JP4859283B2 - Highly stable anti-cataract pharmaceutical composition - Google Patents

Description

【００２２】
Ｃ.使用実験動物
雌性白色家兎(ウサギ、２〜３ｋｇ)を使用し、ウサギは２５±２℃の飼育室でケージに入れ、十分な給水と餌(クレアＣＲ−３)を与えたものを使用した。
【００２３】
２.試験
(Ａ)各処方における(ＤＤＣ)₂Ｚnの溶解度測定法
実験方法
ＨＰＬＣを用いて(ＤＤＣ)₂Ｚnの定量を行った。ＨＰＬＣは島津製作所製LC−10AD、カラムMightysil RP-1８ GP ５０−２.０(３μｍ)(関東化学)を用いた。移動相として０.１％ＴＦＡ を含む４５％アセトニトリルを流速０.２５ ｍL/min、３５℃でＨＰＬＣをおこなった。ＤＤＣの検出には波長２１５nmを使用した。ＨＰＬＣ用サンプルとして検体５０μLに対し、内部標準物質として２.５μｇ/ｍLインドメタシン−メタノール溶液１００μLを添加し、調製した。(ＤＤＣ)₂Ｚnの検量線は(ＤＤＣ)₂Ｚn(４〜４０μｇ/ｍL)５０μLに内部標準物質インドメタシン−メタノール溶液(２.５μｇ/ｍL)１００μLを用いて同上の操作により作成した。
【００２４】
(ＤＤＣ)₂Ｚnのピーク面積を内部標準物質インドメタシンのピーク面積で割った比を縦軸、(ＤＤＣ)₂Ｚnの濃度を横軸にとり、検量線の傾きをもとに、(ＤＤＣ)₂Ｚnの濃度は次のようにして求めた。

【００２５】
実験結果
水に不溶の(ＤＤＣ)₂ＺnがＨＰＣＤを添加することによって、水に溶解され得ることがわかる。さらに加熱処理することによって溶解性が増大した。処方３、５、７の非加熱処理製剤は、ＨＰＭＣ含量の増加に伴い溶解度が上昇したが、加熱処理した処方２、６および８では、ＨＰＭＣ含量の増加に伴い溶解度は劇的に増加した。図１は(ＤＤＣ)₂Ｚnの可溶化に対するＨＰＭＣの添加と加熱処理の影響を示す(Ｘ軸の数字は表１の製剤の処方番号を示す)。
【００２６】
(B)各処方における(ＤＤＣ)₂Ｚnの安定性試験法
実験方法
各処方を８０℃(０、４、８、１６、３２、６４h)、９０℃(０、２、４.５、９、１３.５、１８h)、１００℃(０、０.５、１.５、３、４.５、６ｈ)で加熱した後(A)の溶解度測定法と同様の方法を用いて、(ＤＤＣ)₂Ｚn濃度をＨＰＬＣにより測定した。測定された(ＤＤＣ)₂Ｚn濃度を次の一次速度式を用いて消失速度定数を求めた。
【数１】

ここで、(ＤＤＣ)₂Ｚn初濃度C₀、加熱時間ｔでの(ＤＤＣ)₂Ｚn濃度C、消失速度定数をｋとした。
【００２７】
各処方について、８０℃、９０℃、１００℃における速度定数ｋを求めArrhenius Plotsを作成した。Arrhenius Plotsは直線を示した。また、算出された消失速度定数ｋを次のArrhenius式：
【数２】

