- Email: [email protected]
Intramuscular Drug Administration
3
Intramuscular drug administration Intramuscular depot and drug absorption Absorption from aqueous solutions Absorption from oily solutions Absorption from suspensions Tissue vulnerability
Intramuscular injection of drugs is quite popular in the clinic; about 50% of the medical patients receive at least one intramuscular injection during their stay in the hospital (Greenblatt and Koch-Weser - 1976). However, in experimental studies the use of the in tramuscular route is rather limited. This is due to the technically greater simplicity of other parenteral administration procedures in animals and to the relative small muscle mass available in rodents for disposition of the dose. In contrast to intravascular administration, other parenteral dosing procedures such as intramuscular administration often cause the formation of a drug depot. To reach the blood or lymph vessels the drug must leave this depot. A large series of pharmaceutical factors may influence the rate of release of drugs from such a depot (Wagner - 1961). Consequently, when conditions are not properly controlled, wide variations in the ab sorption phase may occur. On the other hand, with a careful choice of the pharmaceutical formulation, it is possible within limits to regulate the intensity and duration of drug ac tion.
INTRAMUSCULAR DEPOT AND DRUG ABSORPTION Depot form. Intramuscularly injected drug solvent distributes rapidly in the fasciai planes or connective tissue surrounding the muscles. The spreading of aqueous systems is completed almost directly after injection; oily solutions continue to spread from 1 to 5 min before they become to some degree fixed in position. The solvent water spreads more extensively than oily solutions. The injection water is usually taken up by the hyaluronic acid gel; oils localize in the connective tissue spatia in arteficial lacunae. The formed depots take in both cases a flat shape similar to a pod (Ballard - 1968; Schou 1971; Hirano et al. - 1981a). The only slowly cleared oil depots certainly continue to change in shape and distribution with time. Deep, firm massage of muscle tissue follow ing an intramuscular injection favors the spread of the depot over a wider tissue area (Zelman - 1961) so favouring the absorption rate. The absorption process is characterized by a) the diffusion of drug molecules in the extravascular tissue, b) the passage of drug molecules through the capillary wall, c) the tissue perfusion rate with blood. For most compounds the passage through the capillary wall is not the rate- limiting factor for absorption. However, each of the other two proc esses may become the rate-limiting step. A generally useful equation describing the ab sorption kinetics has not been derived; the number of variables involved seems to make this impossible. As an approximation, drug absorption data are treated by many authors as corresponding to a pseudo-first order process, that can be characterized by an absorp tion half-life. Bioavailability of intramuscularly injected drugs is not always complete. Unabsorbed drug may remain permanently bound to the muscle tissue. In addition the drug may de23
Ch. 3 Intramuscular drug administration FIG. 3.1 Serum concentration profile of diphenylhydantoin after a 25 mg/kg dose of the drug given either i.V., i.m. or orally to rabbits (mean ± s.d.). (adapted from Wilensky, A.J., and Lowden, J.A.: Neurology 23, 318-324, 1973.)
40 30
20 10
12
24
CO
Time after administration (h)
compose spontaneously or enzymatically at the injection site. In some cases the decrease in bioavailability is only apparent when the very slow release causes plasma and urine concentrations to fall below detectable levels. This may occur when drugs precipitate af ter intramuscular administration (due to rather unphysiological solvent properties) and thereafter redissolve very slowly. This has been found, for instance, with diazepam and diphenylhydantoin; in clinical use higher (and more reliable) plasma levels are obtained when the compounds are administered orally instead of intramuscularly (Thomas - 1977; Tuttle - 1977). This phenomenon is likewise apparent from experiments in which diphenylhydantoin in a dose of 25 mg/kg was administered to rabbits via the intravenous, intramuscular and oral route, respectively (fig. 3.1). The persistent presence of diphenylhydantoin at the intramuscular injection site was demonstrated by a recovery of 44% of the injected dose in the muscles of the rabbits 48 h after injection (Wilensky and Lowden - 1973). ABSORPTION FROM AQUEOUS SOLUTIONS Absorption of drugs from aqueous solutions after intramuscular injections proceeds rather rapidly and the absorption process can reasonably be described as a pseudo-first order process. In fig 3.2 the absorption of benzylpenicillin from the exterior tibialis muscle of the rat is depicted (10 μΐ, 0.50 mg). The absorption half-life is 4.4 min, so 90% of the dose is absorbed within 15 min. A comparable absorption rate is found for various other compounds (Bederka et al. - 1971). According to these authors, in their study the absorption rate appeared to be independent of the molecular weights, diffusion coefficients, pKa-values and pharmacological class of substances in vestigated. Changes in blood flow, however, markedly affect the absorption rate. Correspondingly, the lower absorption rate for cationic drugs compared to neutral or anionic drugs, as found by Okumara et al. (1972), is thought to be due to their local vaso-active properties. In the rat, within the range of small volumes (5-20 μ\, possibly up to 50 μΐ), the injec tion volume does not significantly affect the absorption rate (Kakemi et al. - 1969; Bederka et al. - 1971). However, above this range, higher volumes tend to decrease the absorption rate. The absorption of sucrose (0.38 mg/ml), 5 min after intramuscular administration to the rat, was 54% from a dose of 64 μ\ compared to 78% from a dose of 4 μ\ (Sund and Schou - 1964a). In 24
Intramuscular drug administration o
■a
100
Ch. 3
FIG. 3.2 Absorption of benzylpenicillin after i.m. injection of a dose of 0.50 mg/10 μΐ to rats (mean ± s.e.). (adapted from Bederka, J. et al: Eur. J. Pharmacol 15, 132-136, 1971.)
T3
40 -Q CO
20 10 Q.
(D
m
0
10
20
Time after administration (min)
comparison to an absorption of benzylpenicillin of about 45% from a dose of 10 μ\ four min after injection, only 8% is absorbed when 100μ\ is given (Bederka et al. - 1971). For a compound like sucrose the absorption rate is over a wide range independent of the drug concentration (rat; range of 0.19-9.6 mg/ml) (Sund and Schou 1964a). Also for unionized drugs like isoniazid no effect of the drug concentration on the absorption rate was found (concentration range studied 17-250 mM) (Kakemi et al. - 1969). In contrast, some decrease in absorption rate is observed for compounds like thiamine and procainamide when administered in higher concentrations (50-100 mM) (Okumura et al. - 1972). Com pounds interfering with the local blood perfusion will also show a concentration dependent clear ance; such a mechanism is suggested for atropine in which case the absorption is markedly dimin ished by increasing concentrations above the threshold of 0.5 mg/ml (Sund and Schou - 1964b). To minimize tissue damage and irritation the tonicity of drug solutions is often adjusted to the level of the interstitial fluid by the addition of salts. However, when injection vol umes are kept low (10-20//l), the use of paratonic solutions does not essentially disrupt the structure and properties of the muscle tissue (Kakemi et al. - 1971). At low osmotic pressure the absorption rate of isonicotinamide (used as a model drug) is markedly de creased, while there is a tendency for a slightly increased absorption rate from hypertonic solutions. As might be expected, the injection of normal saline gives only slight local disturbances, also with greater volumes. Hypertonic NaCl solution (1.7%) then gives rise to little more damage to the muscle than does isosmotic NaCl solution; the oedema which arises is more extensive. However, greater volumes of distilled water will cause severe reactions; besides oedema, numerous muscle fibers are disrupted or altered (rat; 0.2 ml injected into the hindleg) (Paget and McG.Scott - 1957). The rate of absorption from an i.m. depot is decreased when the viscosity of the drug vehicle is increased. The rate of absorption of chloroquine after i.m. injection in rabbits from a solution containing 2% methylcellulose 1500 (viscosity 2430 mPa.s) was over three times slower than from a commercial aqueous solution. Peak whole blood concentrations were 66% of those with the commercial prepa ration, but the acute bioavailability of the two solutions was similar (Prakongpan et al. - 1989). The pH of drug solutions often differs markedly from the pH of the interstitial fluid. 25
Ch. 3
Intramuscular
80
drug
administration FIG. 3.3 Effect of solvent's acidity on drug absorption after i.m. injection in the rat. Amount absorbed within 3 min after dosing of isonicotinamide and isonicotinic acid, from 50 mmol solutions in isotonic buffers at various pH. (adapted from Kakemi, K. et al. : Chem. Pharm. Bull. (Tokyo) 19, 2058-2064, 1971.)
