WO2014081343A2

WO2014081343A2 - Pharmaceutical composition containing nalbuphine hydrochloride, use thereof to treat moderate to severe pain and method for producing said pharmaceutical composition

Info

Publication number: WO2014081343A2
Application number: PCT/RU2013/001031
Authority: WO
Inventors: Николай Александрович ЛЯПУНОВ; Игорь Альбертович ЗУПАНЕЦ; Юрий Михайлович СТОЛПЕР; Сергей Константинович ШЕБЕКО
Original assignee: Общество С Ограниченной Ответственностью "Нпк Трифарма"
Priority date: 2012-11-23
Filing date: 2013-11-18
Publication date: 2014-05-30
Also published as: WO2014081343A3; MD4451C1; EA201301266A1; MD20150057A2; RU2513514C1; EA023024B1; EA201301266A8; UA108307C2; MD4451B1

Abstract

This invention relates to the field of medicine and the chemical/pharmaceutical industry, and more particularly to the creation, production and use of a drug for the treatment (relief) of moderate to severe pain in different branches of medicine, particularly oncology. The aim of the invention is to create novel pharmaceutical compositions in the form of rectal suppositories containing nalbuphine or a salt thereof on various suppository bases, which are intended for treating (relieving) episodes of moderate to severe pain and have an effective and prolonged analgesic effect without having a laxative effect. A further aim of the invention is to provide a method for producing such compositions. In order to achieve this aim, it is proposed to use a nalbuphine salt in the form of suppositories on a hydrophilic emulsion base to treat moderate to severe pain. The pharmaceutical composition in suppository form for treating moderate to severe pain contains nalbuphine hydrochloride as active principle and a suppository base. As the suppository base, the composition contains a hydrophilic emulsion base that includes binders, a poloxamer, a filler, an emulsifier, and propylene glycol and polyethylene oxide-400 as a solvent.

Description

A pharmaceutical composition containing nalbuphine hydrochloride, its use for the treatment of pain syndrome of medium and high intensity and a method for producing

pharmaceutical composition

FIELD OF TECHNOLOGY

The invention relates to the field of medicine and the pharmaceutical industry, specifically to the creation, production and use of a medicament for the treatment (relief) of moderate and high intensity pain in various fields of medicine, in particular in oncology.

BACKGROUND

Pain is an integrative function of many body systems to protect against a harmful factor. These include consciousness, sensation, memory, motivation, autonomic mechanisms, behavioral reactions and emotions. In cancer patients, this phenomenon usually manifests itself in the form of a chronic pain syndrome. The pain aggravating the life of a cancer patient is a serious medical and social problem. Quality of life and the results of any treatment in oncology ^• can not be assessed without taking into account the dynamics of chronic pain. According to WHO, 7 million cancer patients are diagnosed annually in the world, 5 million die from tumor progression. In Russia, more than 450 thousand patients with malignant neoplasms are registered annually. In large cities, about 14% die within 1 month, and 40% within 1 year after confirming the diagnosis due to neglect of the disease. More than 70% of patients in terminal period consider pain the main symptom of the tumor. Statistical studies of pain in cancer patients (nature, frequency, localization, intensity, taking into account the stage) are very difficult to organize.

Known systemic drugs containing opioid analgesics (buprenorphine, tramadol, nalbuphine) for the treatment (relief) of pain of medium and high intensity. Buprenorphine is produced and used in the form of injectable solutions and transdermal therapeutic systems, tramadol - in the form of injectable solutions, oral drops, capsules, tablets and suppositories. Nalbuphine is produced and used only in the form of injectable solutions, which are characterized by disadvantages: trauma to the patient with the introduction of the drug, the need for a sterile syringe and medical personnel, the possibility of infection of the patient with infections associated with the provision of medical care, especially in case of skin disorders, etc.

Nalbuphine hydrochloride is (5α, 6α) -17- (cyclobutylmethyl) -4,5-epoxy-morphinan-3, 6, 14-triol hydrochloride and is an opiate receptor antagonist agonist. Nalbuphine was synthesized based on the powerful analgesic oxymorphone and naloxone antagonist. It has a strong analgesic effect due to the agonistic effect on k-receptors. However, the drug is an antagonist of μ receptors, and therefore does not have pronounced euphoria and drug dependence. By the general nature of the action, nalbuphine is close to pentazocine, but has a stronger analgesic effect with less side effects. effects and less ability to develop tolerance and physical dependence (Lebedeva R.N., Nikoda V.V., Sandrikov V.A. Evaluation of the effectiveness and safety of the use of nalbuphine hydrochloride in patients in the early postoperative period. "Anesthesiology and intensive care", 1994, N ° 2, S.31-34) [1].