(ここで、Ｅaは活性化エネルギー、Ａは頻度係数、Ｒは気体定数、Ｔは絶対温度を表す)に代入し各処方の活性化エネルギー(Ｅa)及び頻度因子(A)をそれぞれ算出した。プロットの傾きは活性化エネルギー(Ｅa)を、Y軸の切片は頻度因子(A)を表す。
【００２８】
実験結果
いずれの処方の製剤もArrhenius Plotsにより直線性が認められたことにより、(ＤＤＣ)₂Ｚnの分解は温度依存性であることが判明した。活性化エネルギーと頻度因子から任意の温度での製剤中の(ＤＤＣ)₂Ｚnの分解速度を算出することができる。
【００２９】
標準温度２５℃での製剤中の(ＤＤＣ)₂Ｚnの分解速度を算出した結果、処方６が最も小さく、ここから更に算出した２５℃での(ＤＤＣ)₂Ｚnの９０％残存に至る時間は約３０年と非常に安定であることが証明された。また、HPMCを含む製剤は非含有の製剤に比較し安定性が高いことが判明した。各処方の熱力学的及び安定性に関するパラメーターを表２に示す。
【００３０】
【表２】

Ｅaは活性化エネルギー、Ａは頻度係数、ｋ_２５℃は２５℃における分解速度、ｔ_{０ . ９ , ２５℃}は２５℃で９０％残存に至る時間である。
【００３１】
(Ｃ)In ｖitroウサギ角膜透過性試験
実験方法
Ｃ−１緩衝液の調製：ＨＥＰＥＳ(+Ｇlc)緩衝液
１０mM ＨＥＰＥＳ、１３６.２mM ＮaＣl、５.３mM ＫＣl、１.０mM Ｋ_２ＨＰＯ_４、１.７mM ＣaＣl_２・２Ｈ_２Ｏ、５.５mＭ glucoseの順に加えて溶解し、３７℃、１Ｎ ＮaОＨでpＨ７.４に調製し、メンブランフィルターMinisart CE(Sartorius,０.２０ μm)でろ過し、以下の実験で使用した。
【００３２】
Ｃ−２角膜透過実験
雌性白色家兎(体重２.５〜３.０ｋｇ)に空気を耳静脈より注入することにより安楽死させた後、眼球を丁寧に摘出し、強膜部分を約１〜２mmを残して角膜部分を傷付けないように摘出した。この角膜をアクリル樹脂製角膜透過セルに装着し、リザーバー側には等張ＨＥＰＥＳ緩衝液(pＨ７.４)、ドナー側には(ＤＤＣ)₂Ｚn製剤(表１の処方５及び６)を注加し、角膜表面温度である３５℃で加熱した。経時的に５０μＬずつリザーバー側から試料を採取し、透過ＤＤＣ量をＨＰＬＣにより測定した
【００３３】
得られたデータは、次式に基づき非線形最小二乗法コンピュータプログラムMULTIを用いて当てはめ計算を行い、速度論的パラメータの算出を行った。
【数３】

ここで、JcはDDCの透過速度、Kmは角膜／製剤の分配係数、Dは角膜内での拡散係数、τはラグタイム、δは角膜の厚さ（平均0.0625 cm）、Aは用いた角膜の有効面積（0.64 cm²）、Qはt時間にリザーバー側に透過した積算薬物量、C_HPCDは(ＤＤＣ)₂Ｚn‐ＨＰＣＤ溶液製剤中の(ＤＤＣ)₂Ｚn濃度である。Jc及びτは、上記の式に当てはめ算出した。
【００３４】
実験結果
実験開始から３時間までは、処方５の非加熱処理製剤と、処方６の加熱処理製剤は、ともに非常にゆっくりした透過を示した。しかし、３時間以降では加熱処理を行った処方６の方が透過速度の増加は大きくなった。図２は(ＤＤＣ)₂Ｚn‐ＨＰＣＤ溶液製剤のin vitroウサギ角膜透過性を示す。また、得られたデータを解析し、透過パラメータを算出した結果を表３に示す。
【００３５】
【表３】

