating the needle preparation. More specifically, the aforementioned precipitation of the zwitterion from the salt in the aforementioned aqueous solution, comprising the zwitterion of trovafloxacin of the acicular form, is carried out at a temperature of at least about 70 ° C. The heated solution is then cooled to a temperature of less than about 70 ° C, and preferably to t.a. The cooling of the solution comprising the sheets allows the conversion of these sheets to the six-sided rods. In contrast to needles and rods, the sheets of this invention do not need to be kept hydrated to retain their crystalline structure, ie, the sheets can be isolated while the needles and rods become other crystalline structures upon dehydration. . As will be understood by those skilled in the art in the light of the present specification, the X-ray data of the "non-insulatable shapes", ie the four-sided and six-sided rod forms, can be obtained by performing a quick scan on a wet filtered cake. Moreover, those skilled in the art will also understand how to determine at which point the wet filtered cake (or the filtered pasta) begins to be converted to another form, so that an X-ray diffractogram can be obtained before said conversion. For example, said conversion point can be determined using polarized light microscopy. The aforementioned conversion points of the four-sided and six-sided rod forms of this invention are easily determined from an aqueous suspension within which they are contained, since water does not evaporate substantially over a period of time suitable for such determination. Furthermore, those skilled in the art will appreciate from the present specification the amount of water suitable for holding, either a four-sided rod shape, or a six-sided rod shape of this invention, in any situation given, during any given period of time. For example, those skilled in the art will understand that it would be counterproductive to allow the surface area of the crystal to dry to an appreciable degree. The heat can be applied to the aqueous solution in any suitable manner and, as described in the Examples given below, it is generally convenient to use a heating mantle. In a similar way, in the methods of this invention, any method of cooling, for example resting at t.a., an ice bath, a cold room, or simply removing the source of heat can be employed. Those skilled in the art will understand from the present specification that the conversion points for any given method of this invention comprising a cooling operation can be manipulated to some degree by the selected cooling rate. For example, the reaction can be cooled over a suitably long period of time, for example about 30 minutes, or it can be cooled over a suitably short period of time, for example a few minutes, and then maintained for a suitable period of time, for example about 24 hours, to achieve the desired degree of conversion. As discussed above, those skilled in the art can observe the progress and degree of conversion for any given method of this invention using, for example, conventional polarized light microscopy. Those skilled in the art will appreciate from this specification that the time periods described for any operation of any given method or methods of this invention depend in part, for example, on parameters such as, for example, pH, temperature and concentration , and the like, and will therefore be able to select, based on the present specification, suitable parameters (such as those cited) to achieve any desired result. It is considered that such modifications are within the scope of the present invention and, accordingly, are deemed to fall within the scope of the appended claims. In the suspensions of this invention, any of the new zwitterionic trovafloxacin crystals of this invention can be used. The new crystals can also be administered in any other suitable dosage form (e.g., tablets, solutions for injection), and those skilled in the art will understand how to prepare any suitable dosage form, based on standard pharmaceutical practice, and in light of the present descriptive memory. However, as discussed above, this invention is directed primarily to providing pharmaceutical compositions in liquid suspension for oral administration. It is preferred that the suspensions of this invention comprise the six-sided rod form because the six-sided rod form is the most stable of the forms discussed herein, in an aqueous environment and approximately at ta, ie all the other forms become the six-sided rods in watery medium to ta In addition, it is also preferred that the pH of the suspension be from about pH 6 to about pH 8, more preferably from about pH 6.7 to about pH 7.3, and most preferably about pH 7. Moreover, it is it also prefers that the pharmaceutically acceptable support, vehicle or diluent of the suspension be water. In the suspensions of this invention, any suitable amount of any of the new zwitterionic forms may be employed, and those skilled in the art will understand how to adjust such amount for any given situation, for example the dosage regimen, or the patient. For example, those skilled in the art will understand how much zwitterion will be suitable for any given patient, depending, for