CN1063944C - Method for preparing compound tobramycin suspension for eye - Google Patents
Method for preparing compound tobramycin suspension for eye Download PDFInfo
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- CN1063944C CN1063944C CN97105772A CN97105772A CN1063944C CN 1063944 C CN1063944 C CN 1063944C CN 97105772 A CN97105772 A CN 97105772A CN 97105772 A CN97105772 A CN 97105772A CN 1063944 C CN1063944 C CN 1063944C
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- suspension
- tobramycin
- dexamethasone
- sterilization
- carboxymethyl cellulose
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Abstract
The present invention relates to a method for preparing compound tobramycin suspension used for eyes, which is used for sterilizing dexamethasone with a dry method by using the methods of thermal process, ultraviolet radiation, radiation, etc. Tobramycin is filtered and sterilized by a degerming filter membrane, then, sodium carboxymethyl cellulose is used as a thickening agent, and tween-80 is used as a wetting agent so as to prepare the suspension by mixing. In the sterilization process of the dexamethasone, the defects of crystal form change, the thermal decomposition of tobramycin, etc. which are caused by moist and heat are prevented, and the size, the crystal form and the dispersion degree of the particles of the prepared suspension all conform to the medicinal standard. The present invention has the advantages of good sedimentation stability of products and good resuspension performance. Besides, the particle size keeps unchanged in long term storage.
Description
The present invention is relevant with eye medicinal preparation, more specifically says so about the production technology of ophthalmic suspension pharmaceutical preparation.
Present domestic eye medicinal market mainly is the hormones anti-inflammatory agent based on the antimicrobial drug of chloromycetin, erythromycin and cortisone acetate (suspensoid), dexamethasone acetate (solution), kind is single, dosage form falls behind, and lacks the antiphlogistic compound preparation that is used to sterilize.The compound recipe ophthalmic suspension of tobramycin and dexamethasone is characterized in sterilization and antiinflammatory are combined in same therapeutic process, and this especially is of great significance in the recovery process behind the ophthalmologic operation at the eye severe infections.Said preparation is produced by U.S. Ai Erkang (ALCON) company, and commodity are called Tobradex (TOBRADEX), have entered China market February nineteen ninety-five.Said preparation is used for the treatment of postoperative bactericidal antiphlogistics such as serious type keratitis, conjunctivitis, glaucoma and cataract, wide application, and determined curative effect, domestic still untapped so far owing to aspect reasons such as Technologies, main dependence on import.
The existing a lot of reports of the preparation method of domestic ophthalmic suspension preparation.The characteristics of suspension mainly show aspects such as granular size and dispersion, therefore the key for preparing suspension formulations is in the process of preparation and storage suspension, how to guarantee not changed, and remain on that homodisperse does not lump in the medium by the crystallite crystal formation and the granular size of dispersed substance.Conventional method is limit heating edge vibration in disinfecting process.As the preparation of cortisone acetate, cortisone acetate has five kinds of crystal formations, and crystalline form I, III are all very stable under drying regime, but in water, special in damp and hot suspension, promptly become aqueous crystal form V rapidly.If transfixion then can be formed the piece cake, so in heat sterilization (100 ℃, 30 minutes) process, will take the operating procedure of sterilization to go to avoid caking phenomenon to take place while vibrating.This method is not easy to operate, and is difficult to guarantee product quality.
For the preparation of compound tobramycin suspension, dexamethasone crystallite wherein, (100 ℃) change crystal formation especially easily in damp and hot liquid.Crystal is grown up into needle-like or cluster shape rapidly or is formed huge crystal, can't solve its crystal formation variation issue with succusion, and this may also be one of domestic untapped so far reason that goes out this type of preparation.In addition, the tobramycin in the said preparation prescription is heated and also decomposes easily, so existing method of producing suspension formulations can not be directly used in the production compound tobramycin suspension for eye.
The object of the present invention is to provide a kind of simple to operately, constant product quality is easy to the production technology of industrial compound tobramycin suspension.
