CN117771160A - Novel oxymetazoline hydrochloride instant ophthalmic gel and preparation method thereof - Google Patents
Novel oxymetazoline hydrochloride instant ophthalmic gel and preparation method thereof Download PDFInfo
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- 229960005162 oxymetazoline hydrochloride Drugs 0.000 title claims abstract description 61
- BEEDODBODQVSIM-UHFFFAOYSA-N oxymetazoline hydrochloride Chemical compound Cl.CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 BEEDODBODQVSIM-UHFFFAOYSA-N 0.000 title claims abstract description 61
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a novel oxymetazoline hydrochloride instant ophthalmic gel and a preparation method thereof; the ophthalmic gel comprises the following components in percentage by mass: 0.05 to 0.20 weight percent of oxymetazoline hydrochloride, 0.10 to 0.60 weight percent of deacetylated gellan gum, 0.10 to 0.50 weight percent of gel matrix, 1.00 to 3.00 weight percent of isotonicity modifier, 0.03 to 0.08 weight percent of dexpanthenol, pH modifier and the balance of water for injection; the pH of the gel is 5.5-7.0. Preparation: s1, stirring and dissolving deacetylated gellan gum and gel matrix in 80-90% of water for injection to obtain gel liquid; s2, mixing and dissolving oxymetazoline hydrochloride, an isotonic regulator and dexpanthenol in the rest water for injection to obtain a solution; s3, mixing the dissolution solution and the gel solution, and adding a pH regulator to regulate the pH of the system to 5.5-7.0 to obtain a mixed solution; s4, performing damp heat sterilization on the mixed solution to obtain the novel oxymetazoline hydrochloride instant ophthalmic gel. The ophthalmic gel is stored in a solution state at normal temperature, forms gel after being dripped into eyes, does not contain preservative, has long drug effect time and has obvious treatment effect on acquired ptosis.
Description
Technical Field
The invention relates to the technical field of medical materials, in particular to a novel oxymetazoline hydrochloride instant ophthalmic gel and a preparation method thereof.
Background
Ptosis (ptosis) is a common clinical manifestation of neurology, which is the partial or complete inability of the upper eyelid to lift, causing excessive limbal coverage of the cornea, resulting in less normal eye fissures in the affected eye. The structure of the upper eyelid is divided into five layers from outside to inside: skin, subcutaneous tissue, eyelid muscles, meibomian, and palpebral conjunctiva. The eyelid skin is thin, subcutaneous tissue is loose, oedema, hemorrhage or inflammation is easy to occur, and the eye crack can be small. The eye fissure refers to a fissure between the upper and lower eyelid when the eye is open. The length of the eyelid crack of the adult human is 20-30mm, and the width (the widest part) is 10-15mm. The width of the eyelid cleavage can be determined by visual inspection and measurement.
Ptosis can be divided into two major categories, congenital and acquired. Congenital is mostly caused by the causes of dysfunction of the nucleus of the eye movement or levator on the upper eyelid, abnormal contraction and relaxation functions of muscle fibers, and the like. The acquired ptosis is mainly caused by lesions of the eyelid itself, but also by nervous system and other systemic lesions, but most often tendinous, due to the climacteric change of the tendinous membrane of the eyelid, stretching or breaking of muscles in cataract surgery, or prolonged wearing of contact lenses. Patients with acquired ptosis may report blurred vision and impaired upper vision, which may interfere with activities of daily living. In addition, the occurrence frequency of the induced factors such as the intraocular surgery and the application of artificial lens is increased, so that the number of patients suffering from ptosis is increased year by year.
Currently, the treatment of ptosis is selected by various surgical methods depending on the degree of ptosis. 1. External surgery: is one of the most commonly used surgical atherectomy procedures. The main disadvantages of this procedure are: epinephrine may affect the function of Muller muscles, and local anesthetics affect the function of the levator muscles, becoming a major error in the intraoperative adjustment of levator muscles; investigation shows that the ratio of re-surgery after the pre-migration of the tenosynovial membrane is about 9% -12%.