Isonicotinamide
60
40
20 i
2
E
<
4
6
8
10
12
pH of solution
Schou (1971) states that fairly concentrated unbuffered solutions of acids can be injected without doing harm to the tissue; the solutions would be neutralized during the injection due to the buffer capacity of the tissue. The buffer capacity of the tissue in the basic range is relatively insufficient and thus basic solutions are potentially more dangerous to the injected muscles (Schou - 1971). Nevertheless, there is no essential difference in the irritating effect of acidic and basic solutions; only the recovery is somewhat more pro longed after injection fluids with a pH of 12 (Shintani et al. - 1967). However, a remarkable decrease of the absorption rate is observed with compounds like isonicotinamide, caffeine or thiamine in buffer solution in the acidic pH range (fig. 3.3) (Kakemi et al. - 1971; Okumura et al. - 1972). Irreversible functional changes occur, apparently caused by morphological damage of the muscular tissue. In contrast to the de crease in absorption rate as is found for absorption from acidic solutions as compared to absorption from neutral conditions, the absorption rate from basic solutions is not dimin ished. The absorption rate may even be increased for compounds with relative high pKavalues, like thiamine, due to restriction of the ionisation of the drug (Okumura et al. 1972).
ou-
50% ethanol
80
^Ν 40
20
^ ^ > ^ 20 %
\N
"^^^
N/N 1 ^^"K \ Ni i \ \ i o% < 0 %
Time after administration (min)
26
FIG. 3.4 Effect of ethanol concentration in drug solvent on the absorption rate of isoni cotinamide given i.m. to rats. Drug disappear ance from the injection site after administration of 10 μΐ of a 50 mmol solution with various ethanol concentrations (mean ± s.d.). (adapted from Kobayashi, K. et al. : Chem. Pharm. Bull. (Tokyo) 25, 2862-2869, 1977.)
Intramuscular drug administration
I
Ch. 3
FIG. 3.5 Effect of ethanol concentration in drug solvent on the plasma level of isonicotinamide given i.m. to rats. A dose of 25 μΐ of a 200 mmol solution with none or 50% ethanol was given (mean ± s.d.). (adapted from Kobayashi, K. et al. : Chem. Pharm. Bull. (Tokyo) 25, 2862-2869, 1977)
12
CD
■o
50 %
E 10
α.
30
15
Time after administration (min)
Alcohols are often used as cosolvents in parenteral solutions to enhance the solubility of drugs or as stabilizing agents. However, the use of cosolvents can markedly affect the rate of drug absorption. The effect of the ethanol concentration on the rate of disappearance of isonicotinamide from the rat hindleg muscle is illustrated in fig. 3.4 (Kobayashi et al. - 1977c). As is apparent from these data, concentrations of ethanol of 20% and higher decrease the tissue clearance dramatically (rat; injec tion volume 10 μΐ; ethanol concentrations 0, 10, 20 and 50% v/v). Such a decrease in absorption rate results in much lower plasma levels (fig. 3.5). As the ethanol will disappear from the depot more rapidly than the drug, the inhibition of the drug clearance from the muscle will diminish so that the drug absorption rate will increase with time (provided that no precipitation of the drug occurs). The effect of ethanol is thought to be due to its influence on extracellular space and connective tissue permeability. Glycerin and propylene glycol (concentration range tested 20-60% and 20-100%, resp.) cause a comparable decrease in absorption rate as do polymeric adjuvants like polyethylene glycol, dextran and methylcellulose (Kakemietal- 1972). Various types of surfactants are used for the solubilization of hydrophobic (often practi cally water-insoluble) drugs. Such micellar solutions can also be used for intramuscular 100 o
Ό
80 \
40 5 μΙ
<
X
Q_
20 30
60
Time after administration (min)
90
FIG. 3.6 Effect of the injection volume on the absorption rate of p-hydroxyazobenzene given i.m. in 10% HCO-40 surfactant to rats. Drug concentrations: 5 mg/ml (5 and 10 μΐ), or 1 mg/ml (25 and 100 μΐ). (adapted from Hirano, K. et al: Chem. Pharm. Bull. (Tokyo) 29, 834843, 1981.) 27
Ch. 3
C/)
"c CO
Intramuscular
drug
administration
1.0
■*-»
CO
c o Ü
0.8
CD CO i_
0.6
c
•
isonicotinamide
D
isonicotinic acid
A
procainamide
T
sulphanylamide
♦
inuline
+
methyl isonicotii ate
O
Q.
k_
0.4
o C/) CO
0.2
O '+* CO
0.01
0.1
1.0
10
Concentration polysorbate 80 (% w/v) FIG. 3.7 Effect of polysorbate 80-concentration in vehicle on drug absorption rate constant of water-soluble micelle-free drugs given i.m. in the rat. The constant is expressed as the ratio relative to that observed with drug in buffer solutions only, injection volume: 10 μΐ; vehicle isotonic phosphate buffer pH 7.0; drug concen trations sulphanilamide 25 mmol, C-inulin 2.5 5Ci/ml, other drugs 50 mmol. (adapted from Kobay ashi, H. et al.: J. Pharm. Sci. 63, 580-584, 1974.)
drug administration. The absorption of solubilized drugs from an intramuscular depot proceeds like the absorption from aqueous solutions according to a pseudo-first-order process and hence is not dependent on the initial drug concentration. However, the halflife is relatively long when compared with the absorption of drugs from aqueous solu tions. For the model compound p-hydroxyazobenzene (PHAB) Hirano et al. (1981c) measured a half-life of about 75 min [male rats; 240-280 g; 5-0.5 mg/ml PHAB; solvent 10% HCO-40 (polyoxyethylene hydrogenated castor oil derivative - a non-ionic surfactant); inj. volume 50 μ\\ m. gastrocnemius]. The absorption rate decreased markedly with increasing injection volumes in the range tested of 5—100 //l (fig. 3.6). Viscosity and osmoticity had little effect on the disappear ance rate of the model compounds from the intramuscular depot. An increase of the surfactant con centration (range studied 5-20%) causes a decrease of the absorption rate constant with a factor 2 3. A comparison of various model compounds solubilized with several surfactants suggests that the intramuscular absorption rate depends mainly on the distribution coefficient K between micellar and aqueous phases. An inhibitory effect of surfactants as such on the intramuscular absorption becomes apparent from studies with water soluble drugs (Kobayashi et al. - 1974, 1975). As can be seen from fig. 3.7 the reduction in absorption is almost similar for various drugs independent of their ionogenic na ture, lipophilicity, molecular size or pharmacological class. The absorption rate (characterized by the absorption rate constant) is greatly diminished already at polysorbate 80 concentrations as low as 0.1%. The mechanism of the absorption inhibitory effect of polysorbate 80 is thought to be due to its influence on the extracellular space and connective tissue permeability through interactions with proteins and mucopolysaccharides (Kobayashi et al. - 1976, 1977a, 1977b). 28
Intramuscular
drug administration
Ch. 3
ABSORPTION FROM OILY SOLUTIONS Drugs with a poor water solubility but a high lipid solubility are often administered parenterally as a solution in oily solvents. Absorption of the drug component from an intra muscular depot of such an oily solution starts with the partition to the aqueous intercellu lar phase. Thereafter the absorption process proceeds by diffusion into the circulation system as occurs after intramuscular injection of aqueous drug solutions. The absorption process can reasonably be described as a pseudo-first order process. The absorption rate is generally much slower than for drug absorption from aqueous so lutions. p-Aminoazobenzene (PAAB), used as a model compound, dissolved in sesame oil is absorbed from an intramuscular depot with an absorption half-life of about 120 min (rat, anaesthetized, 50 μΐ, cone. 5 mg/ml in sesame oil) (Hirano et al. - 1981a). The absorption half-life of the drug is often found to be related to its distribution coefficient (K) between oil phase and water. In fig. 3.8 the absorption of PAAB from various oily solutions is de picted. As is apparent from this graph the absorption rate of PAAB varies widely - when dissolved in diethyl sebacate (K= 9900), the absorption rate is about 5 times lower than when the compound is dissolved in sesame oil (K= 1200). a-Tocopherol acetate in olive oil showed in rabbits a complete lack of i.m. bioavailability, as measured over 72 h post injection (Pedraz et al. - 1989). Corresponding to the pseudo-first-order character of the absorption process, the absorp tion rate is not dependent on the initial drug concentration. In contrast, a significant de crease of the absorption rate is observed with the increase of the injection volume. This effect occurs already in the range of lower volumes (5-25 μ\) and is probably caused by a relative decrease of the absorption area with increasing injection volume. In the con scious rat the absorption rate is larger than in the anaesthetized animal and it is also less affected by changes of the injection volume. Probably the oily depot in the conscious rat is spread more extensively and approaches more a flat shape (Tanaka et al. - 1974; Hirano et al. - 1981a). The absorption rate of a drug from an oily depot is only minimally affected by the viscosity of the vehicle. Though the release of drugs from oily depots may proceed slowly, this process does not necessarily determine the duration time of the maximum effect or the intensity of the biological response (Armstrong and James - 1980). For many (lipophilic) compounds the elimination half-life in the whole body exceeds greatly the half-life in the muscle. » (Λ