【００３６】
実質的な透過速度を表すJcは、加熱処理を行った処方６製剤が処方５製剤より１.８倍大きく、製剤中の(ＤＤＣ)₂Ｚn濃度が高いものほど透過速度が大きくなることが示された。適用製剤中の単位(ＤＤＣ)₂Ｚn量当たりの薬物透過速度であるKpは、ほぼ同じであることから、薬物濃度が高いほど実質的な透過速度Jcを上昇させることが判明した。
【００３７】
【実施例】
実施例１
０.５％(ＤＤＣ)₂Ｚn、１０％ＨＰＣＤ、０.９%ＮaＣl、０.００５%BCに０.１％ＨＰＭＣを加えた後４８時間以上撹拌し、その後、メンブランフィルターMinisart CE(Sartorius、０.２μｍ)を用いてろ過して水性点眼剤を調製した。
【００３８】
実施例２
０.５％(ＤＤＣ)₂Ｚn、１０％ＨＰＣＤ、０.９%ＮaＣl、０.００５%BCに０.１％ＨＰＭＣを加えた後４８時間以上撹拌し、その後、メンブランフィルターMinisart CE(Sartorius、０.２μｍ)を用いてろ過し、沸騰水浴中で３０分間煮沸して水性点眼剤を調製した。
【００３９】
実施例３
０.５％(ＤＤＣ)₂Ｚn、１０％ＨＰＣＤ、０.９%ＮaＣl、０.００５%BCに０％、０.２５％ＨＰＭＣを用いて、実施例１と同様に調製した。
【００４０】
実施例４
０.５％(ＤＤＣ)₂Ｚn、１０％ＨＰＣＤ、０.９%ＮaＣl、０.００５%BCに０％、０.２５％ＨＰＭＣを用いて、実施例２と同様に調製した。
【図面の簡単な説明】
【図１】 (ＤＤＣ)₂Ｚnの可溶化に対するＨＰＭＣの添加と加熱処理の影響を示す棒グラフである(Ｘ軸の数字は表１の製剤の処方番号を示す)。
【図２】 処方５(非加熱処理)および処方６(加熱処理)の(ＤＤＣ)₂Ｚn‐ＨＰＣＤ溶液製剤のin vitroのウサギ角膜透過性を示す折線グラフである。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising a compound having an anti-cataract effect that forms a chelate with diethyldithiocarbamic acid and zinc.
[0002]
[Background Art and Problems to be Solved by the Invention]
The average life expectancy in Japan is the highest in the world, and we are facing an aging society. According to a survey by the Ministry of Health and Welfare, there are over 1.5 million cataract patients in Japan. However, at present, no effective treatment for cataract has been developed other than surgical treatment. Furthermore, this surgical therapy is not only good, but it is also not suitable for surgery for patients with advanced symptoms of diabetes and hypertension, and postoperative cataracts in which the lens inserted in the eye becomes cloudy after surgery. Increasing medical expenses associated with the onset and increased cost of surgery have been greatly highlighted. The present inventors have attempted pharmacotherapy for cataract, and have already disclosed that diethyldithiocarbamic acid (DDC) and its derivatives have an anti-cataract action, and have sought to increase bioavailability by formulation (Japanese Patent Laid-Open No. 7-1993). 233057).
[0003]
DDC is difficult to pass through the cornea because it is water-soluble, so it is hardly taken into the aqueous humor and the lens. Therefore, bioavailability is low, it is easily oxidized and unstable, and it exhibits its medicinal effects. Due to the disadvantage that it cannot be obtained, it was difficult to use it as a drug as it was.
[0004]
[Means for Solving the Problems]
An object of the present invention is to provide a DDC that has high bioavailability, is more stable, and does not affect the anti-cataract effect. This problem is solved by using zinc diethyldithiocarbamate ((DDC) ₂ Zn) chelated with zinc.
[0005]
Accordingly, the first of the present invention provides a highly stable anti-cataract pharmaceutical composition comprising zinc diethyldithiocarbamate ((DDC) ₂ Zn) as an active ingredient.
[0006]
The second aspect of the present invention is an anti-cataract pharmaceutical composition in which (DDC) ₂ Zn chelate compound is further formed into an inclusion complex with cyclodextrin or a derivative thereof, thereby realizing complete solubilization of the compound. I will provide a.
[0007]
(DDC) ₂ Zn has high bioavailability and could solve the purpose of providing a more stable and non-influenced anti-cataract DDC, but it is difficult to apply to aqueous eye drops because it is insoluble in water. It is. Conventionally, for water-insoluble drugs, heterogeneous preparations in which solid or liquid particles are dispersed in water have been exclusively used. Examples of these preparations include suspension preparations, emulsions, and liposome preparations. However, those having low retention in the ocular mucosa, such as eye drops, have the disadvantage that they are washed away by tears before the drug is sufficiently transferred to the cornea or ocular mucosa. Ophthalmic ointments and oily preparations with improved retention in the ocular mucosa have been formulated for the purpose of solving this problem, but ophthalmic drugs used to restore visual acuity have been accompanied by a decrease in visual acuity for a while. Result. In addition, since solution eye drops are considered to have good drug utilization (bioavailability), the water-insoluble drugs described above have been solubilized using surfactants. A surfactant is a compound having an affinity for both water and oil, and has been conventionally used for steroidal anti-inflammatory agents and the like. However, it is considered unsuitable as a solubilizer for drugs used over a long period of time, such as anti-cataract drugs.
In addition, the stability of the compound in an aqueous solution is very poor.
[0008]
By forming an inclusion complex, (DDC) ₂ Zn, which is insoluble in water, can be dissolved in water (FIG. 1), and the permeability of the cornea can be increased, increasing bioavailability. (Fig. 2). It also enhances the safety and stability of anti-cataract drug formulations, enables long-term use (Table 2), and eliminates psychological anxiety during patient use through complete dissolution of the active ingredient drug. .
