Instillation of solution

Lavage systems overcome the compliance problems associated with instillation of solutions in some horses. However, they involve increased expense arising from the costs of the system and from the relatively high drug volumes required, much of which may be wasted in the dead space... 

ABSORPTION, FATE, AND EXCRETION Physostigmine is absorbed readily from the GI tract, subcutaneous tissues, and mucous membranes. The conjunctival instillation of solutions of the drug may result in systemic effects if measures (e.g., pressure on the inner canthus) are not taken to prevent absorption from the nasal mucosa. Parenterally administered physostigmine is largely destroyed within 2 hours, mainly by hydrolytic cleavage by plasma esterases renal excretion plays only a minor role in its elimination. 

Frequent instillation of solution or higher drug concentration is needed to achieve the desired therapeutic response. But this attempt is potentially dangerous if drug solution drained from the eye is systemically absorbed from the nasolacrimal duct. To increase precorneal residence time and ocular bioavailability, different ophthalmic delivery systems such as viscous solutions, ointments, gels, suspensions, or polymeric inserts are used. But because of blurred vision (e.g., ointments) or lack of patient compliance (e.g., inserts), these formulations have not been widely accepted. 

Gel-Forming Solutions. One disadvantage of solutions is their relatively short residence time in the eye. This has been overcome to some degree by the development of solutions that are liquid in the container and thus can be instilled as eyedrops but gel on contact with the tear fluid and provide increased contact time with the possibility of improved drug absorption and increased duration of therapeutic effect. 

In a study performed in rabbits, rhG-CSF in a powder formulation (aerodynamic diameter < 4 pm) was insufflated via an intratracheal tube and compared to intratracheal instillation of a solution of the drug. In this study it was shown that a direct relation exists between the amount of protein that was deposited deep into the lung and the relative bioavailability [33]. 

Skin application on rabbits of a samrated aqueous solution daily for 10 days caused no significant irritation instillation of the same solution into the rabbit eye caused no irritation. Pentaerythritol was negative in bacterial mutagenicity assays with or without metabolic activation." ... 

Solutions - Depending on the severity of inflammation, instill 1 or 2 drops of solution into the conjunctival sac up to every hour during the day and every 2 hours during the night as necessary as initial therapy. 

Medinsky MA, Benson JM, Hobbs CH. 1987. Lung clearance and disposition of Ni in F344/N rats after intratracheal instillation of nickel sulfate solutions. Environ Res 43 168-178. 

Ocular instillation of 10% solution may increase blood pressure... 

Rengstorff et al.2 applied 0.025 ml of a SX solution of CR 5 d/wk for 4 wk. The animals were kept under observation for 60 d. Instillation of the dally doses was followed by a brief period of blepharospasm (about 15 min), after which the eyes appeared to be normal. During the test period, superficial and slit-lamp examination did not reveal any Injury to the eyes. At the end of the experimental period, the eyes were examined by light and electron microscopy. No abnormalities were found. 

Another use for acetylcholinesterase inhibitors is in glaucoma, in which high intraocular pressure can lead to permanent damage to the optic disk, resulting in blindness. The local instillation of physostigmine (8.14) or echothiophate (8.19) solution in the eye results in a long-lasting decrease in the intraocular pressure as well as myosis (contraction of the pupil). 

A severe anaphylactoid reaction occurred immediately after the instillation of a 10% solution of povidone-iodine into a hydatid cyst cavity during surgery. Severe bronchospasm developed immediately and was followed by a coagulopathy and subsequent liver and renal insufficiency (33). 

An absorption promoter can control the extent and pathway of the ocular and systemic absorption of instilled drug solution by altering not only the corneal but also the conjunctival drug penetration. Most of the agents discussed above show different effects on the corneal and conjunctival membranes. The different response of corneal and conjunctival barriers to absorption promoters can be exploited and used to control the extent and pathway of the ocular and systemic absorption of drugs instilled into the eye. The mechanism of action of absorption promoters and the barrier properties of membranes are the two factors that define drug permeability. 

Barriers to ocular drug delivery. The presence of epithelial tight junctions and rapid drainage of the instilled drug solution by tears from the precorneal area result in the permeation of less than 5 percent of the applied dose of a drug.66,67 The cellular calcium levels and actin filaments of the cytoskeleton play a major role in the integrity of tight... 