When administered intramuscularly, nalbuphine is comparable in analgesic activity with morphine. Unlike morphine and fentanyl, nalbuphine does not significantly affect the pressure in the bile ducts and does not inhibit the motility of the gastrointestinal tract. Nalbuphine is a non-narcotic analgesic and has an extremely low degree of development of addiction.

A known dosage form of nalbuphine hydrochloride in the form of a solution for injection in ampoules containing 10 and 20 mg of the drug in 1 ml (see, for example, the Internet, http://rlsm.ru/ls/7538/10087, printed on 11/19/2012) [2].

In injections, nalbuphine is administered intravenously and intramuscularly. With intramuscular use, the duration of the drug is about 3-4 hours with an intravenous bolus - about 1.5-2 hours. There have been attempts to create dosage forms of nalbuphine for oral administration. However, when administered orally, the bioavailability of nalbuphine is very low (16.4-17.7%) (Lo MW, Senary WL, Whitney CC Jr, The disposition and bioavailability of intravenous and oral nalbuphine in healthy volunteers., At J. Clin. Pharmacol 1987 Nov; 27 (ll): 866-73) [3], which is explained by the authors of the study with its strong systemic premetabolism and intrahepatic circulation. It was previously shown that nalbuphine is absorbed into the systemic circulation with rectal administration, however, no efficacy or prolongation of the analgesic effect was found (Bessard G, Alibeu JP, Cartal M, Nicolle E, Serre Debeauvais F, Devillier P. Pharmacokinetics of intrarectal nalbuphine in children undergoing general anaesthesia., at Fundam Clin Pharmacol . 1997; ll (2): 133-7) [4].

At the same time, rectal suppositories, as a dosage form, have certain advantages: high relative bioavailability of the drug substance, which determines the effectiveness of the pharmacotherapeutic action, comparable with its effectiveness when injected; simplicity and the possibility of use on an outpatient basis, the absence of an effect on the active substance of intestinal juice, the possibility of use in patients with a vomiting reflex, and the absence of trauma during administration.

Thus, there is a need for a painkiller of systemic action with strong analgesic activity, the use of which would not be complicated on an outpatient basis and would not be limited in patients with vomiting reflex and muscle dystrophy. For this, pharmaceutical compositions in the form of rectal suppositories can be proposed as technical solutions. Rectal suppositories are solid, single-dose drugs that must be suitable for rectal use in form, volume, and consistency. Suppositories have a solid consistency at room temperature and melt at body temperature (Appendix 1 to the OST Industry Standard 91500.05.001-00 “Drug Quality Standards. The main provisions ") [5]. Suppositories are prepared on lipophilic or hydrophilic bases. In the vast majority of cases, solid fat is used as lipophilic bases, and polyethylene oxide (PEO) alloys with various molecular weights are used as hydrophilic bases. The latter have a significant drawback associated with their high osmotic activity, which causes a dehydrating effect on the rectal mucosa with the manifestation of a pronounced laxative effect up to diarrhea, which eliminates the absorption of drugs into the systemic circulation.

Suppositories are prepared by pressing or molding, which is the main method of their preparation in industrial production. The method includes such stages as: 1) preparation of a suppository base at elevated temperature, ensuring its liquid consistency; 2) introduction to the basis of medicinal substances and homogenization; 3) dosing the resulting suppository mass in cell contour packaging and cooling; 4) packaging and labeling of finished products.

Medicinal substances in the suppository base can be entered in the form of a suspension or in the form of a solution.

Rectal suppositories with tramadol are known, containing tramadol hydrochloride (100 mg) and solid fat, in which tramadol is suspended, as well as glycerol (mono-, di-, tri-) alkanoate (see VIDAL Medical Encyclopedia, http: / /www.vidal.ru/poisk_preparatov/tramadol~19014.htm,

printed on November 20, 2012). They are intended for use with acute and chronic pain syndrome of moderate severity (pre- and postoperative periods, malignant tumors, injuries, neuralgia). However, the effectiveness of tramadol is limited by its toxicity and pronounced side effects. The maximum daily dose is 400 mg. In addition, tramadol is only effective in moderate pain.