[0009]
The third aspect of the present invention provides a highly stable anti-cataract pharmaceutical composition in which heat treatment is performed during the formation of an inclusion complex of (DDC) ₂ Zn and a cyclodextrin compound. By carrying out the heat treatment, the amount of (DDC) ₂ Zn included in the cyclodextrin is increased, or the two molecules are included in the cyclodextrin, so that the solubility is increased. This can increase corneal permeability for a long time and increase bioavailability (FIG. 2).
[0010]
The fourth aspect of the present invention was to establish further stabilization of (DDC) ₂ Zn by adding a soluble cellulose derivative that is a fibrous polymer, such as hydroxypropylmethylcellulose (HPMC) (Table 2) Anti-cataract A pharmaceutical composition is provided.
[0011]
The following formula:
[Chemical 1]
[(C ₂ H ₅ ) ₂ NS ₂ ] ₂ Zn
(DDC) ₂ Zn, which is a white powder having a melting point of 177 ° C., is soluble in organic solvents such as benzene and chloroform, but is insoluble in water, ethanol and the like, natural rubber, styrene-butadiene, acrylonitrile-butadiene. It is used as a vulcanization accelerator for synthetic rubber and latex such as isobutylene-isoprene. Toxicity is low (LD50 (rat, oral) 3340 mg / kg body weight). This compound has never been used in ophthalmic anti-cataract pharmaceutical compositions.
[0012]
Cyclodextrin and derivatives thereof are used as the cyclodextrin compound for forming the inclusion complex used in the present invention, and α-, β-, γ-cyclodextrin, 2,6-di-O-methyl-β- Cyclodextrin, 2,3,6-tri-O-methyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin, 2,3-dihydroxypropyl-β-cyclodextrin, glycosyl-β-cyclodextrin, maltosyl-β-cyclodextrin and the like can be mentioned, preferably 2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl- β-cyclodextrin, 2,3-dihydroxypropyl-β Cyclodextrin, glycosyl -β- cyclodextrin, a maltosyl -β- cyclodextrin, most preferably a 2-hydroxypropyl -β- cyclodextrin.
[0013]
The amount of cyclodextrin and its derivative added to (DDC) ₂ Zn is 0.1 to 50%, preferably 0.5 to 30%, more preferably 0.5 to 20%.
[0014]
Examples of the stabilizer for (DDC) ₂ Zn used in the present invention include sodium carboxymethylcellulose (CMC · Na), methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), sodium alginate and the like. PVA and HPMC are preferable, and HPMC is more preferable.
[0015]
The amount of stabilizer such as HPMC added to (DDC) ₂ Zn is 0.05 to 10%, preferably 0.1 to 5%, more preferably 0.1 to 1.0%.
[0016]
The (DDC) ₂ Zn of the present invention is prepared by ophthalmic preparations, for example, aqueous, together with other drugs and additives such as buffers, isotonic agents, preservatives, thickeners, suspending agents, etc. It can also be formulated into eye drops, aqueous suspension eye drops, non-aqueous (oil-based) eye drops, non-aqueous (oil-based) suspension eye drops, eye washes, eye ointments, etc., but in particular cyclodextrin or its derivatives Can be suitably formulated into aqueous eye drops (including aqueous suspension eye drops).
[0017]
The content of (DDC) ₂ Zn in the ophthalmic preparation is not particularly limited due to its low toxicity, and can be appropriately determined by those skilled in the art and doctors. The dose per dose is 1 μg to 5 mg, per day. The dosage is 5 μg to 50 mg.
[0018]
Pharmacological tests The pharmacological tests (A) to (C) were carried out using the following experimental materials and experimental methods.
(A) (DDC) ₂ Zn solubility measurement test
(B) Thermal stability test of (DDC) ₂ Zn solution formulation
(C) (DDC) ₂ Zn-HPCD solution formulation in vitro rabbit cornea permeability test
Experimental materials and tests 1. Experimental materials A. Reagents
(DDC) ₂ Zn, 2-hydroxylpropyl-β-cyclodextrin (HPCD), hydroxypropylmethylcellulose (HPMC), indomethacin, trifluoroacetic acid (TFA, for high performance liquid chromatography), methanol (for high performance liquid chromatography), Acetonitrile (for high performance liquid chromatography), benzalkonium chloride (BC), sodium chloride (special grade) (NaCl), N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), potassium chloride (special grade) ), Dipotassium hydrogen phosphate (special grade), calcium chloride dihydrate (special grade), glucose (special grade)
[0020]
B. Formulation used: 0.5% (DDC) ₂ Zn, 10% HPCD, 0.9% NaCl, 0.005% BC added 0%, 0.1% or 0.25% HPMC for more than 48 hours Stir.
Then, the filtrate filtered using a membrane filter Minisart CE (Sartorius, 0.2 μm) is used as a sample. The heat treatment was performed by adding the sample to a stoppered test tube and boiling in a boiling water bath for 30 minutes.
The ingredients of each formulation are shown in Table 1 below.
[0021]
[Table 1]

