Stabilized aqueous suspensions for parenteral use

Details Stabilized aqueous suspensions for parenteral use Stabilized aqueous suspensions for parenteral use

2000-05-15

2002-12-17

Badio, Barbara P. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S178000, C514S182000

Reexamination Certificate

active

06495534

ABSTRACT:

SUMMARY OF THE INVENTION
The present invention is in the field of galenic preparations. It concerns in particular a pharmaceutical aqueous suspension of a biologically active compound, e.g. a steroidal compound, having stabilized pH, particularly suitable for parenteral administration.
The inventors of the present invention have found that the pH of a pharmaceutical aqueous suspension of a biologically active compound can be controlled by adding a pH controlling effective concentration of L-Methionine thereto.
Moreover, when a pH controlling effective concentration of L-Methionine is used, it strengthens the buffering capacity of low concentrations of conventional buffering agents with a super-additive (synergistic) effect. In this way the use of conventional buffering agents can be eliminated or limited, thus improving the re-suspendability and controlled flocculation of the pharmaceutical preparation.
BACKGROUND OF THE INVENTION
A pharmaceutical suspension is a coarse dispersion in which insoluble solid particles are dispersed in a liquid medium.
Suspensions contribute to pharmacy and medicine by supplying insoluble and often distasteful substances in a form that is pleasant to the taste, by providing a suitable form for the application of dermatological materials to the skin and sometimes to the mucous membranes, and for the parenteral administration of insoluble drugs. Therefore pharmaceutical suspensions may be classified into three groups: orally administered mixtures, externally applied lotions and injectable preparations.
An acceptable suspension possesses certain desirable qualities, including the followings:
i) the suspended material should not settle rapidly;
ii) the particles that do settle to the bottom of the container must not form a hard cake but should be readily re-dispersed into a uniform mixture when the container is shaken;
iii) the suspension must not be too viscous to pour freely from the orifice of the bottle or to flow through a syringe needle.
It is important that the characteristics of the dispersed phase are chosen with care so to as to produce a suspension having optimum physical, chemical and pharmacological properties. Particle size distribution, specific surface area, inhibition of crystal growth, and changes in the polymorphic form are of special significance and the formulator must ensure that these and other properties do not change sufficiently during storage to adversely affect the performance of the suspensions with aging.
In the field of injectable preparations, aqueous suspensions for parenteral administration have already been described in scientific and patent literature and have been known for a long time. Parenteral suspensions are often prepared with the so called “controlled flocculation” approach, i.e. by the application of known principles of formulation chemistry to produce vehicles which permits drug flocs to form and settle, but which they are easily re-suspended with slight agitation and remain uniformly dispersed or suspended during the period required for therapeutic administration. Specifically, it is well known that one of the main difficulty in formulating parenteral aqueous suspensions of steroids is the overcome of their hydrophobicity, that significantly reduce the wettability, suspendability or re-suspendibility of the active in aqueous media. Both wetting and suspending agents are needed in order to gain the proper formulation of the active compound such as the concomitant use of preservatives. This is described, for example, by Nash and coworkers in the U.S. Pat. No. 3,457,348 where non-ionic surfactants (such as polysorbates) and suspending agents (like polyethylene glycols) are the basic excipients to gain the proper stability of the formulation.
Sometimes, even in the presence of the proper suspending and wetting agents, the suspension is not stable for a long time, but it is necessary to form it just before the administration (while it is stored as lyophilized formulation). This is described, for example, in the case described by Geller and coworkers in the U.S. Pat. No. 5,002,940 and greatly impacts on the cost of the manufacturing process, since an additional freeze-drying process is mandatory.
Even if an improved physical stability of steroidal drug suspensions in water can be gained, as above mentioned, by the use of polyethylene glycols and non-ionic surfactants, some chemical stability issues, such as a relevant pH reduction, are likely to be faced during development.
In fact, for instance, both polyethylene glycols and polysorbates, when in solution, may undergo degradation, leading to the formation of acid species such as formic and acetic acid.
An example of this pH reduction effect is given in Table 1.
TABLE 1
pH of a typical vehicle for parenteral aqueous suspensions formulations
Vehicle composition (batch 13169/12-1A): Methylparaben 0.2%,
propylparaben 0.02%, sodium chloride 0.9%, PEG 4000 3%,
polysorbate 80 0.3%, sodium hydroxide q.s. to pH 6.5 , WH q.s to 100 ml.
Storage condition
PH
Time zero
6.46
10 days at 65° C.
3.43
15 days at 65° C.
3.16
1 month at 65° C.
3.32
3 months at 40° C.
3.24
6 months at 40° C.
3.15
6 months at 25° C.
4.93
This pH reduction occurs both at accelerated testing conditions and at room temperature. Considering that after only 6 months at room temperature a relevant decrease of approximately 1.5 pH unit is experimented, very low pH values (close or below 3) are anticipated after long-term storage (1-2 years). This fact necessarily causes the reduced shelf life of parenteral suspension, being the progressive acidification of the formulation linked to the impossibility to administer the formulation, e.g. by intramuscular or subcutaneous injection, without generating significant pain on patients (it is advisable that the pH value is maintained above 3 for administering a painless formulation).
This pH variation during storage can be minimized by appropriately buffering the formulation. The most obvious approach, in order to maintain the pH within specific and predetermined limits, is the use of buffering agents, such as inorganic acid salts, in appropriate concentrations in order not only to exert but also to maintain their buffering capacity. An example of buffering agents commonly used in parenteral formulations and of their usual concentrations can be found in Pharmaceutical Dosage Form: Parenteral Medications, Volume 1, 2
nd
Edition, Chapter 5, p. 194, De Luca and Boylan, “Formulation of Small Volume Parenterals”, Table 5: Commonly used additives in
Parenteral Products
The use of inorganic acid salts as buffering agents offers to the formulator both advantages and disadvantages. In fact, if a careful control of pH of formulations could be gained, on the contrary, when suspension formulations are concerned, ionic species tend to destabilize the formulations with detrimental effects on the re-suspendability and on the controlled flocculation of the formulation. This means that the use of inorganic acid salt based buffering systems into the formulations has to be minimized.
In fact, when talking about parenteral suspension, according to Nash (Parenteral Suspensions, Bulletin of Parenteral Drug Association, March-April 1972, Vol. 26, No. 2), “. . . indiscriminate use of salts and buffers is normally avoided, provided chemical stability is not a problem since changes in electrolyte concentration often have a profound effect on the absorbed surface charge of suspension particles”.
An example of the relevant pH decrease occurring in a medroxyprogesterone acetate parenteral aqueous suspension is showed in Table 2. This accelerated stability study shows that the pH of an unbuffered formulation significantly decrease from an initial pH value of approx. 6.5 to pH values of 3 or lower than 3. It also demonstrates that, when a usual concentration (approx. 1%) of phosphate buffer is added to control the pH, a detrimental effect on the suspension re-suspendability and syringeability is experimented. In fact an increased time of manual wrist shaking is needed to re-suspend the buffered

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