-2
100 80
40
< <
CL
IPM 20
Time after administration (h)
FIG. 3.8 Effect of oily vehicle on the absorp CO tion rate of p-aminoazobenzene given i.m. to rats. Injection volume 50 μΐ; drug concentra tion: 5 mg/ml. Oily vehicles: DES: diethyl se bacate; Mig: Miglycol 812; CO: castor oil; IPM: isopropylmy ristate; SO: sesame oil. (adapted from Hirano, K. et al: Chem. Pharm. Bull (Tokyo) 29, 519-531, 1981.) 29
Ch. 3 Intramuscular drug administration Table 3.1
Biological half-lives of esters
Compound
C in rat after intramuscular injection of [14C] testosterone and its Half-life (days)
Testosterone -formate - acetate - proprionate - butyrate - valerate
Muscle
Whole body
0.029 0.155 1.74 1.63 2.54 2.97
1.99 2.82 2.94 3.75 4.94 7.43
In table 3.1 the biological half-lives are given for 14C from labelled testosterone in muscle and whole body of rats, after intramuscular injection of [14C] testosterone and its lower esters (male rats; 250 g; injection volume (ethyl oleate) 0.1 ml; 1 mg steroid; m. gluteus) (James et al. 1969). Similarly, investigators from the same laboratory compared in the rat the availability of testos terone proprionate and its biological effect after intramuscular injection in various oily vehicles (Al-Hindawi et al. - 1987). The rate of elimination from the muscle in this experiment was again found to be dependent on the partition coefficient. In contrast, the elimination rate from the whole rat was significantly smaller and independent of the solvent (table 3.2). The longer duration of the elimination from the whole body compared to the elimination from the oily depot is determined by the fate of the compound during and after leaving this depot. Prodrugs like testosterone-esters are in a structure-dependent manner sensitive to degradation to the parent compound. Almost always this parent compound will have a much lower lipophilicity than the pro-drug and in contrast to the unaltered pro-drug it will not (or only in very small amounts) accumulate in body fat. Consequently, the body half-life time of the easily degraded pro-drugs af ter leaving the muscle depot will only be determined by the kinetics of the parent compound. Nev ertheless this half-life may be considerable, for instance through an entero-hepatic circulation as is likely to occur with testosterone. For the more stable pro-drugs the temporary storage in the body fats may be a major factor determining their long whole body half-lives (Al-Hindawi et al. - 1987). However, for an exact knowledge of the bioavailability processes after intramuscular administra tion as an oily solution, for every individual drug detailed analyses are needed in view of the many different biopharmaceutical variables that are involved (Armstrong and James - 1980). The clearance of oil from the injection site mainly occurs by local metabolic degrada tion, absorption in blood and phagocytosis. The half-life values of parenterally adminis tered oils depend on the animal model used; the process extends often over weeks. Table 3.2
Biological half-lives of 14C in rat after intramuscular injection of [14C] testerone proprionate in different solvents
Solvent
Ethyl oleate ^ Octanol Isopropyl myristate Light liquid paraffin
Partition coefficient (X 10"3)
Half-life (h) Muscle
Whole body
6.3 5.3 4.3 1.5
10.3 9.7 7.8 3.2
19.1 19.3 22.1 18.1
*) The difference in half-life values in table 3.1 and table 3.2 for testosterone proprionate in ethyl oleate is at tributed by the authors to the difference of injection site viz. m. gluteus versus m. gastrocnemius. 30
Intramuscular drug administration Ch. 3 In the rat the absorption of [14C] methyl oleate followed apparent first-order kinetics after a lag time of about 7 days. About 15 days after oil deposition 50% had disappeared from the injection site (male rats; 150-180 g; injection volume 10 μΐ; m. rectus femoris) (Tanaka et al. - 1974). In the rabbit ethyl oleate possesses a half-life of about 10 days (injection volume 50-300 μ\) whereas arachis oil shows a half-life of about 23 days (Howard and Hadgraft - 1983). When large oil vol umes are injected (dogs; 5.2-12.4 kg; 0.5-1.0 ml/kg) oil absorption to the regional lymph nodes is seen. Depending on the type of oil used, pulmonary oil micro-embolism may occur (Svendsen and Aaes-Jorgensen - 1979). ABSORPTION FROM SUSPENSIONS The use of aqueous or oleaginous suspensions for the parenteral administration of drugs is rather limited in experimental studies. This will be caused in part by the need for a good control of particle size as well as specific formulation problems associated with these dispersed systems like syringeability, ease of resuspension and drainage (Ballard 1968). In contrast, a carefully balanced formulation may provide effective plasma con centrations over prolonged periods of time, not easily realized with other dosage forms (Ballard - 1980). When injecting an aqueous suspension, the particles are confined to the fibrous or membranous tissues between muscle fibers forming a loose agglomerate, while the aque ous solvent is taken up by the adjacent tissue. The rate of drug clearance from the tissue is limited by the dissolution process and is thus dependent on the effective crystal sur face. So, the absorption rate increases with decreasing particle size and this effect is par ticularly marked in the range of 2-3 μπι, possibly by the fact that particles of this size only form loose aggregates. The dispersing agent may likewise affect the agglomerate formation and influence the clearance rate (Hirano et al. - 1981b). Oleaginous suspensions have a different dépendance of the clearance rate on particle size. Suspensions with micronized particles (<5 μτή) of benzyl penicillin-procaine in oil with 2% aluminium monostearate have a much longer half-life than suspensions with greater particles (>50μιη) (Buckwalter and Dickinson - 1958; Ballard -1980; Pflegel 1982). The absorption rate from suspensions varies widely between compounds and formu lations. Though this dosage form is often used with the intention to realize a long-acting drug depot, under certain conditions an oily solution may turn out to be more effective in this respect (Enever et al. - 1983). TISSUE VULNERABILITY Morphological procedures have been in use for some time for the determination of local reactions of drug preparations for intramuscular administration (for references see Svendsen et al. - 1979). More recently, the determination of serum creatinine phosphokinase (CPK) activity or (decrease of) muscle CPK activity have been used to measure lo cal damaging effects (Steiness et al. - 1978; Svendsen et al. 1979). As indicated above, vehicles like saline and oils cause little damage when appropriate volumes are used for injection. Likewise, 10% solutions of propylene glycol or glycerol formal also cause little effect. In contrast, large area's of damaged tissue are found when these solvents are used undiluted or as 50% solutions (Svendsen et al. - 1979). Many drug preparations have been reported to cause muscle tissue damage upon in tramuscular injection. The intensity of the local damage is highly dependent on the spe cific conditions of the intramuscular drug administration, such as the active compounds, the concentration and volume, and the injection site. It must be realised that also less 31
CL· 3
Intramuscular drug
administration