[0022]
C. Use experimental animals Female white rabbits (rabbit, 2-3 kg) were used. Rabbits were placed in cages at 25 ± 2 ° C and given sufficient water and food (Claire CR-3). used.
[0023]
2. Test
(A) (DDC) ₂ Zn solubility measurement method in each formulation Experimental method (DDC) ₂ Zn was quantified using HPLC. For HPLC, LC-10AD manufactured by Shimadzu Corporation, column Mightysil RP-18 GP 50-2.0 (3 μm) (Kanto Chemical) was used. HPLC was performed at 45 ° C. using 45% acetonitrile containing 0.1% TFA as a mobile phase at a flow rate of 0.25 mL / min. A wavelength of 215 nm was used for detection of DDC. A sample for HPLC was prepared by adding 100 μL of 2.5 μg / mL indomethacin-methanol solution as an internal standard substance to 50 μL of the specimen. (DDC) is a calibration curve of the _{2 Zn (DDC) 2 Zn (} 4~40μg / mL) internal standard indomethacin 50 [mu] L - created by the operation of the same using a methanol solution (2.5μg / mL) 100μL.
[0024]
(DDC) vertical axis divided by the ratio of the peak area of the ₂ Zn peak area of the internal standard substance indomethacin, horizontal axis the concentration of (DDC) ₂ Zn, based on the slope of the calibration curve, (DDC) ₂ Zn The concentration of was determined as follows.

