JPS597684B2 - Ophthalmic sustained release controlled drug using collagen - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to ophthalmic sustained release controlled pharmaceutical agents containing collagen.

More specifically, the present invention relates to an ophthalmic sustained-release controlled pharmaceutical agent characterized by containing one or more of solubilized collagen and an ophthalmic agent.

The present invention effectively and stably releases the minimum required amount of the drug over a long period of time by mixing and binding a drug to the collagen, which is a biopolymer, and administering the drug locally. On the other hand, collagen is related to an ophthalmic therapeutic agent that has the characteristic of dispersing and dissolving and disappearing locally.

While pharmaceuticals play a large role in the treatment of diseases, side effects caused by pharmaceuticals have also become a problem.

In order to make medicines effective and have fewer side effects,
It must reach the desired tissue or organ (referred to as a target) without waste.

However, in administration methods such as oral administration, in order for the drug to reach its target, it is absorbed through the stomach and intestines and enters the bloodstream, during which time it is broken down and metabolized.

In addition, drugs that enter the blood are absorbed from blood vessels throughout the body and reach tissues and organs throughout the body other than the target, often causing side effects, and the amount of drugs that reach the patient is proportional to the dose. It is a trace amount.

Therefore, oral administration requires a much larger amount of drug to be administered than is required by the target.

If it becomes possible to administer directly only to the target,
Furthermore, if the necessary medicines can be administered for a certain period of time, side effects caused by the medicines can be avoided and ideal medicines can be obtained.

Many therapeutic agents for eye diseases are generally used in the form of eye drops or ointments.

Although such treatments are satisfactory for eye diseases where only one or a few medicinal applications are required, patients are not satisfied with the treatment of eye diseases that require more frequent use. It is inconvenient for

Furthermore, in the case of conventional eye drops, more of the eye drops flowed out as tear fluid, and only a portion of the amount of eye drops was actually effective as a medicine.

According to the present invention, collagen is used as a support for pharmaceuticals and used as an ophthalmic drug.
c) By inserting the drug into the nasolacrimal duct and gradually releasing the drug, a sustained drug effect can be obtained by effectively utilizing the drug, and furthermore, the loss of the drug into the nasolacrimal duct can be minimized.

Another feature of the present invention is that collagen is completely dissolved and washed away by lachrymal fluid, so there is no need to take it out.

Collagen is the main protein in animal connective tissue, and most of it is soluble collagen.

The collagen used in the present invention is solubilized collagen as described above, which is produced from collagen in the following manner.

There is a method of solubilizing the insoluble collagen in water using a proteolytic enzyme while retaining the original molecular structure of the collagen (Japanese Patent Publication No. 37-13871, 37'-14426).
and 44-1175), and a method of solubilizing insoluble collagen in the coexistence of an amine, an alkali, and sodium sulfate in exactly the same manner as the enzymatic method (described above) (Japanese Patent Publication No. 46-1
5033) etc.

In either method, the collagen molecule is solubilized in water while maintaining its structure by cleaving the telopeptide chain at the end of the molecule.

Since such collagen does not have a telopeptide moiety, it is characterized as having low immune activity as an artificial organ material, good compatibility with living tissues, and being gradually absorbed into tissues without inflammatory reactions.

In addition, since collagen is a protein, it has the ability to retain various pharmaceuticals, and has good properties as a supporting agent for pharmaceuticals in sustained-release controlled administration, in combination with its low immune activity.

The pharmaceutical agent used in the present invention may be either water-soluble or water-insoluble.

Ophthalmic drugs include mydriatics such as atropine, homatropine, scopolamine, hydroxyamphetamine,
phenylephrine, cyfresin, lakesin, cyclopentolate, tropicamide, etc.

Miotics, such as pilocarpine, physostigmine, carbamylcholine, demecarium, phosphorin iodide, etc.

β-lactam antibiotics of antibiotic f preparations, such as cephalexin, cephalothin.