The eye that the present invention developed is used tobramycin suspension, includes efficacy component and adjuvant components such as disodium edetate, sodium oxide, bromo geramine, thickening agent and wetting agent such as tobramycin, dexamethasone.It is that the sodium carboxymethyl cellulose of 800-1200 centipoise is made thickening agent that the present invention has selected viscosity for use, is wetting agent with the tween 80.The content (weight %) of sodium carboxymethyl cellulose in component is 0.5～1.0%, and tween 80 is 0.1～0.3%.Preparation technology's of the present invention key is according to the formulation components characteristic, with distinct methods difference sterilization treatment, mixes thereafter again and makes suspension.
At first as the dexamethasone of one of key component, be easy to change crystal formation in damp and hot solution, but we discover that dexamethasone is heated under drying condition, its crystal formation is highly stable.The present invention is according to the characteristic of dexamethasone crystallite melting point height (225 ℃), with dexamethasone at high temperature (160 ℃) make in heat sterilization, solved dexamethasone in the damp and hot difficult problem of malleable crystal formation down.In addition, also can reach identical purpose with the dry method sterilization of 2537A wavelength irradiation under ultraviolet ray or with the sterilization of 2-2.5 Megarad method of radiating, dexamethasone is all can keep stable crystal formation under the dry condition.
For tobramycin, the present invention then adopts degerming membrane filtration sterilizing methods, has avoided the decomposes problem of tobramycin.Then still adopt conventional sterilizing methods as for other adjuvants.
The production technology of producing compound tobramycin suspension for eye that the present invention proposes is: through purified thickening agents sodium carboxymethyl cellulose, wetting agent tween 80 and other adjuvants, be made into aqueous solution by prescription, standby with conventional method at 100 ℃ of following heating disinfection postcooling.Powdered dexamethasone is sterilized with dry method.It can be to be used under the dry state full-boiled process sterilization or sterilize or select the radiation sterilization of 2-2.5 Megarad for use with the irradiation under ultraviolet ray of 2537A wavelength.Its preferable methods is 160 ℃ of following dry heating method sterilizations.Dexamethasone cooling back and tween 80 mix homogeneously after the sterilization.Tobramycin is then with behind the water for injection wiring solution-forming, and with the sterilization of degerming membrane filtration, reuse sulphuric acid is regulated pH to 3-4.Then with other adjuvant solution mix homogeneously such as sodium carboxymethyl cellulose after, regulate pH of mixed to 5-6 with sodium hydroxide, again with dexamethasone blending ingredients mix homogeneously, obtain ophthalmic suspension of the present invention.The compound tobramycin suspension for eye of so making, its product quality meets the product standard of United States pharmacopoeia specifications.
Suspension type medicament is meant that the insoluble solid drug particles is dispersed in formed heterogeneous dispersion in the liquid.Microgranule in the suspension is generally more than 1 micron, and the particle requirement 90% in the ophthalmic suspension is below 15 microns, and maximum is no more than 50 microns.Microgranule in the suspension is answered fine and even, and sedimentation is slow, and its sedimentation velocity should not influence correctly the measuring of dosage, microgranule does not lump after sinking, and jolting can homodisperse a little.Particle size remains unchanged in long term store, and not too thickness is easy to topple over, and outstanding more preferably property is arranged.
For showing progressive of the present invention, we select for use Tobradex ophthalmic suspension that U.S. Alcon Universal Ltd. produces in contrast product carry out the sedimentation rate of fineness of the particles, suspension microgranule and outstanding again property mensuration.
1. fineness of the particles is measured.Method by Chinese Pharmacopoeia (95 years version appendix 1) regulation is measured: get test sample, after the powerful jolting, take out an amount of immediately, be equivalent to principal agent 10 micrograms, under the 320-400 power microscope, inspect, the granule that surpasses 50 μ m must not be arranged, determine 4-5 visual field counting then, contain the following granule of 15 μ m and must not be less than 90%.
As stated above, the present invention and reference substance are not all found the granule greater than 15 μ m, and Dispersion of Particles is even, no cluster or caking.