2. Internal surgery: the operator is required to be familiar with the inverted eyelid anatomy, which is suitable for patients with mild ptosis and good levator upper eyelid function. The main disadvantages are: (1) The conjunctival Muller myotomy has strict surgical symptoms, namely mild ptosis, good levator palpebrae function and positive phenylephrine test. In addition, the presence of sutures on the conjunctival surface of the eyelid may irritate or damage the cornea, especially in patients who have incorporated corneal dystrophy, post-myopia laser surgery or other intraocular surgery, with the potential to cause serious complications such as corneal ulcers. (2) The excision of the meibomian by the laminectomy results in increased tissue damage by the procedure and may lead to instability of the appearance of the eyelid after the procedure, such as lid deformity like valgus. However, recent reports indicate that only 3mm meibomian retention is able to maintain eyelid stability. (3) Frontal muscle suspension is prone to postoperative complications such as eyelid insufficiency, exposed keratitis, dry eye, delayed falling of upper eyelid, and eversion of eyelid.
Therefore, the effect of the surgical treatment on the patient is large, and no medicine aiming at the acquired ptosis exists in China at present. The oxymetazoline hydrochloride is an organic compound, belongs to oxazoline derivatives, and has a chemical formula of C 16 H 25 ClN 2 O is a sympathomimetic agent with vasoconstrictor effect. The concentration of the oxymetazoline hydrochloride eye drops which is currently sold in the market is 0.025%, and the oxymetazoline hydrochloride eye drops are long-acting local ocular vasoconstriction, and are used for relieving eye symptoms of allergic conjunctivitis and non-infectious conjunctivitis and relieving eye congestion caused by factors such as allergy, dry eye, swimming, smog, contact lenses, fatigue and the like. Through researches, the oxymetazoline hydrochloride can directly act on a Muller myoadrenoreceptor, can obviously stimulate the contraction and the promotion of the upper eyelid, and increases the visual field, thereby relieving the symptoms of the ptosis of the upper eyelid, and is the only medicine for treating the mild and moderate ptosis at present. The ion-sensitive in-situ gel utilizes the environmental-response polymer to enable the medicine to act on eyes in the form of aqueous solution, and phase change is generated under the physiological environment of the eyes to form gel substances, so that the retention time of the medicine on the eyes is prolonged, the defects of low bioavailability and inaccurate instillation dosage of gel preparation of common eye drops are overcome, and the medicine is applied to eyesThe irritation is small.
Disclosure of Invention
The invention aims to provide a novel oxymetazoline hydrochloride instant eye gel which is stored in a solution state at normal temperature, forms gel after being dripped into eyes, does not contain preservative, has long drug effect time and accurate instilling dosage, and has obvious treatment effect on acquired ptosis; the invention also aims to provide a preparation process of the novel oxymetazoline hydrochloride in-situ forming eye gel, which is simple in process.
The invention is realized by the following technical scheme:
the novel oxymetazoline hydrochloride in-situ forming eye gel is characterized by comprising the following components in percentage by mass: 0.05 to 0.20 weight percent of oxymetazoline hydrochloride, 0.10 to 0.60 weight percent of deacetylated gellan gum, 0.10 to 0.50 weight percent of gel matrix, 1.00 to 3.00 weight percent of isotonicity modifier, 0.03 to 0.08 weight percent of dexpanthenol, pH modifier and the balance of water for injection; the content of the pH regulator is as follows: the pH of the ready-to-use ophthalmic gel is set to 5.5-7.0.
The novel oxymetazoline hydrochloride instant ophthalmic gel component provided by the invention does not contain preservative and is safer.
Further, a novel oxymetazoline hydrochloride in-situ forming ophthalmic gel: the in-situ forming eye gel comprises the following components in percentage by mass: oxymetazoline hydrochloride 0.10wt%, deacetylated gellan gum 0.50wt%, gel matrix 0.20wt%, isotonic regulator 2.00-3.00wt%, dexpanthenol 0.05wt%, pH regulator and water for injection for the rest; the content of the pH regulator is as follows: the pH of the ready-to-use ophthalmic gel is set to 5.5-7.0.
