JP3020209B2 - Rapid miosis by adjusting intraocular pressure - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to miotics useful after cataract and intraocular lens surgery, and more particularly to post-operative miosis.
It relates to the formulation of a drug that regulates intraocular pressure for 4 hours and induces rapid miosis.

[0002]

BACKGROUND OF THE INVENTION Miotics are frequently used by ophthalmologists during intraocular surgery. The anterior chamber is flushed with miotics after inserting a lens in cataract surgery, as in corneal puncture transplant surgery, iridectomy surgery and other anterior segment surgery. Immediate miosis is required to ensure that a spherical pupil is obtained after cataract surgery. If the iris or capsular tag of the eye is removed during the incision, the pupil will be distorted at a later date. Since the inner tag is clear and transparent without the use of miotics, it is easy to lose the inner tag at the incision. Other benefits obtained using miotics are that they facilitate post-scleral placement of the cornea and insertion of the anterior chamber lens, and reduce postoperative anterior segment adhesions. Many ophthalmologists find miotics useful in centering intraocular lens implants.

[0003] Elevated intraocular pressure (IOP) disrupts normal functioning and results in irreversible loss of visual function. Viscoelastic reagents, such as hylon, are often used during lens implantation, resulting in increased IOP with pressure spiking.

With the advent of the latest surgical techniques and the posterior chamber IOL
Due to the tendency of 'inside' placement, more viscoelastic materials have been used. Cataract surgery is often performed on an outpatient basis, and the patient returns to the doctor at a later date. Slit lamps and tonometers are convenient and, after all, many surgeons test better when they admit their patients after surgery. While this improves patient care, perhaps 20-24 hours after cataract surgery I
It would have led to increased interest in OP.

[0005] Pressure studies have been conducted for the first 24 hours after cataract surgery.
It has shown that time IOP may be very important. I
Elevated OP may damage the optic nerve, intraocular vascular supply and corneal endothelium. (15) (7). Ultimately, every effort should be made to control IOP from the onset of the postoperative period.

Acetylcholine (Miochol)
Is the most widely used miotic drug for ophthalmic surgeons. Myochor leads to rapid (within minutes) miosis.
However, this means that even with pressure regulators such as acetazolamide (Diamox), IOP control after a few hours is very poor. Carbachol is not widely used because it does not induce rapid miosis. There is a need for miotics that control intraocular pressure and induce rapid miosis 24 hours after surgery.

[0007] Gormaz (3) reported for the first time in 1962 that the IOP was elevated in the middle stage after cataract extraction. Rich (4) (5) discovered in 1968 and 1969 that a significant increase in IOP was characteristic after cataract surgery. He also showed that α-chymotrypsin was not required to cause this increase. Sodium hyaluronate (Healon; Healo
n) was associated as causing an increase in IOP. Olivius and Sirburn (Thorn)
burn) (6) shows that sodium hyaluronate induces an increase in IOP, which is partially reversible by washing or removing or diluting the viscoelastic material (7). Several drugs have been used to prevent the increase in IOP associated with cataract surgery. Rich (3), in 1969, used a large dose of acetazolamide (Diamox) 24 hours after cataract surgery and showed a decrease in IOP 24 hours after surgery. However, acetazolamide may have unexpected side effects in some patients. However, Timolol
Effectively lowers IOP after ICCE (8), but uses EOL and sodium hyaluronate to reduce EOP.
It was found to have no effect on acute postoperative pressure rise after CCE (9). Recently, simple administration of Pilocarpine gel has been shown to be effective in reducing IOP during the first 24 hours after ECCE using IOL. However, the patient often complained of forehead pain the next day. This same test group felt that there was a tendency for postoperative IOP to decrease using timolol.