Tetracycline antibiotics, e.g. tetracycline.

Aminoglucoside antibiotics, such as streptomycin, kanamycin, ribostamycin, dibekacin, aminodeoxykanamycin.

Macrolide antibiotics, such as midecamycin.

Corticosteroid anti-inflammatory agents, such as cortisone, hydrocortisone, betamethasone, dexamethasone, glednisolone, fluorocortolon, and triamcinolone.

β-receptor blockers, such as glopranolol, vindolol, alprenolol, fufetrol, fufuranolol, fnitrol, plactorol, oxyprenolol, etc. and pharmaceuticals or derivatives thereof, such as idoxuridine, epinephrine, glycyrrhizic acid, vidarabine, etc. , such as salts, covalent derivatives such as esters or amides,
or other therapeutically active forms of the drug.

Regarding pharmaceutical control agents using collagen, Japanese Patent Application Laid-Open No. 50-42025 is disclosed as a prior art.

The content is related to the production of a gel-like or film-like pilocarpine-containing pharmaceutical control agent, which is characterized by bringing collagen, which has a molecular structure in which no telopeptide exists, and pilocarpine, an intraocular hypotensive agent, into contact and mixing the two. be.

When used as a solution, collagen has a maximum concentration of about 20%, but since the viscosity of collagen solutions is extremely high, the use limit for collagen is 5% at most in order to produce the film-like or gel-like forms described in JP-A-50-42025. It is concentration.

Furthermore, in the above manufacturing method, the gel form requires steps such as crosslinking with gamma rays or ultraviolet rays, followed by washing with water, and the film type form using an air drying method requires a long time to dry. When considering the production of dogs, there is a problem with economic efficiency.

In the present invention, the precipitate at the isionic point of collagen dissolved by the enzymatic method or the alkali method, that is, the collagen precipitate at pH 7 to 9 for collagen solubilized by the enzymatic method, and the collagen precipitate at pH 4.8 for collagen solubilized by the alkali method. A precipitate having a collagen concentration of 30 to 70% by weight obtained by concentrating the collagen by centrifugation or pressure filtration is used.

On the other hand, in order to improve moldability, for example, polyethylene glycol is added to this collagen and pharmaceutical mixture.
5 to 2 glopylene glycol or ethyl alcohol
It is used by adding 0% by weight and extrusion molding to form a rond, or by tableting with a tablet machine and drying if necessary.

The pharmaceutical agent of the present invention has the following characteristics: during manufacturing, the steps after drug mixing are simple, and since the water content is low and collagen is highly concentrated, it is easy to dry, and the amount of drug can be kept constant. There is.

Furthermore, the pharmaceutical agent of the present invention is disclosed in the above-mentioned Japanese Patent Application Laid-Open No. 50-4202.
It has a significantly superior long-lasting effect compared to those described in No. 5.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 1 A collagen content of 30% obtained by centrifugally concentrating telopeptide-free solubilized collagen prepared by a method for dissolving insoluble collagen by enzymatic treatment, for example, the method described in Japanese Patent Publication No. 44-1175 at pH 8. 100 g of the collagen precipitate, a solution of pilocarpine hydrochloride 41 dissolved in 25 IrLl of water, and polyethylene glycol to make molding easier by lowering the stickiness of the collagen precipitate and to maintain flexibility after drying. Add 31 pieces of 400 and mix well.

This mixture was extruded through a nozzle with an inner diameter of 2 mrlL and dried.

The diameter of the rondo after drying was 1 mm.

This Rondo was cut into lengths of 6 mm (weight 6η, pilocarpine content 0.7~), and five of them were placed in 200 d of Ringer's solution and the amount of pilocarpine eluted into the solution at 37°C was measured.

The results are shown in Figure 1.

As shown in FIG. 1, the curve plotting the pilocarpine release percentage against time is an integral type exponential function curve, which can be expressed by equation (1) where Y is the release percentage and t is the time.

k is a release constant, which is a value unique to the formulation, and calculated from the experimental values shown in FIG. 1 to be 0.035 m'.