2. the sedimentation of suspension microgranule mensuration is to measure according to the sedimentation volumn method that provides in " pharmaceutics " (China Medicine University compiles, 379 pages), and the volume of promptly measuring precipitum recently compares the stability of suspensoid, the effect of evaluation suspending agent.Its method system places fully stirring and evenly mixing of the identical graduated cylinder of diameter with a certain amount of suspensoid, write down the original height (Ho) of suspensoid, leave standstill then, behind certain hour, observe the boundary at clear liquor and precipitum interface, the precipitum height (Hu) when the sedimentation face of writing down no longer changes.Then the ratio of Hu/Ho is called the sedimentation volumn ratio.Sedimentation volumn is bigger than, and the expression suspensoid is more stable.
The present invention adopts internal diameter 2.0cm, the vial that high 3.0cm is flat, the suspension of high 20mm (Ho) that pack into.Clear liquor and precipitate interface are clear behind the placement 24hr, and sedimentation face no longer changes, and the height (Hu) of measuring precipitum the results are shown in Table 1.
Table 1 the present invention and reference substance sedimentation volumn are frequently
| Batch | The present invention | Reference substance | |||
| 1 | 2 | 3 | Meansigma methods | ||
| Hu(mm) | 2.1 | 2.0 | 2.2 | 2.1 | 0.8 |
| Hu／Ho | 0.105 | 0.1 | 0.11 | 0.105 | 0.03 |
Show that from table 1 data sedimentation volumn of the present invention than greater than reference substance, illustrates that product stability of the present invention is better than reference substance.
3. outstanding again property relatively.Suspension leaves standstill the back and precipitates, but should be easy to shake up, and can not lump.We vibrate to sedimentary suspension is arranged after leaving standstill with electric agitator, and are even until suspension, transfer the required duration of oscillation of even suspension to precipitation and represent the suspension quality of outstanding property again.The results are shown in Table 2.
The outstanding again property of table 2 the present invention and reference substance relatively
| Batch | The present invention | Reference substance | |||
| 1 | 2 | 3 | Meansigma methods | ||
| Time (second) | 9 | 8 | 8 | 8.3 | 13 |
The outstanding again property that shows product of the present invention from table 2 data is better than reference substance.
The invention will be further described for concrete instance of following reuse.
The prescription of preparation is: tobramycin 0.3%, dexamethasone 0.1%, disodium edetate 0.05-0.2%, sodium chloride 0.5-1.0%, tween 80 0.1-0.3%, sodium carboxymethyl cellulose (800-1200 centipoise) 0.5-1.0% bromo geramine 0,01%.
Comprise the adjuvant of sodium carboxymethyl cellulose, tween 80, be made into aqueous solution by prescription, with conventional method under 100 ℃.Heating disinfection sterilization 30 minutes is cooled off standby.Powdered dexamethasone is 160 ℃ of high temperature dry heat sterilizations 3 hours, cooling back and tween 80 mix homogeneously.Tobramycin is sterilized with the degerming membrane filtration with the water for injection wiring solution-forming, and reuse sulphuric acid is regulated pH to 3-4.Then with sodium carboxymethyl cellulose and other adjuvant solution mix homogeneously after, with sodium hydroxide regulate pH of mixed to 5-6 again with dexamethasone blending ingredients mix homogeneously, be ophthalmic suspension finished product of the present invention.Preserve with sealed container.
The invention has the advantages that adjuvant, dexamethasone and tobramycin are respectively with after three kinds of diverse ways sterilizations, mix successively again, regulate pH, overcome the difficult problem of damp and hot change crystal formation of dexamethasone and tobramycin decomposes, improved stability of formulation.
Enumerate several examples below again and further specify the present invention, be not confined to this several examples certainly.
Embodiment one: be used for hot air sterilization processing dexamethasone crystallite and prepare suspension
Hot-air sterilization is by improving the temperature of air, the long-time height of article is heated and reaches sterilization effect.Because the dexamethasone crystallite is unwell to moist heat sterilization, and because of its fusing point height (225 ℃), Undec characteristics are selected dry heat sterilization for use below fusing point.
(1) dexamethasone crystallite 0.5g is placed clean glass dish, 160 ℃ of heating 3.5hr in baking oven, natural cooling.