[0008] Miotics began to be used in about 1970, shortly after the start of ECCE. In 1972, Bee
Beasley (11) showed that miosis was rapid with both 1% acetylcholine and 0.01% carbachol. The miosis persisted for the first day postoperatively with the use of covercol, rather than with acetylcholine, where the miotic effect disappears very quickly. However, Holland, Drance and Schulzer (13) reported that 1% of acetylcholine was carcinogenic.
Bacol was shown to induce more rapid onset of miosis than 0.01%. Holland, Drance and Schulzer (14) showed that 1% acetylcholine administered into the eye chamber during cataract surgery significantly reduced IOP at 3 and 6 hours postoperatively, but had no effect beyond this time. On the other hand, the same group of researchers reduced that 0.01% of Covercol was highly effective in reducing IOP for at least 24 hours postoperatively, and reduced the number of patients whose IOP was greater than 30 mm.Hg. That was shown. Bibliography Bibliography (1) U.S. Patent No. 4,459,309 (2) US Patent No. 4,665,094 (3) GORE - first. A (Gormaz, A.); Eye after cataract surgery
Pressure ( Ocular Tension After Cataract Surgery. ) Americ
an Journal of Ophthalmology, 43: 832, 1962. (4) Rich, WJCC (Rich, WJCC); Cataract extraction
Intraocular Pressures and wound closure
Wound Clousure After Cataract Extraction. ) Trans.Op
hthalmol. Soc., UK88: 437, 1968. (5) Rich, WJCC (Rich, WJCC); Cataract extraction
Further studies on the initial high intraocular pressure after surgery (Further St
udies on Early Post-operative Ocular Hypertension
Following Cataract Extraction. ) Trans.Ophthalmol.
Soc., UK 89: 639, 1969. (6) Olivius, E., and Sirburn, W. (Olivius,
E., and Thornburn, W,); after surgery using hyalon
Of intraocular pressure (Intraocular PressureAfter Surgery wi th Hea
lon ) Am. Intraocular Implant Soc. J. 11: 480,1985. M., Rich WJ, and Wright, G. (Cherfan, GM, Rich, WJ and Wright, G.); Here
Above intraocular pressure for sodium luronate and cataract surgery
Noboru and cord problem (Raised Intraocular Pressure and Ot
her Problems with Sodium Hyaluronate and Cataract S
urgery ). Trans. Ophthalmol. Soc., UK 103: 277,1983 (8) Obstbaum, SA. And Garin, MA (Obs
tbaum, SA and Galin, MA); Cataract extraction of timolol
And The Effects of Timolol on C
atract Extraction and Intraocular Pressure. ) Am.J.
Ophthalmol. 88: 1017,1979 (9) Tomoda, T., Collar, AW, and Word, TO (To
moda, T., Tuverville, AWand Ward, TO); Timolol
And postoperative intraocular pressure (Timolol and Postoperativ e Intr
aocular Pressure. ) Am. Intraocul.Implant Soc. J., 1
0: 180,1984. (10) Ruiz, RS, Wilson, CA Musglob,
KH and Pluga, T, C. (Ruiz, RS, Wilson, CA, Musgr
ove, KH and Prager, TC); increased intraocular pressure after cataract extraction
Treatment (Management of Increased Intraocular Pressu
re After Cataract Extraction ) Am.J.Ophthalmol., 103:
487,1987 (11) bi - Sri -, H (Beasley, H. ); You in cataract surgery.
Kicking miosis (Miotics In Cataract Surgery.) Arch.Ophtha
lmol., 88: 49,1972 (12) Douglas, GR (Douglas, GR) after cataract extraction
Of Acetylcholine and Carbachol in Aquarium (A Compariso
n of Acetylcholine and CarbacholFollowing C ataract
Extraction. ) Can. J. Ophtalmol., 8:75, 1973. (13) Holland, RHDrance, SM and Schulzer, M .;
Effect of intraocular covering after cataract extraction (The
Effect of Intracamerol Carbachol on Intraocular Pr
essure After C ataract Extraction ) Am.J.Ophthalmo
l., 104: 225, 1987. (14) Hollands, RHDrance, SM and Schulzer, M.
Effect of acetylcholine on intraocular pressure early after surgery (The Effe
ct of Acetylcholine on Early Postoperative Intraoc
ular Pressure . ) Am. J. Ophthalmol., 103: 749,1987. (15) Heirich, SS (Hayrch SS); Cataract extraction
Later anterior segment ischemic optic neuropathy, onset of IV (Anterior Isc
hemic Optic Neuropathy, IV, Occurrence After Catract
Extraction. ) Arch.Ophthalmol., 98: 1410,1980.

[0009]

The miotics provided in accordance with the present invention induce rapid miosis with 24 hour intraocular pressure adjustment. The miotics of the present invention reduce or eliminate the need for IOP modulators such as Diamox and reduce IOP after using viscoelastic reagents such as hyalone.