It can also be calculated using the following formula.

T+ is the time at which % of the drug in the formulation is released, hereinafter referred to as the "half-life of release."

T+ is also a formulation specific value. The "half-life of release" in this example was 19.8 minutes.

Vilocarpine hydrochloride is highly soluble in water, and if the experiment shown in Figure 1 is carried out using powdered pilocarpine hydrochloride of 3.5 to 50%, it will instantly dissolve 100%.

Therefore, from the results shown in FIG. 1, it can be seen that the collagen rod effectively controls the elution of pilocarpine.

When one of these 6-eye length Rondo was inserted into the inside of the rabbit's lower eyelid, the pupils began to constrict 7 minutes later, and constriction continued for 6 hours.

Fig. 2 also shows the state of pupil constriction when 0.6% pilocarpine eye drops were instilled into the rabbit's eyes.

When the eye drops were used, the pupil constriction reached its maximum after 20 minutes and returned to normal after 80 minutes, whereas when the collagen rod was inserted, the pupil constriction reached its maximum after 2 hours and continued for up to 6 hours.

Also, this pilocarpine collagen rod 6mm
When a glaucoma patient with a length of

Ringer's solution 200IrL from the formulation shown in Figure 1 above.
Considering the results of the pilocarpine release test in humans and the results of the drug efficacy durability test in animals and patients described above, it is concluded that if the "half-life of release" T+ is set to about 20 minutes, sufficient action will be achieved in the living body. It was found that the formulation has a long-lasting effect and satisfactorily achieves the purpose of the present invention.

Note that the collagen rods dissolved and disappeared within one day.

Example 2 Solubilized collagen free of telopeptides produced by the alkaline method described in Japanese Patent Publication No. 46-15033 was
20000-30000r. p. m.
The precipitate with a collagen concentration of 50% obtained by centrifugation at
In 01, 7 g of pilocarpine hydrochloride was dissolved in 10 ml of water, and 5 g of ethyl alcohol was added to improve moldability, and the mixture was thoroughly kneaded.

This was pressure-molded using a lmrnO type having a length of 8 mm, a width of 2 mm, and a thickness, and then dried.

After drying, length: 7 mm, width: L: 2 mm, thickness: 0. It was 5 mm and weighed 6 m9.

The pilocarpine release constant k of this molded product into 200 ml of Ringer's solution was 0.028 mm ("tear"), and the half-life of pilocarpine release was 24.75 minutes, and the effect was exactly the same as that obtained in Example 1. Yes, when applied to patients with glaucoma,
One molded product sustained the reduction in intraocular pressure for more than one day.

Note that the collagen molded product dissolved and disappeared in 6 hours.

Example 3 Dexamethasone sodium sulfate powder 0.61 was suspended in 20 ml of water to 100 g of a precipitate with a collagen content of 30% at pH 4.8 of solubilized collagen obtained by the alkaline method described in Japanese Patent Publication No. 46-15033. Add the prepared ingredients and knead well to mix.

This mixture was extruded from a nozzle with an inner diameter of 2 mm and dried in the same manner as in Example 1.

The diameter of the rondo after drying was 1 mrlL. Also, the weight of one piece of this Rondo with a length of 6 mm is 5-5 1n.
9 and dexamethasone sodium sulfate 0.1 mI? It contained.

The release properties of dexamethasone M soda from this Rondo were measured using 200 ml of Ringer's solution in the same manner as in the above examples, and the release constant k was 0.021 m-1, and the half-life of release was 33 minutes. This was sufficient to show sustained action in living organisms.

Example 4 1 g of Idoxuridine was added to 100 fl of a precipitate with a collagen content of 30% at pH 4.8 of solubilized collagen obtained by the alkaline method described in Japanese Patent Publication No. 46-15033 and added to 20 l of water. Add the suspension and mix well.