Further, a novel oxymetazoline hydrochloride in-situ forming ophthalmic gel: the pH of the instant ophthalmic gel is 5.8-6.8.
Further, a novel oxymetazoline hydrochloride in-situ forming ophthalmic gel: the gel matrix is selected from one of hypromellose, ethylcellulose, sodium carboxymethylcellulose and xanthan gum.
Further, a novel oxymetazoline hydrochloride in-situ forming ophthalmic gel: the gel matrix is xanthan gum.
Further, a novel oxymetazoline hydrochloride in-situ forming ophthalmic gel: the isotonic regulator is mannitol.
Further, a novel oxymetazoline hydrochloride in-situ forming ophthalmic gel: the pH regulator is a nonionic pH regulator.
Further, a novel oxymetazoline hydrochloride in-situ forming ophthalmic gel: the nonionic pH regulator is tris (hydroxymethyl) aminomethane.
The preparation method of the novel oxymetazoline hydrochloride instant ophthalmic gel is characterized by comprising the following steps of:
s1, stirring and dissolving the deacetylated gellan gum and gel matrix in the formula amount into 80-90% of water for injection to obtain gel liquid;
s2, stirring and dissolving the oxymetazoline hydrochloride, the isotonic regulator and the dexpanthenol in the formula amount into the rest water for injection to obtain a solution;
s3, mixing the dissolution liquid with the gel liquid, then adding a pH regulator to regulate the pH of the system to 5.5-7.0, and uniformly stirring to obtain a mixed liquid;
s4, carrying out damp-heat sterilization on the mixed solution to obtain the novel oxymetazoline hydrochloride instant ophthalmic gel.
Further, a preparation method of the novel oxymetazoline hydrochloride in-situ forming eye gel comprises the following steps: the temperature of the wet heat sterilization in the step S4 is 105 ℃ and the time is 25-40 minutes.
The invention has the beneficial effects that:
(1) The instant eye gel is stored in a solution state at normal temperature, and forms a gel after being dripped into eyes, and the instant eye gel does not contain preservative, has long drug effect time and accurate instillation dosage, and has obvious treatment effect on acquired ptosis.
(2) The preparation method of the novel oxymetazoline hydrochloride in-situ forming eye gel provided by the invention is simple, and the prepared in-situ forming eye gel can be used for treating acquired ptosis, especially light-to-medium ptosis, and has remarkable treatment effect. The invention adopts ion-sensitive in-situ gel technology to initiate a novel slow-release medicament for the disease. The application method comprises instilling the medicine on the surface of eyes 1 time a day, 1 drop each time, and the medicine is used before sleeping, the effect of the medicine lasts for 16-20 hours, the effect is obvious for 2-16 hours, the medicine effect lasts for a long time, the product does not contain preservative, the biocompatibility is good, the irritation is avoided, and the medicine can be used for a long time.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. The following description of at least one exemplary embodiment is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The novel oxymetazoline hydrochloride in-situ forming eye gel is characterized by comprising the following components in percentage by mass: oxymetazoline hydrochloride 0.10wt%, deacetylated gellan gum 0.50wt%, gel matrix (xanthan gum) 0.20wt%, isotonic regulator (mannitol) 2.20wt%, dexpanthenol 0.05wt%, nonionic pH regulator (tris (hydroxymethyl) aminomethane) and the balance water for injection; wherein: the non-ionic pH regulator is used in the following amount: the pH of the ready-to-use ophthalmic gel was set to 6.2.