The closest analogue of the proposed invention is a pharmaceutical composition comprising an effective amount of an opioid analgesic combined with a polymer to form a matrix (US 7201920 B2, publ. 10.04.2007). As one of the options for opioid analgesics mentioned nalbuphine, and as one of the possible dosage forms - suppositories. However, in the patent there is no characteristic of a suppository base when using nalbuphine in the form of suppositories, as well as the analgesic ability and side effects of these suppositories.

SUMMARY OF THE INVENTION

The objective of this group of inventions is to create new pharmaceutical compositions in the form of rectal suppositories containing nalbuphine or its salt on various suppository bases intended for the treatment (relief) of moderate to high intensity pain attacks, as well as to develop methods for preparing these compositions.

The technical result of the group of inventions is to provide effective and prolonged the analgesic effect of rectal suppositories in the absence of a laxative effect,

To solve this problem, it is proposed the use of nalbuphine salt in the form of suppositories on a hydrophilic emulsion basis for the treatment of moderate and high intensity pain.

To solve this problem, a pharmaceutical composition for the treatment of moderate and high intensity pain syndrome in the form of suppositories is also proposed, including nalbuphine hydrochloride and a hydrophilic emulsion base as the active substance in the following ratio of components, g / 100 g of the composition:

nalbuphine hydrochloride 0.0125 - 5.00

hydrophilic emulsion up to 100 g

the basis

In addition, the hydrophilic emulsion base preferably includes formers, poloxamer, filler, emulsifier, propylene glycol and polyethylene oxide 400 as a solvent, in the following ratio, g / 100 g of the composition:

nalbuphine hydrochloride 0.0125 - 5.00 formers 30.0-90.0

Poloxamer 1, 0-61.0

filler 0.5-8.5

complex emulsifier 1, 0-10,0

propylene glycol 2.0-25.0

polyethylene oxide 400 5.0-28.0 Moreover, as forming agents, the composition preferably contains polyethylene oxide 4000 and polyethylene oxide 1500, and the poloxamer is poloxamer 188, in the following ratio, g / 100 g of the composition:

PEO 4000 1,0-61,0

PEO 1500 29-89

Poloxamer 188 1.0-61, 0

Moreover, as a filler, the composition preferably contains solid fat.

In addition, as an emulsifier, the composition preferably contains a complex emulsifier, which is a mixture of an emulsifier of the first kind and an emulsifier of the second kind.

In a particular case, the composition contains a macrogol of 20 cetostearyl ether as an emulsifier of the first kind, and cetostearyl alcohol is used as an emulsifier of the 2nd kind at their mass ratios from 0.5: 5.5 to 2.0: 4.0.

To solve this problem, a method for producing the above-described pharmaceutical composition is also proposed, in which nalbuphine hydrochloride is dissolved in propylene glycol, the solution is mixed with a molten hydrophilic emulsion suppository base and homogenized; the suppository mass in a liquid state is metered into blisters and cooled.

MODES FOR CARRYING OUT THE INVENTION

The claimed ratio of nalbuphine and excipients (target additives) in the pharmaceutical composition compositions with a multicomponent suppository base found experimentally and is optimal.

A mixture of polyethylene oxides (PEO) with different molecular weights and poloxamer is used as a shaper (consistency factor). Poloxamer also acts as a wetting agent and contributes to the effective spreading of molten suppository mass on the mucous membrane of the rectum. It is preferable to use a mixture of PEO 1500 and PEO 4000, as well as Poloxamer 188, having a molecular weight of 7680-9510, in which the molecular weight of hydroxyethyl chains is 79.9-83.7%. The preferred ratio of PEO 1500, PEO 4000 and poloxamer 188 is, g / 100 g of the composition:

PEO 4000 1, 0-61, 0

PEO 1500 29-89

Poloxamer 188 1, 0-61.0

Polyethylene oxide 400 (PEO 400) and propylene glycol are used as hydrophilic non-aqueous solvents. In propylene glycol at a temperature of 25 ° C, 12.7% of nalbuphine hydrochloride is soluble. When the concentration of propylene glycol exceeds 25%, the suppository resistance to crushing becomes insufficient. In a mixture of propylene glycol and PEO 400 6 g: 4 g at a temperature of 25 ° C soluble 12.8% nalbuphine hydrochloride. If the total concentration of solvents exceeds 30%, the suppository resistance to crushing becomes insufficient; taking into account the minimum concentration of propylene glycol of 2.0%, the maximum concentration of PEO 400 should be no more than 28.0%. In the presence of propylene glycol and PEO 400, nalbuphine hydrochloride is present in the composition as a solution rather than a suspension.