specific aspects like restraining during blood sampling may effect serum CPK activity (Meltzer - 1972). Only limited guidance can be obtained from the literature for the opti mal conditions of intramuscular drug administration. When information on possible tis sue damaging effects seems relevant, exploratory investigations will have to be per formed in every new situation. Skeletal muscle damage caused by organic cosolvent systems do not necessarily affect bioavailability. Brazeau and Fung (1990) compared i.m. bioavailability in rabbits of a tracer dose of diazepam in three cosolvent water mixtures (20% v/v propylene glycol, 20% v/v polyethylene glycol 400 and 50% v/v polyethylene glycol 400). Though their in vitro myotoxicity varied 10-fold, the AUCo-720 min w a s comparable for the three formulations. Few oils produce immediate muscle damage such as may occur with aqueous solutions. However, at longer time intervals small cysts appear between the muscle fibers at the in jection site (Paget and McG.Scott - 1957; Svendsen and Aaes-Jorgensen - 1979; Rasmussen - 1980). IN SUMMARY With intramuscular drug administration strict control is needed of the pharmaceutical qualities of the drug solution. The manner of injection has to be standardized; by prefer ence the injection volume must be kept small (in rats less than 50 μΐ). It may be useful to determine the release rate of the drug from the depot, though the drug half-life from the whole body may be controlled by other phases of the drug distribution and metabolism processes. REFERENCES Al-Hindawi, M.K., James, K.C., and Nicholls, P.J.: Influence of solvent on the availability of testosterone propionate from oily, intramuscular injections in the rat. J. Pharm. Pharmacol. 39, 90-95, 1987. Amstrong, N.A., and James, K.C.: Drug release from lipid-based dosage forms I. Int. J. Pharm. 6, 185-193, 1980. Ballard, B.E.: Biopharmaceutical considerations in subcutaneous and intramuscular drug administration. J. Pharm. Sci. 57, 357-378, 1968. Ballard, B.E.: Prolonged-Action Pharmaceuticals. In: Remington's Pharmaceutical Sciences, pp. 1594-1613. Ed. A. Osol. Mack Pubi. Comp.- Easton, Pennsylvania, 1980. Bederka, J., Takemori, A.E., and Miller, J.W.: Absorption rates of various substances administered intramus cularly. Eur. J. Pharmacol. 15, 132-136, 1971. Brazeau, G.A., and Fung, H.L.: Effect of organic cosolvent-induced skeletal muscle damage on the bioavail ability of intramuscular [14C]diazepam. J. Pharm. Sci. 79, 773-777, 1990. Buckwalter, F.H., and Dickinson, H.L.: The effect of vehicle and particle size on the absorption, by the intra muscular route, of procaine penicillin G suspensions. J. Am. Pharm. Ass. 47, 661-666, 1958. Enever, R.P., Fotherby, K., Naderi, S., and Lewis, G.A.: The influence of physicochemical properties of some esters of norethisterone upon the plasma levels of free norethisterone. Steroids 41, 381-396, 1983. Greenblatt, D.J., and Koch-Weser, J.: Intramuscular injection of drugs. New. Engl. J. Med. 295, 542-546, 1976. Hirano, K., Ichihashi, T., and Yamada, H.: Studies on the absorption of practically water-insoluble drugs fol lowing injection: I. Intramuscular absorption from water-immiscible oil solutions in rats. Chem. Pharm. Bull. (Tokyo) 29, 519-531, 1981a Hirano, K., Ichihashi, T., and Yamada, H.: Studies on the absorption of practically water-insoluble drugs fol lowing injection: II. Intramuscular absorption from aqueous suspension in rats. Chem. Pharm. Bull. (Tokyo) 29, 817-827, 1981b. 32
Intramuscular drug administration
Ch. 3
Hirano, K., Ichihashi, T., and Yamada, H.: Studies on the absorption of practically water-insoluble drugs fol lowing injection: III. Intramuscular absorption from aqueous non-ionic surfactant solutions in rats. Chem. Pharm. Bull. (Tokyo) 29, 834-843, 1981c. Howard, J.R., and Hadgraft, J.: The clearance of oily vehicles following intramuscular and subcutaneous in jection in rabbits. Int. J. Pharm. 16, 31-39, 1983. James, K.C., Nicholls, P.J., and Roberts, M.: Biological half-lives of 4-[ 14 C]- testosterone and some of its es ters after injection into the rat. J. Pharm. Pharmacol. 21, 24-27, 1969. Kakemi, K., Sezaki, H., Okumura, K., and Ashida, S.: Absorption and excretion of drugs XXXIX. Absorption of isonicotinic acid derivatives from the skeletal muscle of the rats. Chem. Pharm. Bull. (Tokyo) 17, 1332-1338, 1969. Kakemi, K., Sezaki, H., Okumura, K., and Takada, C: Absorption of drugs from the skeletal muscle of the rats. (2) Chem. Pharm. Bull. (Tokyo) 19, 2058-2064, 1971. Kakemi, K., Sezaki, H., Okumura, K., Kobayashi, H., and Furusawa, S.: Absorption of drugs from the skeletal muscle of the rats (3). Effect of water- soluble adjuvants and vehicles on intramuscular absorption. Chem. Pharm. Bull. (Tokyo) 20, 443-451, 1972. Kobayashi, H., Nishimura, T., Okumura, K., Muranishi, S., and Sezaki, H.: Effect of polysorbates on absorp tion rates of water-soluble, micelle-free drugs administered intramuscularly in the rat. J. Pharm. Sci. 63, 580-584, 1974. Kobayashi, H., Tso-chin Peng, Kagayama, A., Okumara, K., Muranishi, S., and Sezaki.H.: Effect of some ionic and nonionic surfactants on the intramuscular absorption of isonicotinamide. Chem. Pharm. Bull. (Tokyo) 23, 42-47, 1975. Kobayashi, H., Tso-chin Peng, Fujikama, M., Muranishi, S., and Sezaki, H.: Mechanism of the inhibitory ef fect of polysorbate 80 on intramuscular absorption of drugs, 1. Chem. Pharm. Bull. (Tokyo) 24, 23832390, 1976. Kobayashi, H., Tso-chin Peng, Kawamura, R., Maranishi, S., and Sezaki, H.: Mechanism of the inhibitory ef fect of polysorbate 80 on intramuscular absorption of drugs. Chem. Pharm. Bull. (Tokyo) 25, 569-574, 1977a. Kobayashi, H., Tso-chin Peng, Kawamura, R., Muranishi, S., and Sezaki, H.: Mechanism of the inhibitory ef fect of surfactants on intramuscular absorption of drugs. Chem. Pharm. Bull. (Tokyo) 25, 1547-1554, 1977b. Kobayashi, K., Miyoshi, Y., Kitamura, K., Yoshizaki, Y., Muranishi, S., and Sezaki, H.: Effect of ethanol on the intramuscular absorption of watersoluble drugs in the rat. Chem. Pharm. Bull. (Tokyo) 25, 2862-2869, 1977c. Meltzer, H.Y.: Muscle toxicity produced by phencyclidine and restraint stress. Res. Comm. Chem. Pathol. Pharmacol. 3, 369-382, 1972. Okumara, K., Sezaki, H., and Kakemi, K.: Absorption of drugs from skeletal muscle of the rat. (4). Absorption of cationic drugs from the muscle. Chem. Pharm. Bull. (Tokyo) 20, 1607-1611, 1972. Paget, G.E., and Scott, H.McG.: A comparison of the local effects of various intramuscular injections in the rat. Brit. J. Pharmacol. 12, 427-433, 1957. Pedraz, J.L., Calvo, B., Bortolotti, A., Celardo, A., and Bonati, M.: Bioavailability of intramuscular vitamin E acetate in rabbits. J. Pharm. Pharmacol. 41, 415-417, 1989. Pflegel, H.: Biopharmazeutische Aspekte parenteraler Arzneiformen. Pharmazie 37, 307-318, 1982. Prakongpan, S., Sirimai, S., Edwards, G., McGrath, C.S., and White, N.J.: An improved formulation of chloroquine for intramuscular administration: absorption kinetics in rabbits. J. Pharm. Pharmacol. 41, 726-728, 1989. Rasmussen, F.: Tissue damage at the injection site after intramuscular injection of drugs in food-producing animals. In: Trends in veterinary pharmacology. Developments in animal and veterinary sciences. Volume 6, pp 27-33. Ed. A.S.J.P.A.M.van Miert, J.Frens, and F.W.van der Kreek. Elsevier, Amsterdam, 1980. Schou, J.: Subcutaneous and intramuscular injection of drugs. In: Handbook of Experimental Pharmacology Volume 28, Concepts in biochemical pharmacology. Part 1, pp 47-66. Ed. B.B.Brodie and J.R.Gilette Springer Verlag Berlin, 1971. Shintani, S., Yamazaki, M., Nakamura, M., and Nakayama, I.: A new method to determine the irritation of drugs after intramuscular injection. Toxicol. Appi. Pharmacol. 11, 293-301, 1967. Steiness, E., Rasmussen, F., Svendsen, O., and Nielsen, P.: A comparative study of serum creatine phosphokinase (CPK) activity in rabbits, pigs, and humans after intramuscular injection of local damaging drugs. Acta Pharmacol. Toxicol. 42, 357-364, 1978.
33
Ch. 3
Intramuscular drug
administration
Sund, R.B., and Schou, J.: The determination of absorption rates from rat muscles: An experimental approach to kinetic descriptions. Acta Pharmacol. Toxicol. 21, 313-325, 1964a. Sund, R.B., and Schou, J.: Absorption of atropine: Anticholinergics as inhibitors of absorption from muscles. Acta Pharmacol. Toxicol. 21, 339-345, 1964b. Svendsen, O., Rasmussen, F., Nielsen, P., and Steiness.E.: The loss of creatine phosphokinase (CK) from in tramuscular injection sites in rabbits. A predictive tool for local toxicity. Acta Pharmacol. Toxicol. 44, 324-328, 1979. Svendsen, O., and Aaes-Jorgensen.T.: Studies on the fate of vegetable oil after intramuscular injection into experimental animals. Acta Pharmacol. Toxicol. 45, 352-378, 1979. Tanaka, T., Kobayashi, H., Okumura, K., Muranishi, S., and Sezaki, H.: Biopharmaceutical studies on parenteral preparations. 7. Intramuscular absorption of drugs from oily solutions in the rat. Chem. Pharm. Bull. (Tokyo) 22, 1275-1284, 1974. Thomas, J.: Bioavailability of drugs administered intramuscularly. Aust. Fam. Physician 6, 925-934, 1977. Tuttle, C.B.: Intramuscular injections and bioavailability. Am. J. Hosp. Pharm. 34, 965-968, 1977. Wagner, J.G.: Biopharmaceutics, absorption aspects. J. Pharm. Sci. 50, 359-387, 1961. Wilensky, A.J., and Lowden, J.A.: Inadequate serum levels after intramuscular administration of diphenylhydantoin. Neurology 23, 318-324, 1973. Zelman, S.: Notes on techniques of intramuscular injection. The avoidance of needless pain and morbidity. Am. J. Med. Sci. 241, 563-567, 1961.