[0010]

The miotic agent of the present invention has the property of mixing and using an acetylcholine type drug together with a carbachol type drug. This mixing induces rapid onset of miosis, prolongs miotic effects, and provides long-term IOP adjustment over 24 hours. This IOP is 25
The pressure is maintained at or below mmHg, and is almost nonexistent.
ike).

The miotic of the present invention is easy to use. The drug is safe and effective because it is a combination of two drugs permitted to be used for the same procedure. This miotic drug
Would be commonly used in ophthalmic surgery,
It is particularly effective for patients who have started treatment for increased intraocular pressure, such as glaucoma patients. It will also prove to be very effective in procedures using Hyron, which is used to assist in the insertion of intraocular lenses. The acetylcholine and carbachol components are used sequentially or simultaneously. Another aspect of the invention is to package two drugs in a common container having two separate spaces. The drugs are mixed and dissolved in a common carrier just before use. These and other features and attendant advantages of the present invention will become better understood when the following detailed description of the invention is considered in conjunction with the accompanying drawings.

[0012]

EXAMPLE The first active agent in the miotic component of the present invention is represented by the following formula:

[0013]

Wherein R and R ¹ are lower alkyl groups having 1 to 5 carbon atoms and X ⁻ is an anion such as halogen.

A preferred member of this group is acetylcholine where R and R ¹ are all methyl and X ^- is chlorine. Acetylcholine is a parasympathetic drug. It is used at a concentration of 0.1 to 5% by weight, usually 1%. Acetylcholine is provided in a dry powder form because of its instability and is mixed with a physiologically inert, solution carrier prior to use. The dried product can be mixed with an inert lyophilized substance such as mannitol in a ratio of 1/1 to 10/1, usually 3/1 by weight. The regeneration aqueous solution is 1
% Acetylcholine and 3% mannitol by weight. A typical applied dose is about 2 ml.

The second active agent in the miotic component is represented by the following formula:

[0017]

Wherein R ² is a lower alkyl group of 1 to 5 carbon atoms, n is an integer of 0 to 3,
Is an anion such as a halogen).
A preferred component kabokol is that n is 0, R ² is all methyl, and X is chlorine. Carbachol is provided as a sterile salt solution at 0.001 to 1.0% by weight, usually about 0.01% by weight. This isotonic salt carrier comprises the following inert salts; salt % weight NaCl 0.64 KCl 0.075 CaCl ₂ .H ₂ O 0.048 MgCl ₂ .6H ₂ O 0.03 Sodium acetate .3H ₂ O 0.39 Sodium citrate.2H ₂ O 0.17 Adjust the pH to neutral with sodium hydroxide or hydrochloric acid as needed.

Referring now to FIG. 1, two drugs are supplied to a container 10 having two spaces. The container is molded from a single vial 12 having a first section 17 sealed by a first elastic plug 18 and a second section 14 sealed by a second elastic plunger stopper 16.
The first section 17 comprises a unit dose of a first drug such as acetylcholine or a single dose 22 and a lyophilizate such as mannitol, the second section 14 comprises an aqueous solution 20 of a second drug, etc. Included in salt solution of tonicity and concentration. The plunger stopper 16 is pushed downward, which pushes the plug 18 into the lower section. The plunger stopper 16 is provided at the edge 2 of the annular portion 31 of the single medicine bottle 12.
It falls on the shoulder 25 formed along 7 and stops. Solution 20
Dissolves the dried drug 22 into the first section 17. In use, a hypodermic needle, not shown, is inserted through plunger-stopper 16 into second section 14 and the solution is withdrawn. After the dry mixture of compounds has dissolved, the mixed miotic agent is drawn into a syringe and is ready to use.

The experiments were performed continuously and mixed with myochol (acetylcholine) and myostat during the ophthalmic surgical procedure.

The miotic agent of the present invention can be used as follows. The cyst is retained after cataract extraction. It has a front flap. To facilitate the insertion of the lens into the carcass, the carcinoma is inflated and hylon is added.
After the lens is inserted, the myocol is injected.
When the pupil compresses, closure of the wound occurs. The viscoelastic reagent that had covered the sac by suction and inhalation of the salt solution is removed. The myostat solution is then added to the anterior chamber. When the last stitch of the incision is completed, the iris is identified by its spherical shape and the inclusion of the iris or intranasal tag in the incision. When a mixture of acetylcholine and carbohydrate is used in a common carrier, a portion of this mixture is added after insertion of the lens and closure of the resulting wound. The viscoelastic reagent is inhaled from the anterior chamber and the mixture of miotics is added again after the wound is sutured.