example, on the type or types of bacteria with which the patient is infected, the convenient suspension volume to be orally administered (for example, example of about 0.5 ml to about 20 ml), and the potency of the zwitterion. A preferred amount of zwitterion of this invention is from about 1 mg / ml to about 40 mg / ml. A more preferred amount of zwitterion of this invention is from about 10 mg / ml to about 20 mg / ml. As will be appreciated by those skilled in the art, and exemplified by standard pharmaceutical practice, for example the formulation technique, any suitable additional components may be added to the suspensions of this invention, as desired in any given situation. As will be described in more detail below, preferred additional components include suspending agents, anti-caking agents, preservatives, buffering agents, sweetening agents, flavoring agents, pH adjusting agents, and coloring agents such as, for example, dyes. plants, or pigments, for example TiO2, generally in combination with non-ionic plasticizers such as polysorbate 60, polysorbate 80, polyvinylpyrrolidone, and propylene glycol. As will be appreciated by those skilled in the art, the amounts of these agents that are effectively employed in any particular suspension depend in large part on the exact agent selected and on the other components of the given suspension. Based on this specification, those skilled in the art will understand which agent or agents they should select and how much or quantities of these agents should be included in any given suspension. The suspensions of this invention may additionally include one or more suspending agents (also referred to in the art as "viscosity agents" or "thickening agents") in any suitable concentration. In the suspensions of this invention, any suitable suspending agent or suitable combination of suspending agents may be employed. Suitable suspending agents include, for example, hydrocolloid gums, for example xanthan gum, guar gum, locust bean gum, tragacanth gum, and the like. Additional suitable suspending agents include synthetic agents such as, for example, aluminum stearate, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like. A preferred suspending agent is xanthan gum. A preferred amount is from about 0.05% by weight to about 1.0% by weight, based on the total weight of the suspension. A more preferred amount is from about 0.20 wt% to about 0.30 wt%. Those skilled in the art will understand that it is advantageous to include an anti-caking agent in suspensions containing a suspending agent. In the suspensions of this invention, any suitable anti-caking agent or suitable combination of anti-caking agents may be employed. A preferred anti-caking agent is colloidal silicon dioxide. Those skilled in the art will understand how to select an amount of colloidal silicon dioxide suitable for any given suspension, i.e., an amount such that under normal conditions of transport and storage no firm cake forms, difficult to resuspend (without going beyond of gentle physical agitation), but not an amount that causes gelation. A preferred amount of anti-caking agent is from about 0.01% by weight to about 2.0% by weight, based on the total weight of the suspension. A more preferred amount of anti-caking agent is from about 0.05 wt% to about 0.20 wt%. In the suspensions of this invention, any suitable preservative or suitable combination of preservatives may be employed. As with the other additional components of the suspensions of this invention, those skilled in the art will appreciate that the amount of preservative employed in any particular suspension is, to a large extent, a function of the exact preservative employed, the pH of the suspension, and of the other components that constitute the given suspension. Suitable preservatives for inclusion in the suspensions of this invention include, for example, parabens, benzyl alcohol, sodium benzoate, phenol, benzalkonium chloride, thimerosal, chlorobutanol, benzoic acid, sodium bisulfite, and sodium propionate. Parabens are preferred preservatives. For example, a preferred amount of methyl paraben ranges from about 0.5 mg / ml to about 3.0 mg / ml, based on the weight of the suspension, of propyl paraben ranging from about 0.05 mg / ml to about 0. , 3 mg / ml, based on the weight of the suspension, and of butylparaben ranges from about 0.05 mg / ml to about 0.2 mg / ml, based on the weight of the suspension. In the suspensions of this invention, any suitable buffering agent, or suitable combination of buffering agents, may be employed. Suitable buffering agents include, for example, anhydrous dibasic sodium phosphate, monobasic sodium phosphate monohydrate, and combinations thereof. Preferred buffering agents include a combination of anhydrous dibasic sodium phosphate and monobasic sodium phosphate monohydrate. A preferred amount of buffering agent or agents is from about 5 mM to about 100 mM, such that the pH of the suspension, given all components of the suspension, has a pH value from about pH 6 to about pH 8. , preferably from about pH 6.7 to about pH 7.3, and most preferably about pH 7. A more preferred amount is from about 10 mM to about 30 mM. In the suspensions