This mixture was extruded from the same nozzle with an inner diameter of 2 mm as in Example 1 and dried.

The diameter after drying was 1 mrn.

Moreover, the weight of the 6 mm length was 5.5 cm, and it contained 0.17 η of idoxuridine.

The release of idoxuridine from this mixture was determined at 200 m
As a result of measurement using L Ringer's solution, the release constant k is 0.
．． 008mi! L” and the half-life of release is 86.6
The results were sufficient to show that the drug had a sustained action in living organisms.

Reference Example 1 One eye of 7 primary open-angle glaucoma patients was randomly selected and a collagen rod (10 mm long) containing pilocarpine prepared according to Example 1 was inserted into the inferior conjunctival sac, and the intraocular pressure and pupil diameter were measured over time. Observed fluctuations.

Furthermore, after two weeks, 100 μt of 4% pilocarpine was instilled into the eyes, and changes in intraocular pressure and pupil diameter over time were observed.

Figures 3 and 4 show the temporal changes in intraocular pressure and pupil diameter of the experimental eye, with the untreated eye as a control.

When administered encapsulated in collagen, pilocarpine showed a significantly prolonged effect compared to when administered as eye drops, and a statistically significant difference was observed between the two effects at 8 and 24 hours after administration ( P<0.05).

In particular, 24 hours after administration of eye drops, the effects of pilocarpine on the pupil and intraocular pressure disappeared, whereas when administered encapsulated in collagen, a significant reduction in miotic intraocular pressure was observed even after 24 hours.

Reference Example 2 Collagen rods containing pilocarpine (diameter 1.4 m) prepared according to Example 1 were administered to seven patients with open-angle glaucoma.
m, length 10, pilocarpine hydrochloride 1.2~, collagen 5. Or III? ) (hereinafter abbreviated as “Rondo”)
Collagen film containing pilocarpine (thickness 0.46 mm,
Area 0.32 crA, pilocarpine hydrochloride 12.8~,
Collagen 5.1η) (hereinafter abbreviated as “film”)
Next, 100 μt of 4% pilocarpine ophthalmic solution (4 ml of pilocarpine hydrochloride) (hereinafter referred to as "ophthalmic solution") was administered to each eye according to the crossover method at two-week intervals, and the other eye was used as a control. Changes in pressure over time were measured and recorded with a Schwarzer electrotonometer.

Rondo and film were inserted into the inferior conjunctival sac, and eye drops were instilled into the eyes.

The effects of pilocarpine upon administration of each drug completely disappeared two weeks after administration.

The results are shown in Figure 5. From FIG. 5, it can be seen that the collagen rondo of the present invention exhibits a significantly superior long-lasting effect compared to the eye drops and the film described in JP-A-50-42025.

[Brief explanation of drawings]

FIG. 1 shows the release curve of pilocarpine, FIG. 2 shows the miosis curve using collagen rods, FIGS. 3 and 5 show the results of a comparative experiment on intraocular pressure, and FIG. 4 shows the results of a comparative experiment on miosis rate.

Claims (1)

[Claims] 1. The collagen content of the precipitate at the isoionic point is 30
1. An ophthalmic sustained-release controlled pharmaceutical agent, characterized in that it contains ~70% by weight of solubilized collagen and one or more of a drug to be taken, and is in a molded form. 2. The pharmaceutical agent according to claim 1, wherein 5 to 20% by weight of lower or higher polyhydric alcohol is added to the collagen as a shaping aid. 3. The ophthalmic drug is one selected from mydriatic agents, miotic agents, antibiotic preparations, corticosteroid anti-inflammatory agents, beta receptor blockers, idoxuridine, epinephrine, glycyrrhizic acid, and vidarabine. Alternatively, the pharmaceutical agent according to claims 1 to 2, which contains two or more. 4. The pharmaceutical agent according to claims 1 to 3, which is in a rondo form.