The following experiments provide that the mixture of miotics of the present invention demonstrates the ability to provide prolonged IOP regulation without the use of Diamox and excellent regulation in glaucoma patients undergoing ECCE. I do.

The average intraocular administration of myocole is 0.5 to 2 ml of a 1% solution, and the administration of carbacol during surgery is 0.5 to 2 ml of a 0.01% solution. is there.

Intraocular pressure was measured with a Goldman manometer during the preoperative visit on the day before the surgical procedure. Second intraocular pressure was measured at the first visit 20-24 hours after surgery.

Surgical Technique 1. Standard ECCE with intraocular lens implant
PMMA with Prolene loops or all PMMA)]. Patients with ultrasonic cataract emulsification and suction associated with intraocular lens insertion were excluded. All known glaucoma patients were also excluded from the following experiments.

2. Methods and procedures: (a) Honan before surgery
Cuff (Honan cuff), 15-30 minutes, (b) about 11 mm incision,
(C) Manual cataract extraction (pressure reduction, counter pressure increase) by manual (d) Hyron (sodium hyaluronate)
(E) Site unit (Site U
nit) or Series 10,000 Co-Vision Unit (Seri
es10,000 coopervision unit)
Irrigation or aspiration containing epinephrine (f) placement of intraocular lens in posterior chamber intraocular lens (g) irrigation and aspiration of hylon by machine (h) injection of miotic drug into anterior chamber
(I) Intermittent Closure with 10-0 Nylon Suture The surgically injectable drug is Garamycin.
n; 1/2 from 1 cc), and Seresuton (Celestone; 1
/ 2 to 1 cc).

3. Topical drugs used in the above surgery
The agent is Tobrex,Maxidex(Maxide
x),andBetoptic(Betoptic)Met. Sele
Ston, Maxidex, and Vetopick are intraocular pressure
Are underlined because they are known to affect ECCE surgery requires acetylcholine and calcium
Used continuously and mixed, performed on two sets of patients
Was. All surgery is successful for rapid miosis
Twenty-four hours later, a sharp drop in IOP and low IOP were observed.
Was done.

The following table and FIG. 8 show the IOP of 9 patients to whom two miotics were applied sequentially.
Sudden miosis was observed. IOP after surgery (Surgery 2
4 hours later) was the same or lower than the pre-operative pressure.

Table 1 Before and after patient surgery Delta IOP 115 15 152 15 16 13 13 27 7 -5 419 20 15 18 13 -13 625 1616 5 716 10 -6 819 19 369 18 16 -2 The mixed miotics of the invention were applied to 18 more patients. Eye with surgery on IOP and the other eye (pair)
Was measured before surgery (PRE) and 24 hours after surgery (POST). Pupil size was measured at surgery (AT) and 24 hours after surgery (POST). The following table shows the measurements, the difference (delta), and the maximum and minimum of the measurements. Table 2 pupil pupil Delta Delta patient preoperative preoperative (pair) after surgery after surgery (pair) after intraoperative surgery surgery: 1 14 14 13 11 4.5 2 -1 -3 2 22 23 12 26 4 4 -10 3 3 18 18 20 15 5 1.5 2 -3 4 19 19 4 15 4 2.5 -15 -4 5 21 18 25 18 4 1.5 4 0 6 19 18 18 18 3 2 -1 0 7 20 20 21 17 3 2 1 -3 8 16 17 16 14 3.5 2 0 -3 9 18 17 18 12 2.5 2.5 0 -5 10 16 16 4 16 4 2 -12 0 11 18 21 5 20 4 2 -13 -1 12 16 16 18 18 4 2 2 2 13 13 14 16 16 6 3 3 2 14 18 20 18 26 3.5 2 0 6 15 16 16 16 15 4 2.5 0 -1 16 18 19 15 18 3 2 -3 -1 17 14 15 18 18 3.5 2 4 3 18 15 15 12 10 3 2 -3 -5 Max 22 23 25 26 6 4 4 6 Min 13 14 4 10 2.5 1.5 -15 -5 Average 17.278 17.5556 14.944 16.8333 3.81 2.194 -2.333 -0.72222 Standard 2.4688 2.47867 5.8054 4.25994 0.82 0.572 5.9902 3.044871 After surgery The IOP is lower than the pre-op IOP, indicating good control. The pupil is still compressed after 24 hours.

