ChemicalBook > Product Catalog > API > Nervous system drugs > Antiepileptic and anticonvulsant > Pregabalin
Basic information Description Generic formulation Indications Dose titration Plasma levels monitoring Antiepileptic drus and therapeutic drugs for neuropathic pain Cautions Adverse effects Interactions Special populations Behavioural and cognitive effects in patients with epilepsy Psychiatric use Safety Related Supplier
Pregabalin Chemical Properties
- Melting point:194-196°C
- alpha D23 +10.52° (c = 1.06 in water)
- Boiling point:274.0±23.0 °C(Predicted)
- Density 0.997±0.06 g/cm3(Predicted)
- Flash point:9℃
- storage temp. 2-8°C
- solubility deionized water: ≥10mg/mL
- form white powder
- CAS DataBase Reference148553-50-8(CAS DataBase Reference)
Pregabalin Usage And Synthesis
- DescriptionPregabalin is a second- generation antiepileptic drug (AED) known with the proprietary brand name of Lyrica® (Pfizer, Tadworth) in the UK and USA (Pfizer, New York, NY).
- Generic formulationMHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):
- It is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns, such as patient anxiety and risk of confusion/ dosing error.
Adjunctive therapy of focal seizures with and without secondary generalization.
Recommendations summarized from NICE (2012)
- Seizure types—on referral to tertiary care (focal seizures), contraindicated (generalized tonic- clonic seizures, tonic/ atonic seizures, absence seizures, myoclonic seizures).
- Epilepsy types—on referral to tertiary care (benign epilepsy with centrotemporal spikes, panayiotopoulos syndrome, late- onset childhood occipital epilepsy), contraindicated (absence syndromes, idiopathic generalized epilepsy, juvenile myoclonic epilepsy, Dravet syndrome, Lennox– Gastaut syndrome).
Generalized anxiety disorder.
Peripheral and central neuropathic pain.
- Dose titration
- Epilepsy— adjunctive therapy: 25 mg bd for 7 days, to be increased by 50 mg every 7days; usual maintenance 300 mg daily, divided into 2 or 3 doses (max. 600 mg daily, divided into 2 or 3 doses).
- Generalized anxiety disorder: 150 mg daily, divided into 2 or 3 doses, for 7 days, to be increased by 150 mg every 7 days (max. 600 mg daily, divided into 2 or 3 doses).
- Plasma levels monitoringPregabalin pharmacokinetics are linear over the recommended daily dose range; inter- subject pharmacokinetic variability for pregabalin is low (<20%) and multiple dose pharmacokinetics are predictable from single- dose data. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.
- Antiepileptic drus and therapeutic drugs for neuropathic painPregabalin is a new antiepileptic drug, having a γ-amino butyric acid structure on its molecular structure, which has anticonvulsant effects, and is successfully developed by the company Pfizer for the treatment of peripheral neuropathic pain, or adjuvant treatment of partial seizures.
In December 2008, the US Food and Drug Administration (FDA) approved pregabalin (trade name "Lyrica") for the treatment of diabetic peripheral neuropathic pain (DPN) and postherpetic neuralgia (PHN)which are Both the most common neuropathic pains.
Neuropathic pain is one of the most difficult chronic pain syndromes to treat , dull pain, burning, tingling as the main feature, there are a lot of incentives of neuralgia, diabetes, infections (such as herpes zoster), cancer and AIDS, etc. can cause neurological pain, in Europe about 3% of the population suffer from neuralgia torture.
The above information is edited by the chemicalbook of Tian Ye.
- Patients with conditions that may precipitate encephalopathy.
- Patients with severe congestive heart failure.
- Adverse effectsPregabalin can be associated with adverse effects at the level of the nervous system and other systems.
- Since pregabalin is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans, does not inhibit drug metabolism in vitro, and is not bound to plasma proteins, it is unlikely to produce or be subject to pharmacokinetic interactions.
- Pregabalin may potentiate the effects of lorazepam.