As a filler, solid fat is used, which does not have osmotic activity. As a result, solid fat reduces the dose of hydrophilic components and the osmotic activity of the suppository mass. When the concentration of solid fat in excess of 8.5 g / 100 g crush resistance of suppositories becomes insufficient. To emulsify solid fat, a complex emulsifier is used in a concentration of up to 10.0 g / 100 g. It is preferable that it contains a non-ionic emulsifier of the first kind (for example, macrogol 20 cetostearyl ether) and an emulsifier of the second kind (for example, cetostearyl alcohol) in weight ratios from 0.5: 5.5 to 2.0: 4.0 and with a total content of 1.0% to 10.0%. At other ratios, solid fat is poorly emulsified and the candle becomes fragile. When the concentration of the complex emulsifier exceeds 10%, the suppository crush resistance decreases. A complex emulsifier reduces the degree and speed of water absorption by the suppository mass, and therefore reduces the dehydrating effect on the mucous membrane and eliminates the laxative effect.

We give specific examples of the invention. Example 1

The pre-weighed and molten solid fat, and then nalbuphine hydrochloride, which is suspended and homogenized in a molten hydrophobic base, are loaded into a vacuum homogenizer reactor. Suppository mass in a liquid state doser comfort in blisters and cool. Heat seal the top of the tape with in cell packages, cut off the upper edge of the tape and cut the tape. The resulting drug has the following ratio of components, g / 100 g of the composition:

nalbuphine hydrochloride 0.10

solid fat up to 100 g

Example 2

The pre-weighed and molten polyethylene oxide 1500, and then polyethylene oxide 400, are loaded into a vacuum homogenizer reactor, then nalbuphine hydrochloride is mixed and charged, which are suspended and homogenized in a molten hydrophilic base. Suppository mass in a liquid state doser comfort in blisters and cool. Thermal welding of the upper part of the tape with cell packs is carried out, the upper edge of the tape is cut and the tape is cut. The resulting drug has the following ratio of components, g / 100 g of the composition:

nalbuphine hydrochloride

polyethylene oxide 400

polyethylene oxide 1500

Example 3

With heating and stirring, nalbuphine hydrochloride is dissolved in propylene glycol. Pre-weighed solid fat, cetostearyl alcohol, macrogol 20 cetostearyl ether, Poloxamer 188, PEO 4000, PEO 1500 and PEO 400 are sequentially loaded into a vacuum homogenizer reactor. The mass in the reactor is stirred while heating until all components are melted and homogenized to emulsify solid fat. Suppository base is cooled under vacuum while mixing to a temperature of 40-45 ° C, after which it is mixed with a solution of nalbuphine hydrochloride in propylene chicol and homogenized. The suppository mass in a liquid state is metered into blisters and cooled. Heat sealing of the upper part of the tape with cell packs is carried out, the upper edge of the tape is cut and the tape is cut.

The resulting drug has the following ratio of components, g / 100 g of the composition:

nalbuphine hydrochloride 0.10

polyethylene oxide 4000 11, 00

polyethylene oxide 1500 37.00

poloxamer 188 17.90

hard fat 4.50

Macrogol 20 cetostearyl 1, 10

ether

cetostearyl alcohol 5.50

propylene glycol 14.00

polyethylene oxide 400 8.90

Studies were conducted on the analgesic activity of nalbuphine hydrochloride with rectal administration of suppositories on a model of inflammatory hyperalgesia (carrageenin edema) in rats. Previously, in all rats, the initial parameters of the threshold of pain sensitivity (PBC) were determined using an Ugo Basile 37215 analgesimeter, stimulating a pain reaction on the right hind paw.