of this invention, any suitable sweetening agent, or suitable combination thereof, may be employed. Suitable sweetening agents include, for example, sucrose, fructose, glucose, sorbitol, and artificial sweetening agents, for example aspartame, saccharin and xylitol. A preferred sweetening agent is sucrose. A preferred amount of sweetening agent is from about 10% by weight to about 60% by weight, based on the total weight of the suspension. A more preferred amount of sweetening agent is from about 10% by weight to about 30% by weight. Any suitable flavoring agent, or suitable combination thereof, can be employed in the suspensions of this invention. Suitable flavoring agents include, for example, synthetic flavor oils and flavoring flavors and / or natural oils, extracts of plant leaves, flowers, fruits, etc., and combinations thereof. Suitable oils include, for example, cinnamon oil, gualteria oil, peppermint oils, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil , sage oil, bitter almond oil, and cassia oil. Additional suitable flavoring agents include, for example, vanilla, citrus oil (eg, lemon, orange, grapefruit, lime, grapefruit), citric acid, menthol, glycine, orange powder, cream, chocolate, mocha, spearmint, and tail. Suitable flavorings include, for example, apple, apricot, banana, cherry, peach, pear, pineapple, plum, raspberry and strawberry. Any suitable chewing gum flavoring agent may also be employed in the suspensions of this invention. A preferred flavoring agent is strawberry flavor. A preferred amount of flavoring agent is from about 0.01% by weight to about 1.0% by weight, based on the total weight of the suspension. A more preferred amount of flavoring agent is from about 0.30 wt% to about 0.60 wt%. Preferred suspensions of this invention further comprise one or more suspending agents, one or more anti-caking agents, one or more more preservatives, one or more buffering agents, one or more flavoring agents, and one or more sweetening agents. Particularly preferred are suspensions comprising xanthan gum, colloidal silicon dioxide, a combination of methyl-, propyl- and butylparaben, a combination of anhydrous dibasic sodium phosphate and monobasic sodium phosphate monohydrate, and sucrose and strawberry flavor. As discussed above, the suspension formulations of this invention are prepared using the usual pharmaceutical formulation practice. In addition, the activity, the methods to test the activities, the dosages, the dosage forms, the administration methods and the baseline information related to trovafloxacin, are set forth in the patents granted and pending international applications, mentioned above, as well as in the PDR for Tablets and alatrofloxacin mesylate (prodrug) for intravenous administration. In general, the preferred oral administration suspensions of this invention will contain, for non-pediatric patients, the equivalent of about 100 to about 300 mg of zwitterionic glass of trovafloxacin, and for pediatric patients of about 2 to about 5 mg per kg of weight, in each case in an adequate volume. Oral administration of the formulations of this invention is achieved according to the normal mode of administration, by drinking the suspension. Alternatively, the suspension can be mixed with food and drinks, when appropriate. Moreover, any other suitable method of oral administration is considered part of this invention. As discussed above, the patents granted, the pending international applications, and the relevant scientific and medical literature, for example the PDR, all of which are incorporated herein in their entirety, together with the usual pharmaceutical practice and procedures. , in light of the present specification, can be employed by those skilled in the art to prepare the different crystalline forms of the zwitterion of trovafloxacin and the pharmaceutical compositions (in particular the liquid suspensions) comprising the zwitterion, as well as to treat mammals by administering to such mammals zwitterion amounts effective as antibacterials. Preferred mammals include humans and companion animals. Particularly preferred mammals are humans. The following Examples are provided for illustrative purposes only, and do not limit the invention, which is defined by the appended claims. It will also be understood that other changes and modifications that may be made are also part of this invention and, therefore, fall within the scope of the appended claims.
EXAMPLES
EXAMPLE 1 Preparation of needles
Sterile water (2.64 kg) was placed in a 22 l round bottom flask, a salt of trovafloxacin mesylate (123.2 g) was added with stirring, and the flask was protected from light. The solution was stirred for 10 minutes. The pH was adjusted to pH 7.3 by adding 10% NaOH (approximately 91 g, weight / weight) in the course of 1 to 2 minutes, and then adding 1% NaOH (approximately 48 g, weight / weight) in the 1 to 2 minutes, until the pH was 7.3. The solution (protected from light) was stirred for 20 minutes, and the pH was maintained at pH 7.3, forming a wet suspension comprising the zwitterionic crystals of the acicular form that provided the characteristic powder diffraction pattern by X-ray. that has been provided before.