- In the post- marketing experience, there are reports of respiratory failure and coma in patients taking pregabalin and other central nervous system depressant medicinal products. Pregabalin appears to be additive in the impairment of cognitive and gross motor function caused by oxycodone.
- There are no specific foods that must be excluded from diet when taking pregabalin.
- Pregabalin may potentiate the effects of alcohol.
- Special populationsHepatic impairment
No dose adjustment is required for patients with hepatic impairment.
Reduce maintenance dose according to degree of reduction in creatinine clearance.
- There is no adequate data from the use of pregabalin in pregnant women. The potential risk for reproductive toxicity in humans is unknown. Pregabalin should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.
- Pregabalin is excreted into human milk. The effect of pregabalin on newborns/ infants is unknown. A case- by- case decision must be made whether to discontinue breast- feeding or to discontinue pregabalin therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
- Behavioural and cognitive effects in patients with epilepsyPregalin is characterized by a good behavioural profile. This AED does not appear to have significant negative effects on mood or behaviour in patients with epilepsy, although depression has been reported in some patients (dose- dependent effects of mild- to- moderate intensity). A potential abuse or misuse of pregabalin has also been reported, with implications in terms of dependence and withdrawal. pregabalin is also associated with limited negative cognitive effects, mainly related to sedation, decreased arousal, decreased attention and concentration (dose- dependent effects of mild- to- moderate intensity).
- Psychiatric usePregabalin has an approved indication and is widely used for the treatment of generalized anxiety disorder. Several randomized, double- blind, placebocontrolled trials found that pregabalin is an effective treatment for patients with generalized anxiety disorder and social anxiety disorder. Possible implications in the treatment of mood disorders and benzodiazepines dependence are emerging. Moreover, pregabalin may be a therapeutic agent for the treatment of alcohol abuse, in both withdrawal phase and relapse prevention.
- DescriptionAs a follow-up to its g-aminobutyric acid (GABA) agonist gabapentin, Pfizer has developed and launched pregabalin for the treatment of epilepsy and neuropathic pain. Although pregabalin is a structural analog of GABA, it does not interact with GABA-A or GABA-B receptors or influence GABA uptake. The exact mechanism of action is unclear, but pregabalin may reduce excitatory neurotransmitter release by binding to the α2-δ protein subunit of voltage-gated calcium channels. The resulting inhibition of excess neuronal activity is believed to be the basis for pregabalin’s efficacy in epilepsy and neuropathic pain alleviation. Since the activity is attributed to the (S′)-enantiomer alone, an efficient asymmetric synthesis is employed for commercial production. The key step is the asymmetric hydrogenation of 3-cyano-5-methyl-3-hexenoic acid using a chiral rhodium catalyst to afford an intermediate that is enriched in the (S′)-enantiomer. The cyano group is ultimately reduced by routine hydrogenation with a nickel catalyst. Further enrichment of the final product is realized by selective recrystallization with (S′)-mandelic acid or simply recrystallizing from water/isopropanol. Compared to gabapentin, pregabalin is 2- to 10-fold more potent in various animal models. For example, in preventing maximal electroshock seizures (MES) in mice, pregabalin has an ED50 of 20 mg/kg p.o. versus 87 mg/kg for gabapentin. A comparable increase in potency is also observed in the rat MES model (ED50=1.8mg=kg p.o. for pregabalin versus 10.3 mg/kg for gabapentin). In addition, pregabalin’s linear pharmacokinetics (Cmax relates to dose) translates to better predictability of pharmacological effects. It has 90% oral bioavailability, with an elimination half-life of approximately 6 h. The primary route of excretion is via the renal system with negligible metabolism. Furthermore, its lack of activity at the cytochrome P450 enzymes was reflected in an absence of pharmacokinetic drug-drug interactions in relevant studies. In a placebocontrolled, fixed dose (up to 600mg/day) trial with pregabalin as an adjunctive therapy for epilepsy, 14 to 51% of patients showed at least a 50% decrease in seizure frequency with a clear dose-response relationship. In a flexible dosing group, (150 mg/day to 600 mg/day), the seizure reduction rate was 35.4%compared to 40.3% for a fixed dose of 600mg/day and 10.6% for placebo. The most common side effects were dizziness (29%) and somnolence (21%). In addition, weight gain (equal to or more than 7% increase from baseline) occurred in 40% of patients in the 12-week study; however, there was no affect on male fertility or efficacy of oral contraceptives in women. Regarding the use of pregabalin in treating painful diabetic peripheral neuropathy, oral administration of 300 and 600 mg/day t.i.d. was superior to placebo (39–48% compared to 15–18% with placebo) in relieving pain and improving pain-related sleep interference. While pregabalin was originally developed as an anticonvulsant for epilepsy, its success in treating neuropathic pain has led to its exploration in treating other CNS disorders, such as, anxiety, social phobia, and fibromyalgia.