34
Intramuscular drug administration Intramuscular depot and drug absorption Absorption from aqueous solutions Absorption from oily solutions Absorption from suspensions Tissue vulnerability
Intramuscular injection of drugs is quite popular in the clinic; about 50% of the medical patients receive at least one intramuscular injection during their stay in the hospital (Greenblatt and Koch-Weser - 1976). However, in experimental studies the use of the in tramuscular route is rather limited. This is due to the technically greater simplicity of other parenteral administration procedures in animals and to the relative small muscle mass available in rodents for disposition of the dose. In contrast to intravascular administration, other parenteral dosing procedures such as intramuscular administration often cause the formation of a drug depot. To reach the blood or lymph vessels the drug must leave this depot. A large series of pharmaceutical factors may influence the rate of release of drugs from such a depot (Wagner - 1961). Consequently, when conditions are not properly controlled, wide variations in the ab sorption phase may occur. On the other hand, with a careful choice of the pharmaceutical formulation, it is possible within limits to regulate the intensity and duration of drug ac tion.
INTRAMUSCULAR DEPOT AND DRUG ABSORPTION Depot form. Intramuscularly injected drug solvent distributes rapidly in the fasciai planes or connective tissue surrounding the muscles. The spreading of aqueous systems is completed almost directly after injection; oily solutions continue to spread from 1 to 5 min before they become to some degree fixed in position. The solvent water spreads more extensively than oily solutions. The injection water is usually taken up by the hyaluronic acid gel; oils localize in the connective tissue spatia in arteficial lacunae. The formed depots take in both cases a flat shape similar to a pod (Ballard - 1968; Schou 1971; Hirano et al. - 1981a). The only slowly cleared oil depots certainly continue to change in shape and distribution with time. Deep, firm massage of muscle tissue follow ing an intramuscular injection favors the spread of the depot over a wider tissue area (Zelman - 1961) so favouring the absorption rate. The absorption process is characterized by a) the diffusion of drug molecules in the extravascular tissue, b) the passage of drug molecules through the capillary wall, c) the tissue perfusion rate with blood. For most compounds the passage through the capillary wall is not the rate- limiting factor for absorption. However, each of the other two proc esses may become the rate-limiting step. A generally useful equation describing the ab sorption kinetics has not been derived; the number of variables involved seems to make this impossible. As an approximation, drug absorption data are treated by many authors as corresponding to a pseudo-first order process, that can be characterized by an absorp tion half-life. Bioavailability of intramuscularly injected drugs is not always complete. Unabsorbed drug may remain permanently bound to the muscle tissue. In addition the drug may de23
Ch. 3 Intramuscular drug administration FIG. 3.1 Serum concentration profile of diphenylhydantoin after a 25 mg/kg dose of the drug given either i.V., i.m. or orally to rabbits (mean ± s.d.). (adapted from Wilensky, A.J., and Lowden, J.A.: Neurology 23, 318-324, 1973.)
40 30
20 10
12
24
CO
Time after administration (h)
compose spontaneously or enzymatically at the injection site. In some cases the decrease in bioavailability is only apparent when the very slow release causes plasma and urine concentrations to fall below detectable levels. This may occur when drugs precipitate af ter intramuscular administration (due to rather unphysiological solvent properties) and thereafter redissolve very slowly. This has been found, for instance, with diazepam and diphenylhydantoin; in clinical use higher (and more reliable) plasma levels are obtained when the compounds are administered orally instead of intramuscularly (Thomas - 1977; Tuttle - 1977). This phenomenon is likewise apparent from experiments in which diphenylhydantoin in a dose of 25 mg/kg was administered to rabbits via the intravenous, intramuscular and oral route, respectively (fig. 3.1). The persistent presence of diphenylhydantoin at the intramuscular injection site was demonstrated by a recovery of 44% of the injected dose in the muscles of the rabbits 48 h after injection (Wilensky and Lowden - 1973). ABSORPTION FROM AQUEOUS SOLUTIONS Absorption of drugs from aqueous solutions after intramuscular injections proceeds rather rapidly and the absorption process can reasonably be described as a pseudo-first order process. In fig 3.2 the absorption of benzylpenicillin from the exterior tibialis muscle of the rat is depicted (10 μΐ, 0.50 mg). The absorption half-life is 4.4 min, so 90% of the dose is absorbed within 15 min. A comparable absorption rate is found for various other compounds (Bederka et al. - 1971). According to these authors, in their study the absorption rate appeared to be independent of the molecular weights, diffusion coefficients, pKa-values and pharmacological class of substances in vestigated. Changes in blood flow, however, markedly affect the absorption rate. Correspondingly, the lower absorption rate for cationic drugs compared to neutral or anionic drugs, as found by Okumara et al. (1972), is thought to be due to their local vaso-active properties. In the rat, within the range of small volumes (5-20 μ\, possibly up to 50 μΐ), the injec tion volume does not significantly affect the absorption rate (Kakemi et al. - 1969; Bederka et al. - 1971). However, above this range, higher volumes tend to decrease the absorption rate. The absorption of sucrose (0.38 mg/ml), 5 min after intramuscular administration to the rat, was 54% from a dose of 64 μ\ compared to 78% from a dose of 4 μ\ (Sund and Schou - 1964a). In 24
Intramuscular drug administration o
■a
100
Ch. 3
FIG. 3.2 Absorption of benzylpenicillin after i.m. injection of a dose of 0.50 mg/10 μΐ to rats (mean ± s.e.). (adapted from Bederka, J. et al: Eur. J. Pharmacol 15, 132-136, 1971.)
T3
40 -Q CO
20 10 Q.
(D
m
0
10
20
Time after administration (min)
comparison to an absorption of benzylpenicillin of about 45% from a dose of 10 μ\ four min after injection, only 8% is absorbed when 100μ\ is given (Bederka et al. - 1971). For a compound like sucrose the absorption rate is over a wide range independent of the drug concentration (rat; range of 0.19-9.6 mg/ml) (Sund and Schou 1964a). Also for unionized drugs like isoniazid no effect of the drug concentration on the absorption rate was found (concentration range studied 17-250 mM) (Kakemi et al. - 1969). In contrast, some decrease in absorption rate is observed for compounds like thiamine and procainamide when administered in higher concentrations (50-100 mM) (Okumura et al. - 1972). Com pounds interfering with the local blood perfusion will also show a concentration dependent clear ance; such a mechanism is suggested for atropine in which case the absorption is markedly dimin ished by increasing concentrations above the threshold of 0.5 mg/ml (Sund and Schou - 1964b). To minimize tissue damage and irritation the tonicity of drug solutions is often adjusted to the level of the interstitial fluid by the addition of salts. However, when injection vol umes are kept low (10-20//l), the use of paratonic solutions does not essentially disrupt the structure and properties of the muscle tissue (Kakemi et al. - 1971). At low osmotic pressure the absorption rate of isonicotinamide (used as a model drug) is markedly de creased, while there is a tendency for a slightly increased absorption rate from hypertonic solutions. As might be expected, the injection of normal saline gives only slight local disturbances, also with greater volumes. Hypertonic NaCl solution (1.7%) then gives rise to little more damage to the muscle than does isosmotic NaCl solution; the oedema which arises is more extensive. However, greater volumes of distilled water will cause severe reactions; besides oedema, numerous muscle fibers are disrupted or altered (rat; 0.2 ml injected into the hindleg) (Paget and McG.Scott - 1957). The rate of absorption from an i.m. depot is decreased when the viscosity of the drug vehicle is increased. The rate of absorption of chloroquine after i.m. injection in rabbits from a solution containing 2% methylcellulose 1500 (viscosity 2430 mPa.s) was over three times slower than from a commercial aqueous solution. Peak whole blood concentrations were 66% of those with the commercial prepa ration, but the acute bioavailability of the two solutions was similar (Prakongpan et al. - 1989). The pH of drug solutions often differs markedly from the pH of the interstitial fluid. 25
Ch. 3
Intramuscular
80
drug
administration FIG. 3.3 Effect of solvent's acidity on drug absorption after i.m. injection in the rat. Amount absorbed within 3 min after dosing of isonicotinamide and isonicotinic acid, from 50 mmol solutions in isotonic buffers at various pH. (adapted from Kakemi, K. et al. : Chem. Pharm. Bull. (Tokyo) 19, 2058-2064, 1971.)