EXAMPLE 2 Preparation of six-sided rods directly from needles
Needles were prepared in a manner analogous to that described in Example 1. The needles were then allowed to rest at t.a. for about 6 weeks. The resulting crystals provided the X-ray powder diffraction pattern characteristic of the six-sided rods that has been provided above.
EXAMPLE 3 Preparation of sheets directly from needles
Sterile water (2.64 kg) was placed in a 22 l round bottom flask, a salt of trovafloxacin mesylate (123.2 g) was added with stirring, and the flask was protected from light. The solution was stirred for 10 minutes. The pH was adjusted to pH 7.3 by adding 10% NaOH (approximately 91 g, weight / weight) in the course of 1 to 2 minutes, and then adding 1% NaOH (approximately 48 g, weight / weight) in the 1 to 2 minutes, until the pH was 7.3, heating above 70 C. The solution (protected from light) was stirred for 20 minutes, and the pH was maintained at pH 7.3. The resulting crystals provided the X-ray powder diffraction pattern characteristic of the sheets, which has been provided earlier.
EXAMPLE 4 Preparation of six-sided rods from sheets
Slides were prepared in a manner analogous to that described in Example 3. The aqueous solution was allowed to cool. The resulting crystals provided the X-ray powder diffraction pattern characteristic of the six-sided rods that has been provided above.
EXAMPLE 5 Preparation of four-sided rods from needles, passing through sheets
Sterile water (2.64 kg) was placed in a 22 l round bottom flask, a salt of trovafloxacin mesylate (123.2 g) was added with stirring, and the flask was protected from light. The solution was stirred for 10 minutes. The pH was adjusted to pH above 9.5 by adding 10% NaOH (approximately 91 g, weight / weight) over the course of 1 to 2 minutes, and then adding 1% NaOH (approximately 55 g, weight / weight) in the course of 1 to 2 minutes, until the pH was above 9.5, heating above 70 C. The solution was cooled to rt, and allowed to stand at for about 24 hours. The resulting crystals provided the characteristic crystalline parameters of the six-sided rods, which have been provided earlier.
EXAMPLE 6 Preparation of six-sided rods from four-sided rods
Four-sided rods were prepared in a manner analogous to that described in Example 5, and then the solution was allowed to stand at t.a. during
additional days The resulting crystals provided the X-ray powder diffraction pattern characteristic of the six-sided rods that has been provided above.
EXAMPLE 7 Preparation of sheets from six-sided rods
The experiment was performed in triplicate, that is, the six-sided rods were prepared in a manner analogous to that described in Examples 2, 4 and 6. Next, each of the rod preparations was heated to about 70 ° C. The resulting crystals provided the X-ray powder diffraction pattern characteristic of the sheets that has been provided earlier.
EXAMPLE 8 Preparation of a suspension comprising six-sided rods
Needles were prepared in a manner analogous to that described in Example 1. Sterile water (5.75 kg) was added to a 12 I round bottom flask, and heated to a temperature of about 67 ° C to about 70 ° C. C. Methylparaben (10.0 g), propylparaben (2.0 g) and butylparaben (1.0 g) were added to the flask. The solution was stirred until the parabens had dissolved, and then cooled to t.a. Anhydrous dibasic sodium phosphate (28.2 g) and monobasic sodium phosphate monohydrate (14.0 g) were then added, followed by sucrose (2.0 kg), with stirring until the sucrose had dissolved. The pH of the resulting excipient solution was maintained at pH 7.3. The excipient solution was then mixed by adding it to the solution containing the needles. Strawberry flavor (60.0 g, density 0.9354 g / ml) was added. The resulting suspension formulation was stirred, and the pH of the formulation was maintained in solution at pH 7.3. The needles were kept at t.a., and turned into six-sided rods in about 6 weeks. The resulting crystals provided the X-ray powder diffraction pattern characteristic of the six-sided rods that has been provided above.