(2) the refining sodium carboxymethyl cellulose of 2.5g is dissolved in the water for injection, add 5% bromo geramine 1ml, mixing, take by weighing NaCl4g then, disodium edetate 0.5g mixes with the former in low amounts of water dissolving back, and 200 order nylon mesh are filtered, be settled to 400ml, 100 ℃, 30min moist heat sterilization, natural cooling.
(3) take by weighing the 1g tween 80 and put in the small beaker, add the 30ml water dissolution, 100 ℃, 30min moist heat sterilization, natural cooling.
(4) take by weighing the former powder 1.65g of tobramycin of 908 μ/mg, be dissolved in the 30ml water, transfer pH3-4 with dilute sulfuric acid, with 0.22 μ degerming membrane filtration, mixed liquor mix homogeneously in filtrate and (2) is then with rare NaoH accent pH to 5-6.
(5) dexamethasone and tween 80 are put in the aseptic mortar ground, add the blending ingredients mixing in (4) behind the mixing, be settled to 5000ml, while stirring packing.
The every index of suspension of this method preparation all can reach quality standards, and dexamethasone content can be because of high-temperature process reduce, and sterilization effect is good, and suspension granular size and crystal formation do not change, good dispersion.
Embodiment two: handle the dexamethasone crystallite with radiation sterilization and prepare suspension.
(1) dexamethasone crystallite 0.5g is shone with cobalt-60 (60 ℃), dosage is 2.5 * 106 rads.
(2) the 4.0g sodium carboxymethyl cellulose is dissolved in the water for injection, add 5% bromo geramine 1ml, mixing takes by weighing Nacl4g then, disodium edetate 0.5g, in low amounts of water, after the dissolving, mix 200 order nylon net filters again with the former, be settled to 400ml, 100 ℃, 30min moist heat sterilization, natural cooling.
(3) weighing 0.5g tween 80 is put in the small beaker, adds the 30ml water dissolution, and 100 ℃, 30min moist heat sterilization, natural cooling.
(4) take by weighing the tobramycin of 908 μ/mg, former powder 1.65g is dissolved in the 30ml water, transfers pH3-4 with dilute sulfuric acid, and with 0.22 μ degerming membrane filtration, the mixed liquor mix homogeneously in filtrate and (2) is transferred pH to 5-6 with NaoH then.
(5) dexamethasone and tween 80 are put in the aseptic mortar ground, add the blending ingredients mixing in (4) behind the mixing, be settled to 500ml, while stirring packing.
The every index of suspension of this method preparation all can reach quality standards, and dexamethasone content can be because of radiation change, and crystal formation and size do not change yet, and sterilization effect is also better.
Embodiment three usefulness ultraviolet sterilizations are handled the dexamethasone crystallite and are prepared suspension
Ultraviolet is widely used in air sterilization and surface sterilizing, because a little less than its penetration power, so seldom be used for the pressed powder sterilization.But in this example, dexamethasone is spread out straticulation, place the ultraviolet lamp box of sealing, apart from 30 centimetres of uviol lamps (2357_), long-time irradiation (more than the 2hr) still can reach germ-resistant purpose.
(1) dexamethasone crystallite 0.5g is spread out straticulation in clean plate, place the ultraviolet lamp box of sealing, apart from 30 centimetres of uviol lamps (2357_), irradiation 5hr.
(2) the refining sodium carboxymethyl cellulose of 3.5g is dissolved in the water for injection, add 5% bromo geramine 1ml, mixing takes by weighing Nacl4g then, disodium edetate 0.5g, after the dissolving, again with the former mixing, 200 order nylon mesh are filtered in low amounts of water, be settled to 400ml, 100 ℃, 30min moist heat sterilization, natural cooling.
(3) weighing 0.75g tween 80 places small beaker, add the 30ml water dissolution after, 100 ℃, 30min moist heat sterilization, natural cooling.