Isonicotinamide
60
40
20 i
2
E
<
4
6
8
10
12
pH of solution
Schou (1971) states that fairly concentrated unbuffered solutions of acids can be injected without doing harm to the tissue; the solutions would be neutralized during the injection due to the buffer capacity of the tissue. The buffer capacity of the tissue in the basic range is relatively insufficient and thus basic solutions are potentially more dangerous to the injected muscles (Schou - 1971). Nevertheless, there is no essential difference in the irritating effect of acidic and basic solutions; only the recovery is somewhat more pro longed after injection fluids with a pH of 12 (Shintani et al. - 1967). However, a remarkable decrease of the absorption rate is observed with compounds like isonicotinamide, caffeine or thiamine in buffer solution in the acidic pH range (fig. 3.3) (Kakemi et al. - 1971; Okumura et al. - 1972). Irreversible functional changes occur, apparently caused by morphological damage of the muscular tissue. In contrast to the de crease in absorption rate as is found for absorption from acidic solutions as compared to absorption from neutral conditions, the absorption rate from basic solutions is not dimin ished. The absorption rate may even be increased for compounds with relative high pKavalues, like thiamine, due to restriction of the ionisation of the drug (Okumura et al. 1972).
ou-
50% ethanol
80
^Ν 40
20
^ ^ > ^ 20 %
\N
"^^^
N/N 1 ^^"K \ Ni i \ \ i o% < 0 %
Time after administration (min)
26
FIG. 3.4 Effect of ethanol concentration in drug solvent on the absorption rate of isoni cotinamide given i.m. to rats. Drug disappear ance from the injection site after administration of 10 μΐ of a 50 mmol solution with various ethanol concentrations (mean ± s.d.). (adapted from Kobayashi, K. et al. : Chem. Pharm. Bull. (Tokyo) 25, 2862-2869, 1977.)
Intramuscular drug administration
I
Ch. 3
FIG. 3.5 Effect of ethanol concentration in drug solvent on the plasma level of isonicotinamide given i.m. to rats. A dose of 25 μΐ of a 200 mmol solution with none or 50% ethanol was given (mean ± s.d.). (adapted from Kobayashi, K. et al. : Chem. Pharm. Bull. (Tokyo) 25, 2862-2869, 1977)
12
CD
■o
50 %
E 10
α.
30
15
Time after administration (min)
Alcohols are often used as cosolvents in parenteral solutions to enhance the solubility of drugs or as stabilizing agents. However, the use of cosolvents can markedly affect the rate of drug absorption. The effect of the ethanol concentration on the rate of disappearance of isonicotinamide from the rat hindleg muscle is illustrated in fig. 3.4 (Kobayashi et al. - 1977c). As is apparent from these data, concentrations of ethanol of 20% and higher decrease the tissue clearance dramatically (rat; injec tion volume 10 μΐ; ethanol concentrations 0, 10, 20 and 50% v/v). Such a decrease in absorption rate results in much lower plasma levels (fig. 3.5). As the ethanol will disappear from the depot more rapidly than the drug, the inhibition of the drug clearance from the muscle will diminish so that the drug absorption rate will increase with time (provided that no precipitation of the drug occurs). The effect of ethanol is thought to be due to its influence on extracellular space and connective tissue permeability. Glycerin and propylene glycol (concentration range tested 20-60% and 20-100%, resp.) cause a comparable decrease in absorption rate as do polymeric adjuvants like polyethylene glycol, dextran and methylcellulose (Kakemietal- 1972). Various types of surfactants are used for the solubilization of hydrophobic (often practi cally water-insoluble) drugs. Such micellar solutions can also be used for intramuscular 100 o
Ό
80 \
40 5 μΙ
<
X
Q_
20 30
60
Time after administration (min)
90
FIG. 3.6 Effect of the injection volume on the absorption rate of p-hydroxyazobenzene given i.m. in 10% HCO-40 surfactant to rats. Drug concentrations: 5 mg/ml (5 and 10 μΐ), or 1 mg/ml (25 and 100 μΐ). (adapted from Hirano, K. et al: Chem. Pharm. Bull. (Tokyo) 29, 834843, 1981.) 27
Ch. 3
C/)
"c CO
Intramuscular
drug
administration
1.0
■*-»
CO
c o Ü
0.8
CD CO i_
0.6
c
•
isonicotinamide
D
isonicotinic acid
A
procainamide
T
sulphanylamide
♦
inuline
+
methyl isonicotii ate
O
Q.
k_
0.4
o C/) CO
0.2
O '+* CO
0.01
0.1
1.0
10
Concentration polysorbate 80 (% w/v) FIG. 3.7 Effect of polysorbate 80-concentration in vehicle on drug absorption rate constant of water-soluble micelle-free drugs given i.m. in the rat. The constant is expressed as the ratio relative to that observed with drug in buffer solutions only, injection volume: 10 μΐ; vehicle isotonic phosphate buffer pH 7.0; drug concen trations sulphanilamide 25 mmol, C-inulin 2.5 5Ci/ml, other drugs 50 mmol. (adapted from Kobay ashi, H. et al.: J. Pharm. Sci. 63, 580-584, 1974.)
drug administration. The absorption of solubilized drugs from an intramuscular depot proceeds like the absorption from aqueous solutions according to a pseudo-first-order process and hence is not dependent on the initial drug concentration. However, the halflife is relatively long when compared with the absorption of drugs from aqueous solu tions. For the model compound p-hydroxyazobenzene (PHAB) Hirano et al. (1981c) measured a half-life of about 75 min [male rats; 240-280 g; 5-0.5 mg/ml PHAB; solvent 10% HCO-40 (polyoxyethylene hydrogenated castor oil derivative - a non-ionic surfactant); inj. volume 50 μ\\ m. gastrocnemius]. The absorption rate decreased markedly with increasing injection volumes in the range tested of 5—100 //l (fig. 3.6). Viscosity and osmoticity had little effect on the disappear ance rate of the model compounds from the intramuscular depot. An increase of the surfactant con centration (range studied 5-20%) causes a decrease of the absorption rate constant with a factor 2 3. A comparison of various model compounds solubilized with several surfactants suggests that the intramuscular absorption rate depends mainly on the distribution coefficient K between micellar and aqueous phases. An inhibitory effect of surfactants as such on the intramuscular absorption becomes apparent from studies with water soluble drugs (Kobayashi et al. - 1974, 1975). As can be seen from fig. 3.7 the reduction in absorption is almost similar for various drugs independent of their ionogenic na ture, lipophilicity, molecular size or pharmacological class. The absorption rate (characterized by the absorption rate constant) is greatly diminished already at polysorbate 80 concentrations as low as 0.1%. The mechanism of the absorption inhibitory effect of polysorbate 80 is thought to be due to its influence on the extracellular space and connective tissue permeability through interactions with proteins and mucopolysaccharides (Kobayashi et al. - 1976, 1977a, 1977b). 28
Intramuscular
drug administration
Ch. 3
ABSORPTION FROM OILY SOLUTIONS Drugs with a poor water solubility but a high lipid solubility are often administered parenterally as a solution in oily solvents. Absorption of the drug component from an intra muscular depot of such an oily solution starts with the partition to the aqueous intercellu lar phase. Thereafter the absorption process proceeds by diffusion into the circulation system as occurs after intramuscular injection of aqueous drug solutions. The absorption process can reasonably be described as a pseudo-first order process. The absorption rate is generally much slower than for drug absorption from aqueous so lutions. p-Aminoazobenzene (PAAB), used as a model compound, dissolved in sesame oil is absorbed from an intramuscular depot with an absorption half-life of about 120 min (rat, anaesthetized, 50 μΐ, cone. 5 mg/ml in sesame oil) (Hirano et al. - 1981a). The absorption half-life of the drug is often found to be related to its distribution coefficient (K) between oil phase and water. In fig. 3.8 the absorption of PAAB from various oily solutions is de picted. As is apparent from this graph the absorption rate of PAAB varies widely - when dissolved in diethyl sebacate (K= 9900), the absorption rate is about 5 times lower than when the compound is dissolved in sesame oil (K= 1200). a-Tocopherol acetate in olive oil showed in rabbits a complete lack of i.m. bioavailability, as measured over 72 h post injection (Pedraz et al. - 1989). Corresponding to the pseudo-first-order character of the absorption process, the absorp tion rate is not dependent on the initial drug concentration. In contrast, a significant de crease of the absorption rate is observed with the increase of the injection volume. This effect occurs already in the range of lower volumes (5-25 μ\) and is probably caused by a relative decrease of the absorption area with increasing injection volume. In the con scious rat the absorption rate is larger than in the anaesthetized animal and it is also less affected by changes of the injection volume. Probably the oily depot in the conscious rat is spread more extensively and approaches more a flat shape (Tanaka et al. - 1974; Hirano et al. - 1981a). The absorption rate of a drug from an oily depot is only minimally affected by the viscosity of the vehicle. Though the release of drugs from oily depots may proceed slowly, this process does not necessarily determine the duration time of the maximum effect or the intensity of the biological response (Armstrong and James - 1980). For many (lipophilic) compounds the elimination half-life in the whole body exceeds greatly the half-life in the muscle. » (Λ