[0025]
The experimental results show that (DDC) ₂ Zn insoluble in water can be dissolved in water by adding HPCD. Further, the solubility was increased by heat treatment. The non-heat-treated preparations of Formulations 3, 5, and 7 increased in solubility with an increase in HPMC content. In Formulations 2, 6, and 8 that were heat-treated, the solubility increased dramatically with an increase in HPMC content. FIG. 1 shows the effect of HPMC addition and heat treatment on the solubilization of (DDC) ₂ Zn (the numbers on the X axis indicate the formulation number of the formulation in Table 1).
[0026]
(B) (DDC) ₂ Zn stability test method in each formulation Experimental method Each formulation is 80 ° C. (0, 4, 8, 16, 32, 64 h), 90 ° C. (0, 2, 4.5, 9, 13.5, 18 h), after heating at 100 ° C. (0, 0.5, 1.5, 3, 4.5, 6 h), using a method similar to the solubility measurement method in (A), (DDC) ₂ Zn concentration was measured by HPLC. The disappearance rate constant was determined from the measured (DDC) ₂ Zn concentration using the following first-order rate equation.
[Expression 1]

Here, (DDC) ₂ Zn initial concentration C ₀ , (DDC) ₂ Zn concentration C at heating time t, and disappearance rate constant were set to k.
[0027]
For each formulation, Arrhenius Plots were created by determining the rate constant k at 80 ° C., 90 ° C., and 100 ° C. Arrhenius Plots showed a straight line. Further, the calculated disappearance rate constant k is expressed by the following Arrhenius equation:
[Expression 2]

(Here, Ea is the activation energy, A is the frequency coefficient, R is the gas constant, and T is the absolute temperature), and the activation energy (Ea) and frequency factor (A) of each formulation were calculated. The slope of the plot represents the activation energy (Ea), and the Y-axis intercept represents the frequency factor (A).
[0028]
Experimental results It was found that the decomposition of (DDC) ₂ Zn was temperature-dependent, because linearity was recognized by Arrhenius Plots in the preparations of any prescription. The decomposition rate of (DDC) ₂ Zn in the preparation at any temperature can be calculated from the activation energy and the frequency factor.
[0029]
As a result of calculating the decomposition rate of (DDC) ₂ Zn in the preparation at the standard temperature of 25 ° C., the formulation 6 was the smallest, and the time required for 90% remaining of (DDC) ₂ Zn at 25 ° C. calculated further from here was Proven to be very stable for about 30 years. In addition, the formulation containing HPMC was found to be more stable than the formulation containing no HPMC. Table 2 shows the thermodynamic and stability parameters for each formulation.
[0030]
[Table 2]

Ea is activation energy, A is the frequency factor, _{k 25 ° C.} is an exploded _{rate, t 0. 9, 25 ℃} leads to 90% residual at 25 ° C. Time at 25 ° C..
[0031]
(C) In vitro rabbit corneal permeability test experimental method C-1 buffer preparation: HEPES (+ Glc) buffer 10 mM HEPES, 136.2 mM NaCl, 5.3 mM KCl, 1.0 mM K ₂ HPO ₄ , 1. 7 mM CaCl ₂ · 2H ₂ O, 5.5 mM glucose was added in order, dissolved, and adjusted to pH 7.4 with 37 ° C., 1N NaOH, filtered through a membrane filter Minisart CE (Sartorius, 0.20 μm), and the following: Used in the experiment.
[0032]
C-2 Corneal Permeation Experiment After euthanizing by injecting air into a female white rabbit (body weight 2.5-3.0 kg) through the ear vein, the eyeball was carefully removed, and the sclera portion was approximately 1 to The corneal portion was removed leaving 2 mm so as not to be damaged. This cornea is attached to a corneal permeation cell made of acrylic resin, and isotonic HEPES buffer (pH 7.4) is added to the reservoir side, and (DDC) ₂ Zn preparation (formulations 5 and 6 in Table 1) is injected to the donor side. And heated at 35 ° C. which is the corneal surface temperature. Samples were taken from the reservoir side by 50 μL over time, and the amount of permeated DDC was measured by HPLC.
The obtained data was subjected to fitting calculation using the nonlinear least square computer program MULTI based on the following equation, and the kinetic parameters were calculated.
[Equation 3]