(4) take by weighing the former powder 1.65g of tobramycin of 908 μ/mg, be dissolved in the 30ml water, transfer pH3-4 with dilute sulfuric acid, with 0.22 μ degerming membrane filtration, the mixed liquor mix homogeneously in filtrate and (2) is transferred pH to 5-6 with rare NaoH then.
(5) dexamethasone and tween 80 are put in the aseptic mortar ground, add the blending ingredients mixing in (4) behind the mixing, be settled to 500ml, while stirring packing.
The every index of suspension of this method preparation all can reach quality standards, and this method sterilization effect is good, and dexamethasone crystal formation and granular size are not all exerted an influence.
Claims (4)
1. the method for making of a compound tobramycin suspension for eye is characterized in that
1-1. with the sodium carboxymethyl cellulose is thickening agent, is wetting agent and other adjuvants with the tween 80, is made into aqueous solution by component, in 100 ℃ of following heating disinfection sterilizations, cooling;
1-2. powdered dexamethasone is used for method sterilization postcooling;
1-3. dexamethasone and the tween 80 after the sterilization, mix homogeneously;
1-4. tobramycin with the water for injection wiring solution-forming after, with the sterilization of degerming membrane filtration;
1-5. regulate tobramycin solution pH to 3-4 with sulphuric acid,, and regulate pH to 5-6 with sodium hydroxide again with sodium carboxymethyl cellulose and other adjuvant solution mix homogeneously;
1-6. tobramycin blending ingredients and dexamethasone blending ingredients mix homogeneously are obtained described compound tobramycin suspension for eye.
2. according to the method for making of the described suspension of claim 1, it is characterized in that said dexamethasone dry method sterilizing methods, can select 160 ℃ of following dry heat sterilizations for use or with the sterilization of the irradiation under ultraviolet ray of 2537A wavelength or select 2-2.5 Megarad radiation sterilization method for use.
3. according to the method for making of the described suspension of claim 1, the thickening agent and the wetting agent that it is characterized in that being used for preparing suspension at component content (weight %) are: the sodium carboxymethyl cellulose of 0.5-1.0 and the tween 80 of 0.01-0.3.
4. according to the method for making of claim 1 or 3 described suspensions, it is characterized in that the viscosity as the sodium carboxymethyl cellulose of thickening agent is 800～1200 centipoises.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97105772A CN1063944C (en) | 1997-04-14 | 1997-04-14 | Method for preparing compound tobramycin suspension for eye |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN97105772A CN1063944C (en) | 1997-04-14 | 1997-04-14 | Method for preparing compound tobramycin suspension for eye |
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| Publication Number | Publication Date |
|---|---|
| CN1164392A CN1164392A (en) | 1997-11-12 |
| CN1063944C true CN1063944C (en) | 2001-04-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN97105772A Expired - Lifetime CN1063944C (en) | 1997-04-14 | 1997-04-14 | Method for preparing compound tobramycin suspension for eye |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101970042A (en) | 2008-02-25 | 2011-02-09 | 眼门药品公司 | Enhanced delivery of a therapeutic to ocular tissues through iontophoresis |
| CN103565816A (en) * | 2012-07-25 | 2014-02-12 | 天津金耀集团有限公司 | Tobramycin-dexamethasone eye drops |
| CN104083323B (en) * | 2014-06-27 | 2016-06-08 | 新乡医学院 | Comprise the eye suspension of tobramycin and Betamethasone Valerate |
| CN105997866B (en) * | 2016-07-13 | 2019-08-20 | 成都明慈医药科技有限公司 | A kind of suspension and preparation method thereof containing dexamethasone |
| CN115006412B (en) * | 2022-05-20 | 2023-11-10 | 北京诺康达医药科技股份有限公司 | Compound tobramycin eye drops and preparation method thereof |
| CN115487153B (en) * | 2022-10-25 | 2023-11-03 | 成都青山利康药业股份有限公司 | Method for protecting crystal forms of compounds |
-
1997
- 1997-04-14 CN CN97105772A patent/CN1063944C/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| 大连医科大学学报，18(4) 1996.1.1 刘波等人"点必舒在治疗眼感染和减少术后眼症中的疗效观察" * |
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| CN1164392A (en) | 1997-11-12 |
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