The preparation method of the novel oxymetazoline hydrochloride in-situ forming eye gel described in the embodiment 1 comprises the following specific steps:
s1, firstly, 80% of water for injection by volume is measured, the water for injection is added into a reaction container, the temperature is raised to 70 ℃, then, the deacetylated gellan gum and gel matrix with the formula amounts are weighed and added into the reaction container, and the mixture is stirred and dissolved to obtain gel liquid for standby;
s2, measuring the residual volume of water for injection, adding the water into another reaction container, adding the oxymetazoline hydrochloride, the isotonic regulator and the dexpanthenol according to the formula amount into the reaction container, and uniformly stirring to obtain a solution;
s3, adding the prepared solution into the gel solution, then adding a pH regulator to adjust the pH value of the system to 6.2, and uniformly stirring to obtain a mixed solution;
s4, carrying out wet heat sterilization on the obtained mixed solution at 105 ℃ for 30 minutes to obtain the novel sterile oxymetazoline hydrochloride instant ophthalmic gel.
Example 2
The novel oxymetazoline hydrochloride in-situ forming eye gel is characterized by comprising the following components in percentage by mass: oxymetazoline hydrochloride 0.15wt%, deacetylated gellan gum 0.40wt%, gel matrix (hypromellose) 0.25wt%, isotonic regulator (mannitol) 2.00wt%, dexpanthenol 0.05wt%, nonionic pH regulator (tris (hydroxymethyl) aminomethane) and the balance water for injection; wherein: the non-ionic pH regulator is used in the following amount: the pH of the ready-to-use ophthalmic gel was set to 5.8.
The preparation method of the novel oxymetazoline hydrochloride in-situ forming eye gel described in the embodiment 2 comprises the following specific steps:
s1, firstly, weighing 85% of water for injection by volume, adding the water for injection into a reaction container, heating to 80 ℃, then weighing the deacetylated gellan gum and gel matrix in the formula amount, adding the deacetylated gellan gum and the gel matrix into the reaction container, and stirring for dissolving to obtain gel liquid for standby;
s2, measuring the residual volume of water for injection, adding the water into another reaction container, adding the oxymetazoline hydrochloride, the isotonic regulator and the dexpanthenol according to the formula amount into the reaction container, and uniformly stirring to obtain a solution;
s3, adding the prepared solution into the gel solution, then adding a pH regulator to adjust the pH value of the system to 5.8, and uniformly stirring to obtain a mixed solution;
s4, carrying out wet heat sterilization on the obtained mixed solution at 105 ℃ for 35 minutes to obtain the novel sterile oxymetazoline hydrochloride instant ophthalmic gel.
Example 3
The novel oxymetazoline hydrochloride in-situ forming eye gel is characterized by comprising the following components in percentage by mass: oxymetazoline hydrochloride 0.08wt%, deacetylated gellan gum 0.60wt%, gel matrix (sodium carboxymethyl cellulose) 0.10wt%, isotonic regulator (mannitol) 2.50wt%, dexpanthenol 0.05wt%, non-ionic pH regulator (tris (hydroxymethyl) aminomethane) and the balance water for injection; wherein: the non-ionic pH regulator is used in the following amount: the pH of the ready-to-use ophthalmic gel was set to 6.5.
The preparation method of the novel oxymetazoline hydrochloride in-situ forming eye gel described in the embodiment 3 comprises the following specific steps:
s1, firstly, measuring 90% of water for injection by volume, adding the water for injection into a reaction container, heating to 90 ℃, then weighing the deacetylated gellan gum and gel matrix with the formula amount, adding the deacetylated gellan gum and the gel matrix into the reaction container, and stirring and dissolving to obtain gel liquid for standby;
s2, measuring the residual volume of water for injection, adding the water into another reaction container, adding the oxymetazoline hydrochloride, the isotonic regulator and the dexpanthenol according to the formula amount into the reaction container, and uniformly stirring to obtain a solution;
s3, adding the prepared solution into the gel solution, then adding a pH regulator to adjust the pH value of the system to 6.5, and uniformly stirring to obtain a mixed solution;
s4, carrying out wet heat sterilization on the obtained mixed solution at 105 ℃ for 40 minutes to obtain the novel sterile oxymetazoline hydrochloride instant ophthalmic gel.