After that, no less than 30 minutes later, all rats reproduced aseptic exudative inflammation on the right hind paw by subplanetary administration of 0.1 ml of 1% solution carrageenin. 1 hour after the reproduction of the pathology in 3 groups of rats, a nalbuphine hydrochloride was once administered rectally with a probe in the form of a suppository mass on three different bases containing 0.10 mg / g of active

5 substances. In the 4th group of rats, nalbuphine hydrochloride in the form of a solution for injection was injected intramuscularly into the femoral muscle of the hind left paw.

0.5, 1, 2, 3, and 4 hours after the administration of nalbuphine, the threshold of pain sensitivity (PBC) was determined in all rats and

10 calculated analgesic activity (AA) by the level of decrease in the degree of hyperalgesia compared with control animals, expressing AA as a percentage:

APBCHk - APBCHo

AA = x 100%, where

APBCHk

APBCH - the percentage of changes in the level of pain sensitivity in the experimental group before and after the reproduction of 15 inflammatory hyperalgesia and the introduction of the test drug;

APBChk - the percentage change in the level of pain sensitivity in the group of control animals before and after the reproduction of inflammatory hyperalgesia.

Table 1

Analgesic activity (AA) of nalbuphine hydrochloride in suppositories on various types of bases compared to AA with intramuscular injection

AA (%) after drug administration through:

An object

0.5 h 1 h 2 h W h 4 h

Nalbufin in the form of

suspensions based on 30, 1 ± 3.4 58.2 ± 4.5 17.8 ± 2.2 0 0 solid fat rectally

Nalbuphine hydrochloride has an analgesic effect when rectally administered to rats in the form of suppositories on all three types of bases: solid fat (hydrophobic base), polyethylene oxide base (hydrophilic water-soluble 5 base) and hydrophilic emulsion base (table 1). However, in terms of effectiveness and duration of action of suppositories based on solid fat and PEO based, in which nalbuphine hydrochloride was introduced in the form of a suspension, they were inferior to the action of nalbuphine hydrochloride upon intramuscular injection of a solution

10 for injection (table 1).

It was unexpectedly discovered that nalbuphine hydrochloride has the most effective and prolonged effect when administered rectally on a hydrophilic emulsion base into which nalbuphine hydrochloride was introduced in the form of a solution

15 (table 1). In the composition of the hydrophilic emulsion base of calboufin, the hydrochloride showed not only the highest level of activity in comparison with the bases of other types, but also the totality of observations exceeded the level of activity of the injectable form. At the same time, 1 hour after administration, the level of activity of nalbuphine hydrochloride in the hydrophilic emulsion base was close to that at 5 intramuscular injection and then after 2, 3 and 4 hours it exceeded this indicator by approximately 2 times. It should also be noted the long duration of analgesic activity, a statistically significant level of which was observed for 4 hours (table 1).

10 Based on the results obtained, a hydrophilic emulsion base was used to determine the analgesic activity of nalbuphine hydrochloride during rectal administration in different doses. The obtained research results are presented in table 2.

15 table 2

Analgesic activity (AA) of various doses of nalbuphine hydrochloride upon rectal administration in the form of suppositories on hydrophilic

an emulsion base containing different concentrations of it, 20 compared to AA for intramuscular injection

at a dose of 1.5 mg / kg

Nalbuphine 109.6 ± 6.4 136.6 ± 4.8 67.0 ± 4.4 33.3 ± 2.2 0 intramuscularly

dose of 1.0 mg / kg

Nalbuphine hydrochloride has an analgesic effect upon rectal administration to rats in the form of suppositories on a hydrophilic emulsion base in doses of 0.125 mg / kg and higher (Table 2). The highest level of analgesic activity was

5 is registered 1-2 hours after rectal administration of a suppository mass containing nalbuphine hydrochloride. Further, the activity of the drug either disappeared (doses 0, 125-0.25 mg / kg) or gradually decreased (doses 0.50-1, 50 mg / kg) (Table 2). At doses of 1, 00-1, 50 mg / kg, analgesic activity persists for 4

10 hours, whereas with intramuscular injection of a solution for injection, AA lasts only for 3 hours with a maximum of AA per 1 hour. Between 2 to 4 hours after. rectal administration of nalbuphine hydrochloride in doses of 1, 00-1, 50 mg / kg; analgesic activity significantly exceeds AA

15 with intramuscular injection of a solution for injection at a dose of 1, 00 mg / kg

The developed composition during rectal administration made it possible to maintain a high level of analgesic activity in rats for a rather long time (1 hour longer than with 0 intramuscular injection of a solution for injection), which, if used in humans, will allow to achieve a longer interval between doses of the drug and a higher analgesic effect.