-2
100 80
40
< <
CL
IPM 20
Time after administration (h)
FIG. 3.8 Effect of oily vehicle on the absorp CO tion rate of p-aminoazobenzene given i.m. to rats. Injection volume 50 μΐ; drug concentra tion: 5 mg/ml. Oily vehicles: DES: diethyl se bacate; Mig: Miglycol 812; CO: castor oil; IPM: isopropylmy ristate; SO: sesame oil. (adapted from Hirano, K. et al: Chem. Pharm. Bull (Tokyo) 29, 519-531, 1981.) 29
Ch. 3 Intramuscular drug administration Table 3.1
Biological half-lives of esters
Compound
C in rat after intramuscular injection of [14C] testosterone and its Half-life (days)
Testosterone -formate - acetate - proprionate - butyrate - valerate
Muscle
Whole body
0.029 0.155 1.74 1.63 2.54 2.97
1.99 2.82 2.94 3.75 4.94 7.43
In table 3.1 the biological half-lives are given for 14C from labelled testosterone in muscle and whole body of rats, after intramuscular injection of [14C] testosterone and its lower esters (male rats; 250 g; injection volume (ethyl oleate) 0.1 ml; 1 mg steroid; m. gluteus) (James et al. 1969). Similarly, investigators from the same laboratory compared in the rat the availability of testos terone proprionate and its biological effect after intramuscular injection in various oily vehicles (Al-Hindawi et al. - 1987). The rate of elimination from the muscle in this experiment was again found to be dependent on the partition coefficient. In contrast, the elimination rate from the whole rat was significantly smaller and independent of the solvent (table 3.2). The longer duration of the elimination from the whole body compared to the elimination from the oily depot is determined by the fate of the compound during and after leaving this depot. Prodrugs like testosterone-esters are in a structure-dependent manner sensitive to degradation to the parent compound. Almost always this parent compound will have a much lower lipophilicity than the pro-drug and in contrast to the unaltered pro-drug it will not (or only in very small amounts) accumulate in body fat. Consequently, the body half-life time of the easily degraded pro-drugs af ter leaving the muscle depot will only be determined by the kinetics of the parent compound. Nev ertheless this half-life may be considerable, for instance through an entero-hepatic circulation as is likely to occur with testosterone. For the more stable pro-drugs the temporary storage in the body fats may be a major factor determining their long whole body half-lives (Al-Hindawi et al. - 1987). However, for an exact knowledge of the bioavailability processes after intramuscular administra tion as an oily solution, for every individual drug detailed analyses are needed in view of the many different biopharmaceutical variables that are involved (Armstrong and James - 1980). The clearance of oil from the injection site mainly occurs by local metabolic degrada tion, absorption in blood and phagocytosis. The half-life values of parenterally adminis tered oils depend on the animal model used; the process extends often over weeks. Table 3.2
Biological half-lives of 14C in rat after intramuscular injection of [14C] testerone proprionate in different solvents
Solvent
Ethyl oleate ^ Octanol Isopropyl myristate Light liquid paraffin
Partition coefficient (X 10"3)
Half-life (h) Muscle
Whole body
6.3 5.3 4.3 1.5
10.3 9.7 7.8 3.2
19.1 19.3 22.1 18.1
*) The difference in half-life values in table 3.1 and table 3.2 for testosterone proprionate in ethyl oleate is at tributed by the authors to the difference of injection site viz. m. gluteus versus m. gastrocnemius. 30
Intramuscular drug administration Ch. 3 In the rat the absorption of [14C] methyl oleate followed apparent first-order kinetics after a lag time of about 7 days. About 15 days after oil deposition 50% had disappeared from the injection site (male rats; 150-180 g; injection volume 10 μΐ; m. rectus femoris) (Tanaka et al. - 1974). In the rabbit ethyl oleate possesses a half-life of about 10 days (injection volume 50-300 μ\) whereas arachis oil shows a half-life of about 23 days (Howard and Hadgraft - 1983). When large oil vol umes are injected (dogs; 5.2-12.4 kg; 0.5-1.0 ml/kg) oil absorption to the regional lymph nodes is seen. Depending on the type of oil used, pulmonary oil micro-embolism may occur (Svendsen and Aaes-Jorgensen - 1979). ABSORPTION FROM SUSPENSIONS The use of aqueous or oleaginous suspensions for the parenteral administration of drugs is rather limited in experimental studies. This will be caused in part by the need for a good control of particle size as well as specific formulation problems associated with these dispersed systems like syringeability, ease of resuspension and drainage (Ballard 1968). In contrast, a carefully balanced formulation may provide effective plasma con centrations over prolonged periods of time, not easily realized with other dosage forms (Ballard - 1980). When injecting an aqueous suspension, the particles are confined to the fibrous or membranous tissues between muscle fibers forming a loose agglomerate, while the aque ous solvent is taken up by the adjacent tissue. The rate of drug clearance from the tissue is limited by the dissolution process and is thus dependent on the effective crystal sur face. So, the absorption rate increases with decreasing particle size and this effect is par ticularly marked in the range of 2-3 μπι, possibly by the fact that particles of this size only form loose aggregates. The dispersing agent may likewise affect the agglomerate formation and influence the clearance rate (Hirano et al. - 1981b). Oleaginous suspensions have a different dépendance of the clearance rate on particle size. Suspensions with micronized particles (<5 μτή) of benzyl penicillin-procaine in oil with 2% aluminium monostearate have a much longer half-life than suspensions with greater particles (>50μιη) (Buckwalter and Dickinson - 1958; Ballard -1980; Pflegel 1982). The absorption rate from suspensions varies widely between compounds and formu lations. Though this dosage form is often used with the intention to realize a long-acting drug depot, under certain conditions an oily solution may turn out to be more effective in this respect (Enever et al. - 1983). TISSUE VULNERABILITY Morphological procedures have been in use for some time for the determination of local reactions of drug preparations for intramuscular administration (for references see Svendsen et al. - 1979). More recently, the determination of serum creatinine phosphokinase (CPK) activity or (decrease of) muscle CPK activity have been used to measure lo cal damaging effects (Steiness et al. - 1978; Svendsen et al. 1979). As indicated above, vehicles like saline and oils cause little damage when appropriate volumes are used for injection. Likewise, 10% solutions of propylene glycol or glycerol formal also cause little effect. In contrast, large area's of damaged tissue are found when these solvents are used undiluted or as 50% solutions (Svendsen et al. - 1979). Many drug preparations have been reported to cause muscle tissue damage upon in tramuscular injection. The intensity of the local damage is highly dependent on the spe cific conditions of the intramuscular drug administration, such as the active compounds, the concentration and volume, and the injection site. It must be realised that also less 31
CL· 3
Intramuscular drug
administration