Comparative example 1
Comparative example 1 differs from example 1 in that: no deacetylated gellan gum was added in comparative example 1, and the remainder was the same as in example 1.
And (3) testing:
(1) Stability test: the novel oxymetazoline hydrochloride-type ophthalmic gel prepared in example 1 was stored under accelerated stability conditions (40±2 ℃,25% ±5%) and the properties, content, viscosity (25 ℃ viscosity, 34 ℃ viscosity after mixing with tears), pH and osmotic pressure of the preparation were measured after being left under accelerated conditions for a period of time, and stability data are shown in table 1.
Table 1 shows the results of stability test of the novel oxymetazoline hydrochloride as-is ophthalmic gel obtained in example 1
From the test results in table 1, it can be seen that, after six months of investigation, the indexes of the novel oxymetazoline hydrochloride i.e. the ophthalmic gel prepared in the embodiment 1 of the present invention have no significant change, the quality is stable, and it can be inferred that the preparation is stable for 24 months at room temperature.
(2) In vitro release study:
(1) dissolution medium: naCl 6.78g,KCl 1.38g,NaHCO 3 2.18g，CaCl 2 ·H 2 O0.084 g was added to 1L deionized water to give a dissolution medium.
(2) The operation is as follows: performing in vitro release test by dialysis bag method, using 500ml artificial tear as release medium, adding 50g of the instant ophthalmic gel obtained in example 1 into the dialysis bag, regulating the rotation speed of a dissolution instrument to 40rpm, and controlling the temperature to 34+ -0.5deg.C; then sampling 5ml each time in 1h, 2h, 4h, 8h, 12h, 16h, 20h and 24h respectively, and supplementing 5ml of STF at the same time; the main component content was measured, and the cumulative release percentage was calculated as shown in Table 2.
Table 2 shows the in vitro release rate
| Cumulative percent release% | EXAMPLE 1% | Comparative example 1% |
| 1h | 9 | 45 |
| 2h | 21 | 73 |
| 4h | 36 | 85 |
| 6h | 41 | 97 |
| 8h | 55 | 98 |
| 12h | 67 | 98 |
| 16h | 86 | 98 |
| 20h | 95 | 98 |
| 24h | 98 | 98 |
The results in Table 2 show that comparative example 1 reached 98% release in 6 hours, and the drug release was complete. Example 1 released about 10% at 1h, and the cumulative release rate at 16h reached 86% with substantially complete release at 24 h. The results show that the instant ophthalmic gel prepared by the invention has good long-acting slow release effect.
(3) Clinical effects:
the purpose is as follows: comparison evaluation of changes in two measurement indexes after external application of the novel oxymetazoline hydrochloride in-situ forming ophthalmic gel prepared in example 1: upper eyelid position, lower eyelid position.
Sample: the ready-to-use ophthalmic gel prepared in example 1. Patient: healthy people with mild-moderate ptosis, 2 men and women, age 35-50 years.
Group entry criteria: the upper eyelid margin covers the upper limbus of the cornea and is less than or equal to 2mm as a normal value when eyes are opened and the eyes are in plane view; the upper eyelid sagging is diagnosed when the coverage is more than or equal to 2 mm. When eyes look forward in a head-on manner, the difference between the actual value of the upper eyelid margin covering the cornea and the normal value (2 mm) is the sagging amount. The measured sagging amount is divided into light, medium and heavy three degrees, and the light upper eyelid sagging: the sagging amount is 1-2mm, and the upper eyelid margin is positioned at the upper edge of the pupil; moderate ptosis: 3-4mm of sagging amount, and the upper eyelid margin covers the pupil less than 1/2; severe ptosis: the sagging amount is more than or equal to 4mm, and the upper eyelid margin covers the pupil more than 1/2.
The operation is as follows: one drop of the ophthalmic solution A was applied to each eye of the patient 2, and the eye drops were measured once for 2 hours, 8 hours, 16 hours and 24 hours.