EXAMPLE 9 Preparation of a suspension comprising six-sided rods
A suspension of approximately 100 mg / ml of a trovafloxacin mesylate salt in water was prepared at t.a., mixing the trovafloxacin mesylate and water. While stirring at approximately 220 rpm, the pH of the suspension was adjusted to a pH of about pH 4.0 to about pH 4.6 by adding 10% NaOH (92 mg per ml of the suspension) in the course of about 20 minutes. , and agitation was suitably increased, to ensure a uniform pH within the suspension. After stirring for 1 hour, the suspension was allowed to stand, without stirring, for 24 hours. During this period of time, in the wet mass, the needles became the six-sided rods. The complete conversion was verified by powder diffraction by X-rays, and by microscopy. The resulting crystals provided the X-ray powder diffraction pattern characteristic of the six-sided rods that has been provided above. After crystalline conversion, the pH of the suspension was adjusted to pH 7.3 with 1% NaOH. A solution of excipients was prepared in a manner analogous to that described in Example 8. The suspension was diluted with the excipient solution (1: 9, suspension: excipient solution) to achieve a 10 mg / ml suspension of the rods. of six sides.
EXAMPLE 10 Preparation of a suspension comprising six-sided rods
A suspension of approximately 100 mg / ml of a salt of trovafloxacin mesylate in water was prepared at t.a., by mixing trovafloxacin mesylate (1.245 g) and water (7.862 g). While stirring at approximately 220 rpm, the pH of the suspension was adjusted to a pH of about pH 4.0 to about pH 4.6 by adding 10% NaOH (0.9111 g) over the course of about 20 minutes, and was increased. suitably stirring, to ensure a uniform pH within the suspension. After stirring for 1 hour, the suspension was allowed to stand, without stirring, for 24 hours (at which time the complete conversion had occurred). The suspension was then diluted to 35 mg / ml by the addition of water (18.726 g). The pH was adjusted to a value of about pH 6.8 to about pH 7.2 with about 0.480 g of 1% NaOH. A solution of excipients was prepared by adding methylparaben (0.100 g), propylparaben (0.020 g) and butylparaben (0.010 g) to water (57.606 g), and stirring while heating to a temperature of about 67 C to about 73 ° C. Stirring was continued for 1 hour. The solution was cooled to a temperature of about 34 ° C to about 40 ° C. Xanthan gum (0%) was added to the solution, 271 g), monobasic sodium phosphate monohydrate (0.100 g), dibasic anhydrous sodium phosphate (0.350 g), sucrose (20,000 g) and colloidal silicon dioxide (0.108 g), and the solution was stirred until these components had dissolved. . The suspension and the excipient solution were combined. Strawberry flavor (0.600 g) was added with stirring. The pH was adjusted to a value from about pH 6.7 to about pH 7.3 with 1% NaOH or 1% HCl.
EXAMPLE 11 Preparation of a suspension comprising needles from a Tablet
A Tablet (100 mg) was added to water (10 ml) in a flask, and allowed to disintegrate for 5 minutes. Then, sodium bicarbonate solution (10 ml, prepared by adding sodium bicarbonate) was added with stirring.
(2.5 g) to water (800 ml), and diluting to 1 l with water). The resulting suspension contained 10 mg / ml needles.
Claims (29)
1. - A zwitterionic crystal of Trovafloxacin Formula which has a six-sided rod shape, and which has the following characteristic pattern of wet cake diffraction by X-rays:
2. - A trovafloxacin crystal having a four-sided rod shape, and having the following characteristic X-ray crystal parameters: formula - C20H? 5N4? 3F3 (zwitterion), C20Hi4N4? 3F3"Na + 4.75 H20 (512.9); cell dimensions - a = 11, 202 (2) A, b = 15.2630 (1) Á, c = 15.8910 (1) A, a = 103.24 (1) °, ß = 110.02 (1) °,? = 108.71 (1) °, V = 2235.8 (4) A3; and space group - P1 bar.
3.- A zwitterionic crystal of trovafloxacin of Formula which has a foil shape, and which has the following characteristic pattern of powder diffraction by X-rays
4. A process for preparing the crystal defined in claim 1, comprising, in sequence, the steps of: preparing an aqueous solution of a salt of trovafloxacin by the addition of acids; precipitating said zwitterion from said salt by adjusting the pH of said solution to a pH of about pH 4 at about pH 10; and maintaining said solution at room temperature for a period of time.