In in vitro experiments, the kinetics of absorption was studied by dialysis through a semipermeable 5 cellophane membrane. water suppositories on different bases (table. 3). The greater the mass of absorbed water in the first hours of the experiment, the stronger the dehydrating effect of suppositories on the rectal mucosa will be and the more likely the occurrence of a laxative effect or diarrhea.

Table 3

Mass (t) of water (as a percentage of the mass of the suppository) absorbed in

time molten suppository masses at

temperature 37 ° С

in in vitro experiments by dialysis through semipermeable

membrane

PEO-based suppositories in the first 2 hours of the experiment absorb significant amounts of water up to 260%, which can lead to a high probability of diarrhea. Suppositories on a hydrophilic emulsion base (GEO), due to the optimal selection of excipients, absorb 3 times less water in the first 2 hours, which virtually eliminates the occurrence of diarrhea (Table 3).

Thus, preclinical studies have confirmed that the drugs in accordance with the invention have a different analgesic effect on rectal administration, and when using a hydrophilic emulsion base, they have prolonged analgesic activity in the absence of conditions for the occurrence of a dehydrating effect and diarrhea. Different efficacy and duration of analgesic action makes it possible to choose the optimal dose and suppository basis of the drug for use in different clinical situations. Rectal administration of drugs is atraumatic, not complicated on an outpatient basis, and is not limited in patients with vomiting reflex and muscle dystrophy.

The resulting compositions containing nalbuphine hydrochloride on different suppository bases · meet the regulatory requirements for pharmacotechnological tests of suppositories and uniformity of the content of the active substance and have a shelf life of more than 2 years. Substantiated methods for producing these compositions.

All of the above confirms the fulfillment of the objective of the invention - the creation of new pharmaceutical compositions in the form of rectal suppositories containing nalbuphine or its salt on different suppository bases, intended for the treatment (relief) of moderate to high intensity pain attacks with an effective and prolonged analgesic effect in the absence of laxative effect, as well as in the development of methods for producing these compositions.

Claims

Claim

1. The use of nalbuphine salt in the form of suppositories on a hydrophilic emulsion basis for the treatment of moderate and high intensity pain.

2. A pharmaceutical composition for the treatment of moderate to high intensity pain in the form of suppositories, comprising as an active ingredient nalbuphine hydrochloride and a hydrophilic emulsion base in the following ratio, g / 100 g of the composition:

nalbuphine hydrochloride 0.0125 - 5.00

hydrophilic emulsion up to 100 g

the basis

3. The composition according to p. 2, characterized in that the hydrophilic emulsion base includes molds, poloxamer, filler, emulsifier, propylene glycol and polyethylene oxide 400 as a solvent, in the following ratio, g / 100 g of the composition:

nalbuphine hydrochloride 0.0125 - 5.00 formers 30.0-90.0

poloxamer 1.0-61, 0

filler 0.5-8.5

complex emulsifier 1, 0-10,0

propylene glycol 2.0-25.0

polyethylene oxide 400 5.0-28.0

4. The composition according to p. 3, characterized in that as forming agents contains polyethylene oxide 4000 and polyethylene oxide 1500, and poloxamer is poloxamer 188, in the following ratio of components, g / 100 g of the composition:

PEO 4000 1.0-61.0

PEO 1500 29-89

Poloxamer 188 1, 0-61, 0

5. The composition according to p. 3, characterized in that the filler contains solid fat.

6. The composition according to p. 3, characterized in that as an emulsifier contains a complex emulsifier, which is a mixture of an emulsifier of the first kind and an emulsifier of the second kind.

7. The composition according to p. 6, characterized in that it contains cetostearyl ether as an emulsifier of the first kind, and cetostearyl alcohol as an emulsifier of the second kind in their mass ratios from 0.5: 5.5 to 2.0: 4.0 .

8. A method of obtaining a pharmaceutical composition according to any one of paragraphs. 2-6, in which nalbuphine hydrochloride is dissolved in propylene glycol, the solution is mixed with the molten hydrophilic emulsion base and homogenized; the suppository mass in a liquid state is metered into blisters and cooled.