Evaluation index: the subjects were looking straight ahead at the fixed position, at different time points after administration, pupil center to upper eyelid height, pupil center to lower eyelid height were measured, and the average value was calculated. The results are shown in Table 3:
table 3 shows the change in upper and lower eyelid heights
From the results in table 3, it can be seen that: the instant ophthalmic gel prepared by the invention has obvious effect after eye drop for 2 hours, the action time lasts for 16-24 hours, and the instant ophthalmic gel is repeatedly used and has the same clinical effect.
The above-described preferred embodiments of the present invention are only for illustrating the present invention, and are not to be construed as limiting the present invention. Obvious changes and modifications of the invention, which are introduced by the technical solution of the present invention, are still within the scope of the present invention.
Claims (10)
1. The novel oxymetazoline hydrochloride in-situ forming eye gel is characterized by comprising the following components in percentage by mass: 0.05 to 0.20 weight percent of oxymetazoline hydrochloride, 0.10 to 0.60 weight percent of deacetylated gellan gum, 0.10 to 0.50 weight percent of gel matrix, 1.00 to 3.00 weight percent of isotonicity modifier, 0.03 to 0.08 weight percent of dexpanthenol, pH modifier and the balance of water for injection; the content of the pH regulator is as follows: the pH of the ready-to-use ophthalmic gel is set to 5.5-7.0.
2. The novel oxymetazoline hydrochloride in-situ forming ophthalmic gel as claimed in claim 1, wherein the in-situ forming ophthalmic gel comprises the following components in mass fraction: oxymetazoline hydrochloride 0.10wt%, deacetylated gellan gum 0.50wt%, gel matrix 0.20wt%, isotonic regulator 2.00-3.00wt%, dexpanthenol 0.05wt%, pH regulator and water for injection for the rest; the content of the pH regulator is as follows: the pH of the ready-to-use ophthalmic gel is set to 5.5-7.0.
3. The novel oxymetazoline hydrochloride in-situ forming ophthalmic gel as claimed in claim 1, wherein the pH of the in-situ forming ophthalmic gel is from 5.8 to 6.8.
4. The novel oxymetazoline hydrochloride in-situ forming eye gel as defined in claim 1, wherein the gel matrix is selected from one of hypromellose, ethylcellulose, sodium carboxymethyl cellulose, xanthan gum.
5. The novel oxymetazoline hydrochloride in-situ forming eye gel as defined in claim 4, wherein the gel matrix is xanthan gum.
6. The novel oxymetazoline hydrochloride on-demand ophthalmic gel as claimed in claim 1, wherein the isotonicity modifier is mannitol.
7. The novel oxymetazoline hydrochloride in-situ forming eye gel as defined in claim 1, wherein the pH adjustor is a nonionic pH adjustor.
8. The novel oxymetazoline hydrochloride as defined in claim 7, wherein the nonionic pH adjuster is tris (hydroxymethyl) aminomethane.
9. A method for preparing a novel oxymetazoline hydrochloride on-demand ophthalmic gel as claimed in any one of claims 1 to 8, comprising the steps of:
s1, stirring and dissolving the deacetylated gellan gum and gel matrix in the formula amount into 80-90% of water for injection to obtain gel liquid;
s2, stirring and dissolving the oxymetazoline hydrochloride, the isotonic regulator and the dexpanthenol in the formula amount into the rest water for injection to obtain a solution;
s3, mixing the dissolution liquid with the gel liquid, then adding a pH regulator to regulate the pH of the system to 5.5-7.0, and uniformly stirring to obtain a mixed liquid;
s4, carrying out damp-heat sterilization on the mixed solution to obtain the novel oxymetazoline hydrochloride instant ophthalmic gel.
10. The method for preparing a novel oxymetazoline hydrochloride in-situ forming eye gel as claimed in claim 9, wherein the temperature of the wet heat sterilization in step S4 is 105 ℃ for 25-40 minutes.
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