Retrospective intraocular pressure (r) before and after surgery was applied to patients who applied acetylcholine or Kabacol during cataract extraction using an intraocular lens.
etrospective) and clinical experiments were performed. Surgery was performed in the same manner as one surgeon (author). Intraocular pressure was measured using a Godman manometer on the day before surgery at the pre-operative visit. The second intraocular pressure was measured using a Godman manometer at the first visit 20-24 hours after surgery.

In the early stages of this retrospective experiment, it was evident that pressure spikes occurring 20-24 hours after surgery were a major problem. In this retrospective experiment, post-operative intraocular pressure (IOP) is compared for four groups after standard cataract extraction using an intraocular lens (ECCE using IOL). These four groups consisted of myocole (acetylcholine hydrochloride) alone, myocole and 500
There were four groups: mg diamox (acetazolamine) orally administered at 18:00, myostat (ca-bacol) and 500 mg diamox orally administered at 18:00, and fourthly myostat alone. 2 and 3 show spiking of a group of patients treated with myocohol and diamox (presence / absence). 4th and 5th
The figure shows that the groups treated with myostat and diamox (presence / absence) had good adjustment of IOP. Surprisingly, the group that did not receive Diamox had better coordination.

Patients receiving only myocole had a mean preoperative intraocular pressure of 14.2 and a mean postoperative pressure of 26.5. However, four of the eleven patients had more than 30 spikes, one at 44 mmHg. The average increase in intraocular pressure is 12.3
mmHg.

To reduce pressure spikes, 35 patients received 500 mg orally of myochol at 18:00 on the day of surgery. The average post-operative pressure is 20.1 and the average increase in pressure is
It was 6.8 mmHg. However, in this group, 9 out of 35 had intraocular pressure of 25 or higher, reaching a height of 42. At the time of surgery, 38 patients received 500 mg of Diamox on the day of surgery, 18
Sometimes given myostat. Mean postoperative intraocular pressure is 16.9
And the average increase in intraocular pressure was 2.3 mm. Only 3 out of 38 had more than 25 pressures, with a maximum of 29. It is evident that for both groups using myocol there was an improvement in the adjustment of intraocular pressure after 20-24 hours.

[0036] Thirty-six patients received only myostat without diamox on the day of surgery. The mean post-operative intraocular pressure decreased by 0.8 mm. Of the 36, only one patient had a postoperative intraocular pressure of 25 or greater. This test group showed at least as good clinical control as the test group that received myostat with Diamox, and was certainly better controlled than the myocol test group.

During this retrospective experiment, 16 known clinical cases were found to be glaucoma, an apparently small population. All clinical cases of glaucoma were on medication and felt controlled, but a total of two people, one in each group, had 25 preoperative intraocular pressures. Eight of these patients received myocol during surgery and 8
A person was administered myostat. All of these patients received 500 mg of Diamox at 18:00 on the day of surgery. (a)
Surgical techniques other than complete iridectomy performed as needed were the same. (b) Drugs that could be administered at the time of surgery were galamycin and celestone . (c) Drugs used topically at the completion of surgery include Tobrex and Maxi
Decks and betop ticks . In all cases, Diamox 500 mg was used orally at 18:00 on the day of surgery.

FIG. 6 is data for eight patients who received myocole during a surgical procedure. The mean intraocular pressure before surgery was 21, and the mean postoperative intraocular pressure was 37, an increase of 16.3 mm. Seven out of eight had an intraocular pressure of 30 or more, and one patient's pressure spiked to 54 mm.

FIG. 7 shows data for eight patients who received myostat during surgery. The mean preoperative intraocular pressure was 17, and the postoperative mean intraocular pressure was the same. Only two patients had an intraocular pressure of 21 or more, one with 26 and one with 28. A comparison of postoperative intraocular pressure in the glaucoma group shows that significant intraocular pressure spiking occurred 20-24 hours later in the myocol group than in the myostat group.

This retrospective clinical experiment using standard ECCE supports the safety and efficacy of the mixed miotics of the present invention. The miotic agent of the present invention containing both this myocol and myostat (carbacol.01%) was tested for IOP control after 20-24 hours, when measured with an applanation tonometer. -A better drug than miotics containing acetylcholine chloride (1%). In a standard treatment of ECCE using the IOL, using the miotics of the invention containing both myocol and myostat, it seems that oral administration of 500 mg of Diamox at 18:00 is not necessary. . In glaucoma, the miotics of the invention are effective in causing rapid miosis during the control of the IOP 20-24 hours after surgery.