5. The process defined in claim 4, wherein said salt of trovafloxacin by addition of acids is trovafloxacin mesylate.
6. - The method defined in claim 4, wherein said pH is from about pH 6 to about pH 8, and said period of time is at least about 1 week.
7. The process defined in claim 4, wherein said pH is from about pH 4 to about pH 4.6, and said period of time is less than about 24 hours.
8. A process for preparing the crystal defined in claim 2, comprising, in sequence, the steps of: preparing an aqueous solution of a salt of trovafloxacin by the addition of acids; precipitating said zwitterion from said salt by adjusting the pH of said solution to a pH of about pH 9 to about pH 12, at a first temperature of at least about 70 ° C; and cooling said solution to a second temperature below about 70 ° C.
9. The process defined in claim 8, wherein said acid addition salt is trovafloxacin mesylate, said pH is adjusted with NaOH; said first temperature is approximately 70 ° C, and said second temperature is the ambient temperature.
10. The method defined in claim 8, further comprising, after said cooling, maintaining said solution for a period of time.
11. The method defined in claim 10, wherein said second temperature is the room temperature and said time period is from about 12 to about 36 hours.
12. - The process defined in claim 10, wherein said acid addition salt is trovafloxacin mesylate, said pH is adjusted with NaOH; said first temperature is approximately 70 ° C, and said second temperature is the ambient temperature.
13. The method defined in claim 12, wherein said time period is from about 12 to about 36 hours.
14. A process for preparing the crystal defined in claim 1, comprising, in sequence, the steps of: preparing an aqueous solution of a salt of trovafloxacin by the addition of acids; precipitating said zwitterion from said salt by adjusting the pH of said solution to a pH of about pH 9 to about pH 12, at a first temperature of at least about 70 ° C; cooling said solution to a second temperature below about 70 ° C, and maintaining said solution for a period of time greater than about 48 hours.
15. The process defined in claim 14, wherein said acid addition salt is trovafloxacin mesylate, said pH is adjusted with NaOH; said first temperature is approximately 70 ° C, and said second temperature is the ambient temperature.
16. The method defined in claim 14, wherein said second temperature is the ambient temperature, and said period of time is approximately 5 days.
17. The process defined in claim 16, wherein said acid addition salt is trovafloxacin mesylate, said pH is adjusted with NaOH; and said first temperature is about 70 ° C.
18. A process for preparing the crystal defined in claim 3, comprising, in sequence, the steps of: preparing an aqueous solution of a salt of trovafloxacin by the addition of acids; and precipitating said zwitterion from said salt by adjusting the pH of said aqueous solution to a pH of about pH 4 at about pH 10, at a temperature of at least about 70 ° C.
19. The process defined in claim 18, wherein said trovafloxacin salt by addition of acids is trovafloxacin mesylate, said pH is about 7, and said temperature is about 70 ° C.
20. A process for preparing the crystal defined in claim 1, comprising, in sequence, the steps of: preparing an aqueous solution of a salt of trovafloxacin by the addition of acids; precipitating said zwitterion from said salt by adjusting the pH of said aqueous solution to a pH of about pH 4 to about pH 10, at a first temperature of at least about 70 ° C; and cooling said solution to a second temperature below about 70 ° C.
21. The process defined in claim 20, wherein said trovafloxacin salt by acid addition is trovafloxacin mesylate, said pH is about 7, said first temperature is about 70 ° C; and said second temperature is the ambient temperature.
22. A pharmaceutical composition comprising the crystal defined in claim 1, and a pharmaceutically acceptable carrier, diluent or carrier.
23. A pharmaceutical composition for oral administration, as defined in claim 22.
24.- A suspension as defined in claim 23, provided that said suspension comprises an amount of water sufficient to maintain said six-sided rod shape.
25. A pharmaceutical composition comprising the crystal defined in claim 2, and a pharmaceutically acceptable carrier, diluent or carrier.
26. A pharmaceutical composition for oral administration, as defined in claim 25.
27.- A suspension as defined in the claim 26, provided that said suspension comprises an amount of water sufficient to maintain said four-sided rod shape.