specific aspects like restraining during blood sampling may effect serum CPK activity (Meltzer - 1972). Only limited guidance can be obtained from the literature for the opti mal conditions of intramuscular drug administration. When information on possible tis sue damaging effects seems relevant, exploratory investigations will have to be per formed in every new situation. Skeletal muscle damage caused by organic cosolvent systems do not necessarily affect bioavailability. Brazeau and Fung (1990) compared i.m. bioavailability in rabbits of a tracer dose of diazepam in three cosolvent water mixtures (20% v/v propylene glycol, 20% v/v polyethylene glycol 400 and 50% v/v polyethylene glycol 400). Though their in vitro myotoxicity varied 10-fold, the AUCo-720 min w a s comparable for the three formulations. Few oils produce immediate muscle damage such as may occur with aqueous solutions. However, at longer time intervals small cysts appear between the muscle fibers at the in jection site (Paget and McG.Scott - 1957; Svendsen and Aaes-Jorgensen - 1979; Rasmussen - 1980). IN SUMMARY With intramuscular drug administration strict control is needed of the pharmaceutical qualities of the drug solution. The manner of injection has to be standardized; by prefer ence the injection volume must be kept small (in rats less than 50 μΐ). It may be useful to determine the release rate of the drug from the depot, though the drug half-life from the whole body may be controlled by other phases of the drug distribution and metabolism processes. REFERENCES Al-Hindawi, M.K., James, K.C., and Nicholls, P.J.: Influence of solvent on the availability of testosterone propionate from oily, intramuscular injections in the rat. J. Pharm. Pharmacol. 39, 90-95, 1987. Amstrong, N.A., and James, K.C.: Drug release from lipid-based dosage forms I. Int. J. Pharm. 6, 185-193, 1980. Ballard, B.E.: Biopharmaceutical considerations in subcutaneous and intramuscular drug administration. J. Pharm. Sci. 57, 357-378, 1968. Ballard, B.E.: Prolonged-Action Pharmaceuticals. In: Remington's Pharmaceutical Sciences, pp. 1594-1613. Ed. A. Osol. Mack Pubi. Comp.- Easton, Pennsylvania, 1980. Bederka, J., Takemori, A.E., and Miller, J.W.: Absorption rates of various substances administered intramus cularly. Eur. J. Pharmacol. 15, 132-136, 1971. Brazeau, G.A., and Fung, H.L.: Effect of organic cosolvent-induced skeletal muscle damage on the bioavail ability of intramuscular [14C]diazepam. J. Pharm. Sci. 79, 773-777, 1990. Buckwalter, F.H., and Dickinson, H.L.: The effect of vehicle and particle size on the absorption, by the intra muscular route, of procaine penicillin G suspensions. J. Am. Pharm. Ass. 47, 661-666, 1958. Enever, R.P., Fotherby, K., Naderi, S., and Lewis, G.A.: The influence of physicochemical properties of some esters of norethisterone upon the plasma levels of free norethisterone. Steroids 41, 381-396, 1983. Greenblatt, D.J., and Koch-Weser, J.: Intramuscular injection of drugs. New. Engl. J. Med. 295, 542-546, 1976. Hirano, K., Ichihashi, T., and Yamada, H.: Studies on the absorption of practically water-insoluble drugs fol lowing injection: I. Intramuscular absorption from water-immiscible oil solutions in rats. Chem. Pharm. Bull. (Tokyo) 29, 519-531, 1981a Hirano, K., Ichihashi, T., and Yamada, H.: Studies on the absorption of practically water-insoluble drugs fol lowing injection: II. Intramuscular absorption from aqueous suspension in rats. Chem. Pharm. Bull. (Tokyo) 29, 817-827, 1981b. 32
Intramuscular drug administration
Ch. 3
Hirano, K., Ichihashi, T., and Yamada, H.: Studies on the absorption of practically water-insoluble drugs fol lowing injection: III. Intramuscular absorption from aqueous non-ionic surfactant solutions in rats. Chem. Pharm. Bull. (Tokyo) 29, 834-843, 1981c. Howard, J.R., and Hadgraft, J.: The clearance of oily vehicles following intramuscular and subcutaneous in jection in rabbits. Int. J. Pharm. 16, 31-39, 1983. James, K.C., Nicholls, P.J., and Roberts, M.: Biological half-lives of 4-[ 14 C]- testosterone and some of its es ters after injection into the rat. J. Pharm. Pharmacol. 21, 24-27, 1969. Kakemi, K., Sezaki, H., Okumura, K., and Ashida, S.: Absorption and excretion of drugs XXXIX. Absorption of isonicotinic acid derivatives from the skeletal muscle of the rats. Chem. Pharm. Bull. (Tokyo) 17, 1332-1338, 1969. Kakemi, K., Sezaki, H., Okumura, K., and Takada, C: Absorption of drugs from the skeletal muscle of the rats. (2) Chem. Pharm. Bull. (Tokyo) 19, 2058-2064, 1971. Kakemi, K., Sezaki, H., Okumura, K., Kobayashi, H., and Furusawa, S.: Absorption of drugs from the skeletal muscle of the rats (3). Effect of water- soluble adjuvants and vehicles on intramuscular absorption. Chem. Pharm. Bull. (Tokyo) 20, 443-451, 1972. Kobayashi, H., Nishimura, T., Okumura, K., Muranishi, S., and Sezaki, H.: Effect of polysorbates on absorp tion rates of water-soluble, micelle-free drugs administered intramuscularly in the rat. J. Pharm. Sci. 63, 580-584, 1974. Kobayashi, H., Tso-chin Peng, Kagayama, A., Okumara, K., Muranishi, S., and Sezaki.H.: Effect of some ionic and nonionic surfactants on the intramuscular absorption of isonicotinamide. Chem. Pharm. Bull. (Tokyo) 23, 42-47, 1975. Kobayashi, H., Tso-chin Peng, Fujikama, M., Muranishi, S., and Sezaki, H.: Mechanism of the inhibitory ef fect of polysorbate 80 on intramuscular absorption of drugs, 1. Chem. Pharm. Bull. (Tokyo) 24, 23832390, 1976. Kobayashi, H., Tso-chin Peng, Kawamura, R., Maranishi, S., and Sezaki, H.: Mechanism of the inhibitory ef fect of polysorbate 80 on intramuscular absorption of drugs. Chem. Pharm. Bull. (Tokyo) 25, 569-574, 1977a. Kobayashi, H., Tso-chin Peng, Kawamura, R., Muranishi, S., and Sezaki, H.: Mechanism of the inhibitory ef fect of surfactants on intramuscular absorption of drugs. Chem. Pharm. Bull. (Tokyo) 25, 1547-1554, 1977b. Kobayashi, K., Miyoshi, Y., Kitamura, K., Yoshizaki, Y., Muranishi, S., and Sezaki, H.: Effect of ethanol on the intramuscular absorption of watersoluble drugs in the rat. Chem. Pharm. Bull. (Tokyo) 25, 2862-2869, 1977c. Meltzer, H.Y.: Muscle toxicity produced by phencyclidine and restraint stress. Res. Comm. Chem. Pathol. Pharmacol. 3, 369-382, 1972. Okumara, K., Sezaki, H., and Kakemi, K.: Absorption of drugs from skeletal muscle of the rat. (4). Absorption of cationic drugs from the muscle. Chem. Pharm. Bull. (Tokyo) 20, 1607-1611, 1972. Paget, G.E., and Scott, H.McG.: A comparison of the local effects of various intramuscular injections in the rat. Brit. J. Pharmacol. 12, 427-433, 1957. Pedraz, J.L., Calvo, B., Bortolotti, A., Celardo, A., and Bonati, M.: Bioavailability of intramuscular vitamin E acetate in rabbits. J. Pharm. Pharmacol. 41, 415-417, 1989. Pflegel, H.: Biopharmazeutische Aspekte parenteraler Arzneiformen. Pharmazie 37, 307-318, 1982. Prakongpan, S., Sirimai, S., Edwards, G., McGrath, C.S., and White, N.J.: An improved formulation of chloroquine for intramuscular administration: absorption kinetics in rabbits. J. Pharm. Pharmacol. 41, 726-728, 1989. Rasmussen, F.: Tissue damage at the injection site after intramuscular injection of drugs in food-producing animals. In: Trends in veterinary pharmacology. Developments in animal and veterinary sciences. Volume 6, pp 27-33. Ed. A.S.J.P.A.M.van Miert, J.Frens, and F.W.van der Kreek. Elsevier, Amsterdam, 1980. Schou, J.: Subcutaneous and intramuscular injection of drugs. In: Handbook of Experimental Pharmacology Volume 28, Concepts in biochemical pharmacology. Part 1, pp 47-66. Ed. B.B.Brodie and J.R.Gilette Springer Verlag Berlin, 1971. Shintani, S., Yamazaki, M., Nakamura, M., and Nakayama, I.: A new method to determine the irritation of drugs after intramuscular injection. Toxicol. Appi. Pharmacol. 11, 293-301, 1967. Steiness, E., Rasmussen, F., Svendsen, O., and Nielsen, P.: A comparative study of serum creatine phosphokinase (CPK) activity in rabbits, pigs, and humans after intramuscular injection of local damaging drugs. Acta Pharmacol. Toxicol. 42, 357-364, 1978.
33
Ch. 3
Intramuscular drug
administration
Sund, R.B., and Schou, J.: The determination of absorption rates from rat muscles: An experimental approach to kinetic descriptions. Acta Pharmacol. Toxicol. 21, 313-325, 1964a. Sund, R.B., and Schou, J.: Absorption of atropine: Anticholinergics as inhibitors of absorption from muscles. Acta Pharmacol. Toxicol. 21, 339-345, 1964b. Svendsen, O., Rasmussen, F., Nielsen, P., and Steiness.E.: The loss of creatine phosphokinase (CK) from in tramuscular injection sites in rabbits. A predictive tool for local toxicity. Acta Pharmacol. Toxicol. 44, 324-328, 1979. Svendsen, O., and Aaes-Jorgensen.T.: Studies on the fate of vegetable oil after intramuscular injection into experimental animals. Acta Pharmacol. Toxicol. 45, 352-378, 1979. Tanaka, T., Kobayashi, H., Okumura, K., Muranishi, S., and Sezaki, H.: Biopharmaceutical studies on parenteral preparations. 7. Intramuscular absorption of drugs from oily solutions in the rat. Chem. Pharm. Bull. (Tokyo) 22, 1275-1284, 1974. Thomas, J.: Bioavailability of drugs administered intramuscularly. Aust. Fam. Physician 6, 925-934, 1977. Tuttle, C.B.: Intramuscular injections and bioavailability. Am. J. Hosp. Pharm. 34, 965-968, 1977. Wagner, J.G.: Biopharmaceutics, absorption aspects. J. Pharm. Sci. 50, 359-387, 1961. Wilensky, A.J., and Lowden, J.A.: Inadequate serum levels after intramuscular administration of diphenylhydantoin. Neurology 23, 318-324, 1973. Zelman, S.: Notes on techniques of intramuscular injection. The avoidance of needless pain and morbidity. Am. J. Med. Sci. 241, 563-567, 1961.
34