Having described only the preferred embodiments of the invention, it is likely that many substitutions, modifications and changes will be permitted without departing from the spirit and scope defined by the following claims of the invention. Must be recognized.

[Brief description of the drawings]

FIG. 1a is an enlarged view of a package containing the components of the miotic agent of the present invention. FIG. 1b is a cross-sectional view along 1b-1b of FIG. 1a. FIG. 1c is similar to FIG. 1b, but shows that the unit solution and the combined aqueous solution and can be immediately inhaled with a hypodermic injection needle.

FIG. 2 is a curve showing the preoperative and postoperative intraocular pressure IOP of a group of patients receiving myocol together with Diamox.

FIG. 3 is a curve showing preoperative and postoperative intraocular pressure IOP for a group of patients receiving myocol without Diamox.

FIG. 4 is a curve showing pre- and post-operative intraocular pressure IOP for a group of patients receiving myostat with Diamox.

FIG. 5 is a curve showing pre- and post-operative intraocular pressure IOP for a group of patients receiving myocol without Diamox.

FIG. 6 is a curve showing preoperative and postoperative intraocular pressure IOP of a group of glaucoma patients receiving myocol.

FIG. 7 is a curve showing preoperative and postoperative intraocular pressure IOP of a glaucoma patient group that received myostat.

FIG. 8 is a series of bar graphs illustrating pre- and post-operative IOP of 18 patients administered a mixed miotic agent of the invention.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References Chemical Abstracts, Vol. 109 (1988) Abstract No. 105304 (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/22 A61K 45/02 CA (STN) REGISTRY (STN)

Claims (13)

(57) [Claims] A unit dosage container having miotic ability capable of inducing rapid miosis while adjusting intraocular pressure, comprising: Wherein R and R ¹ are lower alkyl groups containing from 1 to 5 carbon atoms and X ⁻ is an anion such as a halogen, in unit dose of the first miotic in dry powder form A first sterile container containing an amount; and an aqueous salt solution that is a solvent for the first miotic agent, of the formula: Wherein R ² is a lower alkyl group of 1 to 5 carbon atoms, n is an integer of 0 to 3 and X ⁻ is an anion such as a halogen. A unit dosage container comprising a combination of a second sterile container. 2. The container of claim 1, wherein said container is physically connected. 3. The container of claim 2 wherein said container is joined by an elastomeric seal pierceable by a hypodermic injection needle. Wherein a R and R ¹ are methyl and X ^-
The container of claim 1 wherein is chlorine. 5. The container according to claim 4, wherein R ² is methyl, n is 0, and X ⁻ is chlorine. 6. The container of claim 1, wherein the solution of the first drug further comprises a lyophilized substance in a weight ratio of 1/1 to 10/1 relative to the drug. 7. The container of claim 6, wherein the lyophilized substance is mannitol present in an amount of about 3% by weight. 8. The container of claim 1, wherein the second drug is present in the pharmaceutically acceptable isotonic aqueous salt solution in an amount from 0.001% to 1.0% by weight. 9. The container of claim 8, wherein the second drug is present in the salt solution in an amount of 0.01% by weight. 10. A container according to claim 9, wherein both miotic agents are dissolved in a pharmaceutically acceptable aqueous salt solution as a common carrier. 11. The drug of claim 1, wherein the first drug, which is a dry powder, and the unit dose of mannitol, which is a dry powder, are processed in a sterile sealed container and dissolved in the salt solution in a unit dose. 11. The method of claim 10, wherein the second drug is processed in a second sterile container, and wherein a solution of the two drugs is made in the salt solution by mixing the contents of the two containers. container. 12. A topical, ophthalmic, pharmaceutical composition for achieving rapid miosis as well as controlling intraocular pressure, comprising a compound of the formula: Wherein R and R ¹ are lower alkyl groups containing 1 to 5 carbon atoms and X ⁻ is an anion such as a halogen. And a first compound of the formula: Wherein R ² is a lower alkyl group of 1 to 5 carbon atoms, n is an integer of 0 to 3 and X ⁻ is an anion such as a halogen. A pharmaceutical composition comprising 0.001 to 1.0% by weight of a second compound; and a pharmaceutically acceptable carrier. 13. The composition according to claim 12, wherein the carrier is a water-soluble carrier.