28. A pharmaceutical composition comprising the crystal defined in claim 3, and a pharmaceutically acceptable carrier, diluent or carrier. 29. A pharmaceutical composition for oral administration, as defined in claim 28. 30.- A suspension as defined in the claim
29. 31. A method for treating a bacterial infection in a mammal, comprising administering to said mammal an effective amount for the treatment, of a crystal as defined in claim 1. 32.- The method defined in claim 31 , in which said mammal is a human being. 33. A method for treating a bacterial infection in a mammal, comprising administering to said mammal an effective amount for the treatment of a crystal as defined in claim 2. 34.- The method defined in claim 33 , in which said mammal is a human being. 35. A method for treating a bacterial infection in a mammal, comprising administering to said mammal an effective amount for treatment, of a crystal as defined in claim 3. 36. The method defined in claim 35, in which said mammal is a human being. 37. The suspension defined in claim 24, wherein the pH is from about pH 6 to about pH 8. 38. The suspension defined in claim 37, wherein the amount of said crystal is about 1 mg. / ml at approximately 40 mg / ml. 39. The suspension defined in claim 37, further comprising a suspending agent, an anti-caking agent, one or more preservatives, and one or more buffering agents. 40. The suspension defined in claim 39, further comprising a sweetening agent. 41. The suspension defined in claim 40, further comprising a flavoring agent. 42. The suspension defined in claim 41, wherein said suspending agent is xanthan gum, said anti-caking agent is colloidal silicon dioxide, said preservatives consist of methylparaben, propylparaben and butylparaben, said buffering agents consist of sodium phosphate dibasic anhydrous and monobasic sodium phosphate monohydrate, said sweetening agent is sucrose, and said flavoring agent is strawberry flavor. 43.- The suspension defined in claim 42, wherein the amount of said crystal is from about 1 mg / ml to about 40 mg / ml, the amount of said xanthan gum being about 0.05% in at about 1.0 wt%, the amount of said colloidal silicon dioxide is from about 0.01 wt% to about 2.0 wt%, the amount of said methyl parabens being about 0.05 mg / ml to about 3.0 mg / ml, the amount of said propylparaben is from about 0.05 mg / ml to about 0.3 mg / ml, the amount of said butylparaben being about 0.05 mg / ml at approximately 0.2 mg / ml, the amount of each of said sodium dibasic anhydrous phosphate and monobasic sodium phosphate monohydrate is from about 5 mM to about 100 mM, the amount of said sucrose being from about 10% by weight to about 60% by weight, and the amount of said strawberry flavor is from about 0.01% by weight to about 1.0% by weight, wherein the% by weight is based on the total weight of said suspension. 44. The suspension defined in claim 43, wherein said amount of said crystal is from about 10 mg / ml to about 30 mg / ml, said amount of said xanthan gum being about 0.20% by weight at about 0.30% by weight, said amount of said colloidal silicon dioxide is about 0, 05% by weight to about 0.20% by weight, said amount of each of said anhydrous dibasic sodium phosphate and said monobasic sodium phosphate monohydrate being from about 10 mM to about 30 mM, said amount of said sucrose being located about 10% by weight to about 30% by weight, and said amount of said strawberry flavor is from about 0.30% by weight to about 0.60% by weight. 45. The suspension defined in claim 44, wherein said amount of said crystal is about 10 mg / ml, said amount of said xanthan gum is about 0.25% by weight, said amount of said colloidal silicon dioxide is about 0.10% by weight, said amount of said methylparaben is about 1.0 mg / ml, said amount of said propylparaben is about 0.2 mg / ml, said amount of said butylparaben is about 0.10 mg / ml , said amount of each of said anhydrous dibasic sodium phosphate and said monobasic sodium phosphate monohydrate is about 30 mM, said amount of said sucrose is about 20% by weight, and said amount of said strawberry flavor is about 0.60% by weight. weight. 46. An aqueous suspension comprising a crystal as defined in claim 1 and an amount of water sufficient to maintain said six-sided rod shape. 47. An aqueous suspension comprising a crystal as defined in claim 2 and an amount of water sufficient to maintain said four-sided rod shape.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/137,463 | 1999-06-04 |
Publications (1)
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MXPA00005554A true MXPA00005554A (en) | 2001-11-21 |
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