Later, Lizio et al. [78] used a new aerosol delivery system (ASTA-ADS) to investigate the pulmonary absorption and tolerability of four different cetrorelix formulations delivered as nebulized aerosols to orotracheally cannulated rats. After only 5 min exposure to the cetrorelix aerosol, serum testosterone concentrations were reduced to subnormal levels over a 24-h period. After dose adjustment (dose delivered minus exhaled amount), the bioavailabilities for pulmonary delivery ranged from 48.4 27.0% to 77.4 44.0% compared to IV administration. In addition, the lung function parameters did not reveal any formulation-related changes. Overall, the results of cetrorelix aerosol administration compared well with those obtained with intratracheal instillation of cetrorelix solution [77]. 

Nasal drops rely upon the instillation of one or more drops of drag solution, either from a dropper with a flexible (rubber) teat, or directly from a squeezable plastic container into the nasal cavity. 

The surface tension of tear fluid at the eye temperature has been measured as 43.6 to 46.6 rriNm-1 for normal eyes and 49.6 mNm"1 for patients with dry eye. The instillation of a solution containing drugs or adjuvants that lower the surface tension may dismpt the outmost lipid of the tear film into numerous oily droplets, which become solubilized. The protective effect of the oily film against evaporation of the tear film aqueous layer disappears and diy spots will be formed. The dry spots are painful and irritant and elicit reflex blinks to eliminate the material. This irritation does not always occur immediately after the instillation. In many cases it appears 30 minutes to 1 hour following the application and is dependent on the substance and on its concentration. The tear film is destabilized when the surface tension of the instilled solution is much lower than the surface tension of the lacrimal fluid. 

Beubler and Badhri (1990) used the PGE2-induced net fluid secretion in the jejunum and colon in the rat to evaluate the antisecretory effects of antidiarrhoeal drugs. Polyethylene catheters were placed into the jejunum and colon and Tyrode solution was instilled into the loops. Net fluid transfer rates were determined gravimetrically 30 min after instillation of Tyrode solution. 

Wistar-derived male or female rats weighing 200 g, which fasted 24 hours, were used. Distal colitis was induced by intracolonic instillation of 2,4-dinitrobenzene sulfonic acid, which was injected to ensure that the solution remained in the colon. The Step 3... 

Anti-inflammatory testing was performed using the acetic acid colitis rat model described by Fretland (2). Experimental agents were administered 24,16, and 4 hours prior to the 40 second instillation of 3% acetic acid solution in the proximal 6 cm of the colon under light anesthesia. The colon was immediately washed with 5 ml saline and neutrophil inflammation determined by measuring MPO levels in the scraped colonic mucosa. Testing results are provided in Table 2. 

Figure 2-8 The mean residual activity on the ocular surface after instillation of 25 mcl of various ophthalmic solutions containing 0.5% pilocarpine salts. (Modified from Meseguer G, Buri P, Plazonnet B, et al. Gamma scintigraphic comparison of eyedrops containing pilocarpine in healthy volunteers.) Ocul PharmacolTher 1996 12 483.)...

Although refrigeration of solutions may help to prolong shelf life, there appears to be little difference in local ocular irritation caused by eyedrops stored in the refrigerator or at room temperature. Cold drops, however, often can serve to reinforce proper eyedrop self-administration technique for patients who have difficulty ascertaining when the drops have been properly instilled. 

Figure 3-3 Traditional technique for instillation of topical ocular solutions.The patient s head is inclined backward, the lower Ud is retracted, the globe is elevated, and the dropper tip is kept at least 2 cm from the globe.

Without touching lashes or eyelids, instill one drop of solution into conjunctival sac. 

For mydriasis, instillation of 2.5% or 10% solution results in maximum dilation within 45 to 60 minutes depending on the concentration instilled (Figure 8-2). Recovery from mydriasis occurs in 6 to 7 hours. 

Topical instillation of a 1% solution in eyes with normal adrenergic innervation causes mydriasis and also some vasoconstriction. However, hydroxyamphetamine is used only as a mydriatic agent. After topical application onset occurs within 15 minutes, maximum dilation occurs within 60 minutes, and the duration of mydriasis is approximately 6 hours. The U.S. Food and Drug Administration has labeled this drug as a Pregnancy Category C. 

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