Where Jc is the permeation rate of DDC, Km is the distribution coefficient of the cornea / formulation, D is the diffusion coefficient in the cornea, τ is the lag time, δ is the thickness of the cornea (average 0.0625 cm), and A is the cornea used. Effective area (0.64 cm ² ), Q is the cumulative amount of drug permeated to the reservoir side at time t, and C _HPCD is the (DDC) ₂ Zn concentration in the (DDC) ₂ Zn-HPCD solution formulation. Jc and τ were calculated by fitting to the above formula.
[0034]
Experimental Results From the start of the experiment up to 3 hours, both the non-heat-treated preparation of Formula 5 and the heat-treated preparation of Formula 6 showed very slow permeation. However, after 3 hours, the increase in permeation rate was greater in Formula 6 where the heat treatment was performed. FIG. 2 shows the in vitro rabbit corneal permeability of the (DDC) ₂ Zn-HPCD solution formulation. Table 3 shows the results of analyzing the obtained data and calculating the transmission parameters.
[0035]
[Table 3]

[0036]
Jc, which represents the substantial permeation rate, indicates that the heat-treated prescription 6 preparation is 1.8 times larger than the prescription 5 preparation, and the higher the (DDC) ₂ Zn concentration in the preparation, the greater the permeation rate. It was done. Since the Kp, which is the drug permeation rate per unit amount (DDC) ₂ Zn in the applied preparation, is almost the same, it was found that the higher the drug concentration, the higher the permeation rate Jc.
[0037]
【Example】
Example 1
After adding 0.1% HPMC to 0.5% (DDC) ₂ Zn, 10% HPCD, 0.9% NaCl, 0.005% BC, the mixture was stirred for 48 hours or more, and then the membrane filter Minisart CE (Sartorius, The aqueous eye drop was prepared by filtration using 0.2 μm).
[0038]
Example 2
After adding 0.1% HPMC to 0.5% (DDC) ₂ Zn, 10% HPCD, 0.9% NaCl, 0.005% BC, the mixture was stirred for 48 hours or more, and then the membrane filter Minisart CE (Sartorius, 0.2 μm) and boiled in a boiling water bath for 30 minutes to prepare an aqueous eye drop.
[0039]
Example 3
Prepared as in Example 1 using 0.5% (DDC) ₂ Zn, 10% HPCD, 0.9% NaCl, 0.005% BC with 0% and 0.25% HPMC.
[0040]
Example 4
Prepared as in Example 2, using 0.5% (DDC) ₂ Zn, 10% HPCD, 0.9% NaCl, 0.005% BC with 0% and 0.25% HPMC.
[Brief description of the drawings]
FIG. 1 is a bar graph showing the effect of HPMC addition and heat treatment on the solubilization of (DDC) ₂ Zn (the numbers on the X-axis indicate the formulation numbers of the formulations in Table 1).
FIG. 2 is a line graph showing the in vitro rabbit cornea permeability of (DDC) ₂ Zn-HPCD solution preparations of Formulation 5 (non-heat treatment) and Formulation 6 (heat treatment).

Claims (2)

An anti-cataract pharmaceutical composition comprising zinc diethyldithiocarbamate as an active ingredient ,
An anti-cataract pharmaceutical composition in which at least a part of the zinc diethyldithiocarbamate forms an inclusion complex with a cyclodextrin compound, and heat treatment is performed when the inclusion compound is formed,
Furthermore, the anti-cataract pharmaceutical composition which contains 0.1-1.0% of hydroxypropyl methylcellulose (HPMC) as a stabilizer.   The pharmaceutical composition according to claim 1, which is in the form of an aqueous eye drop.

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