- Chemical PropertiesOff-White Solid
- OriginatorWarner-Lambert (US)
- UsesS-Enantiomer of Pregabalin. A GABA analogue used as an anticonvulsant. Anxiolytic analgesic used to treat peripheral neuropathic pain and fibromyalgia.
- UsesPregabalin is an anticonvulsant drug used for neuropathic pain, as an adjunct therapy for partial seizures, and in generalized anxiety disorder. It was designed as a more potent successor to gabapentin. Pregabalin is marketed by Pfizer under the trade nam
- brand nameLyrica (CP).
- Chemical SynthesisSeveral syntheses of pregabalin (X) have been disclosed in the literature, including process scale-up comparison of
several different routes. The most cost efficient route
as described in the publication is shown in the Scheme.
Condensation of diethyl malonate 69 in the presense of
diisopropyl amine in acetic acid gave a,b-unsaturated diester
70 in high yield. Reaction of the enone diester with
potassium cyanide gave cyano diester 71 in 95% yield. In a
remarkable three step, one pot process, the nitrile in 71 was
hydrolyzed followed by decarboxylation of one of the esters
to provide 72 in 73% yield. Resolution of the two
enantiomers was achieved using (S)-(+)-mandellic acid, one
of the best acid found after many salt screening, to give, after
two recrystallization, a 99:1 ratio of the desired diastereomer.Removal of the acid was done with wet THF instead of base
separation, to avoid salt impurities, and one recrystallization
in ethanol gave 100% ee diastereomer in 25 – 29% overall
It’s worth noting that the Pfizer group have come up with a new process of preparing pregabalin (X) via enantioselective reduction, that promises to further reduce cost and waste associated with the manufacture of this drug.
- 1-(2,6-Dimethylphenoxy)-2-propanamine Thiophanate-methyl Pregabalin-d4 INTERMEDIATE OF PREGABALIN Pregabalin-d10 3-Carbamoymethyl-5-methylhexanoic acid (Pregabalin) (S)-N-Methyl-d3 Pregabalin RAC PREGABALIN-D7 (-Pregabalin-13C3,rac Pregabalin-13C3 3-(Aminomethyl)-5-methylhexanoic acid (S)-N-Methyl Pregabalin 3-(AMinoMethyl)-5-Methylhexanoic Acid-d7 (+/-)-Pregabalin,RAC PREGABALIN HEXANOIC-6,6,6-D3 ACID Pregabalin Ethyl Hexanoate Methyl Parathion-methyl
- Company Name:Jinan Jianfeng Chemical Co., Ltd. Gold
- Company Name:Shandong Mingfeng Pharmaceutical and Technology Co. Ltd Gold
- Company Name:Guangzhou Belka Biological Technology Co., Ltd. Gold
- Company Name:Hefei HomeSunshine Pharmaceutical Technology Co., Ltd. Gold
- Company Name:Nanjing Gold Pharmaceutical Technology Co. Ltd. Gold